CLASSES

NS3/4A Protease Inhibitor Antivirals in Combination with NS5A Protein Inhibitor Antivirals for Hepatitis C

BOXED WARNING

Use of direct-acting antivirals (DAA), such as elbasvir and grazoprevir, to treat hepatitis C virus (HCV) infection in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and hepatitis B exacerbation. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. HBV reactivation is characterized as an abrupt increase in viral replication manifesting as a rapid increase in serum HBV DNA concentration. In patients with resolved HBV infection, the reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis (i.e., increases in aminotransferase concentrations) and, in severe cases, increases in bilirubin concentrations, liver failure, and death can occur. To decrease the risk of reactivating an HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring the hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting elbasvir; grazoprevir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If an elbasvir; grazoprevir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection as clinically indicated.

DEA CLASS

Rx

DESCRIPTION

Combination product containing an NS5A inhibitor (elbasvir) and an NS3/4A protease inhibitor (grazoprevir)
Used to treat adults and pediatric patients weighing at least 30 kg with HCV genotypes 1 and 4 infections
Contraindicated in patients with moderate to severe hepatic impairment or history of hepatic decompensation; potential for significant drug interactions

COMMON BRAND NAMES

ZEPATIER

HOW SUPPLIED

ZEPATIER Oral Tab: 50-100mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

1 tablet/day PO (elbasvir 50 mg/day PO; grazoprevir 100 mg/day PO).

1 tablet/day PO (elbasvir 50 mg/day PO; grazoprevir 100 mg/day PO).

1 tablet/day PO (elbasvir 50 mg/day PO; grazoprevir 100 mg/day PO).

12 years: 1 tablet/day PO (elbasvir 50 mg/day PO; grazoprevir 100 mg/day PO).
younger than 12 years weighing 30 kg or more: 1 tablet/day PO (elbasvir 50 mg/day PO; grazoprevir 100 mg/day PO).
younger than 12 years weighing less than 30 kg: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Dosage adjustments are not required for mild hepatic impairment (Child-Pugh Class A). Use is contraindicated in patients with moderate impairment (Child-Pugh B), severe impairment (Child-Pugh C), and in those with any history of prior hepatic decompensation.

No dosage adjustments are needed for any degree of renal impairment. Further, guidelines recommend elbasvir; grazoprevir as a preferred direct acting antiviral regimen for treatment of HCV genotypes 1a, 1b, and 4 in patients with chronic kidney disease (i.e., GFR less than 30 mL/min/1.73 m2), including kidney transplant recipients.
 
Hemodialysis
No dosage adjustments are needed.

ADMINISTRATION

 
NOTE: Prior to initiation of therapy, test patients infected with hepatitis C virus genotype 1a for NS5A resistance-associated polymorphisms. If present, elbasvir; grazoprevir must be administered in combination with ribavirin and the duration of therapy must be extended to 16 weeks. Ribavirin must be administered with food.

STORAGE

ZEPATIER:
- Protect from moisture
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in original package until time of use

CONTRAINDICATIONS / PRECAUTIONS

Missing doses of direct-acting antiviral (DAA) therapy, such as elbasvir; grazoprevir, is relatively common; however, outcome data in patients with incomplete adherence is limited and the threshold at which a lack of adherence to treatment results in a reduced systemic viral response (SVR) is unknown. Based on adherence and outcome data from the SIMPLIFY study, HCV guidelines consider a treatment interruption of less than 7 days unlikely to impact the SVR. Longer durations of missed doses, however, may affect the response to treatment. In these cases, the patient should be managed in consultation with an expert. Question all patients with incomplete adherence about contributing factors and counsel them regarding the importance of adherence to treatment.

Elbasvir; grazoprevir is contraindicated for use in patients with moderate to severe hepatic disease (Child-Pugh B or C) and in those with any history of hepatic decompensation. The inappropriate use of HCV NS3/4A protease inhibitor-containing regimens, including elbasvir; grazoprevir, in patients with advanced hepatic disease has been associated with cases of hepatic decompensation and hepatic failure (some with fatal outcomes). Reported cases occurred in drug recipients who had baseline cirrhosis with and without moderate or severe hepatic impairment, as well as some patients without cirrhosis. However, according to an FDA Drug Safety Communication more than half of the cases that reported no or compensated cirrhosis (Child-Pugh A) were incorrectly classified and had evidence of advanced hepatic disease (e.g., decreased platelets, portal hypertension) or preexisting risk factors (e.g., hepatocellular cancer, alcoholism, serious hepatic medical illness). Closely monitor for signs and symptoms of worsening hepatic function during treatment (e.g., jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage). Instruct patients to immediately report episodes of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces. Health care providers are advised to monitor liver function tests prior to initiating therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, an additional test is recommended at treatment week 12. In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced hepatic disease, more frequent testing may be warranted. Discontinue use of the drug in patients who develop evidence of hepatic decompensation or if hepatic enzyme elevations are accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. Health care providers are advised that elevations in hepatic enzymes generally occur at or after treatment week 8, are asymptomatic, and resolve with ongoing therapy or after completion of therapy; however, a subpopulation analysis found higher rates of ALT elevations occurring in those patients with increased grazoprevir plasma concentrations, which included females (2%, n = 10/608), Asian patients (2%, n = 4/164), and geriatric patients (2, n = 3/177). Health care providers are also advised to avoid use of the drug in patients who have undergone or are awaiting liver transplant; safety and efficacy in these populations have not been established.[60523] [64589]

In certain patient populations, elbasvir; grazoprevir is recommended for use with ribavirin; therefore, any contraindication to ribavirin will also apply to the combination regimen. See the ribavirin monograph for additional information. In addition, significant drug interactions may occur with elbasvir; grazoprevir. According to the manufacturer, use is contraindicated with efavirenz, inhibitors of the organic anion transporting polypeptide 1B1/3 (OATP 1B1/3), and with strong inducers of CYP3A4. Concurrent administration with moderate CYP3A4 inducers and certain strong CYP3A4 inhibitors should also be avoided, if possible. Evaluate the medication profile of all potential drug recipients prior to and during treatment with elbasvir; grazoprevir.

Elbasvir; grazoprevir is approved for use in patients coinfected with hepatitis C and HIV. HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

No adequate, well-controlled studies have been conducted in pregnant humans, and it is unknown whether elbasvir; grazoprevir poses a risk to the developing fetus. In animal studies, adverse effects on embryo-fetal development and pre/postnatal development were not identified in rats and rabbits exposed to doses higher than the recommended human dose. However, in both rats and rabbits, elbasvir and grazoprevir were shown to cross the placenta. For elbasvir, drug concentrations in fetal plasma at gestation day 20 were up to 0.8% (rabbits) and 2.2% (rats) of those observed in the mother. Grazoprevir fetal concentrations at gestation day 20 were 7% (rabbit) and 89% (rats) of the maternal concentration. In certain patient populations, elbasvir; grazoprevir must be administered with ribavirin. Use of elbasvir; grazoprevir in combination with ribavirin is contraindicated in pregnant women. Ribavirin may cause birth defects and death of the exposed fetus; thus, the drug is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

According to the manufacturer, it is not known if elbasvir; grazoprevir is excreted in human breast milk. It is also unknown if the drug adversely affects human breast milk production. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

In certain patient populations, elbasvir; grazoprevir must be administered with ribavirin. Use of elbasvir; grazoprevir in combination with ribavirin is contraindicated in male partners of women who are pregnant. Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use in men whose female partners are pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. Patients and their partners are required use 2 reliable forms of effective contraception during treatment and for 6 months after use of the combination therapy. Patients who are not willing to practice strict contraception should not receive elbasvir; grazoprevir with ribavirin. Females must also undergo pregnancy testing immediately prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

Use of direct-acting antivirals (DAA), such as elbasvir and grazoprevir, to treat hepatitis C virus (HCV) infection in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and hepatitis B exacerbation. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. HBV reactivation is characterized as an abrupt increase in viral replication manifesting as a rapid increase in serum HBV DNA concentration. In patients with resolved HBV infection, the reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis (i.e., increases in aminotransferase concentrations) and, in severe cases, increases in bilirubin concentrations, liver failure, and death can occur. To decrease the risk of reactivating an HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring the hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting elbasvir; grazoprevir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If an elbasvir; grazoprevir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection as clinically indicated.

Caution is advised when prescribing elbasvir; grazoprevir to patients receiving concurrent anticoagulant therapy, specifically warfarin. Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.

A safety review of direct-acting antivirals (DAAs) was conducted and it was determined that there is an association between these medications and episodes of dysglycemia (both hypoglycemia and hyperglycemia). At the time of the safety review, 36 case reports describing a possible link between the use of DAAs and dysglycemia were identified. Of the 36 reports, 24 were related to hyperglycemia or new-onset diabetes (including 1 death), 8 were related to hypoglycemia or improved diabetes, and 4 were reported as other (1 abnormal blood glucose, 2 loss of blood glucose control, 1 both hyperglycemia and hypoglycemia). A further evaluation concluded that 27 of the case reports (including the 1 fatality) were possibly linked to the use of a DAA, 3 were not likely associated with DAA use, and the rest could not be assessed due to insufficient data. Closely monitor blood glucose concentrations during treatment with elbasvir; grazoprevir. For patients with diabetes mellitus who are receiving concurrent treatment with antidiabetic agents, dose adjustments of the antidiabetic agents may be needed in order to prevent the occurrence of hypoglycemia.

ADVERSE REACTIONS

hepatic decompensation / Delayed / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
angioedema / Rapid / Incidence not known

anemia / Delayed / 0-8.0
dyspnea / Early / 4.0-4.0
depression / Delayed / 1.0-2.0
elevated hepatic enzymes / Delayed / 1.0-1.0
hyperbilirubinemia / Delayed / 1.0-1.0

headache / Early / 3.0-14.0
nausea / Early / 5.0-11.0
fatigue / Early / 6.0-11.0
diarrhea / Early / 2.0-5.0
insomnia / Early / 3.0-5.0
rash / Early / 4.0-4.0
pruritus / Rapid / 4.0-4.0
irritability / Delayed / 1.0-3.0
abdominal pain / Early / 2.0-2.0
arthralgia / Delayed / 2.0-2.0

DRUG INTERACTIONS

Abiraterone: (Moderate) Administering abiraterone with elbasvir; grazoprevir may result in elevated abiraterone plasma concentrations. Abiraterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Acarbose: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with grazoprevir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of grazoprevir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If grazoprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Grazoprevir is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like grazoprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If grazoprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetohexamide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Albiglutide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Aldesleukin, IL-2: (Moderate) Administering elbasvir; grazoprevir with aldesleukin, IL-2 may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Aldesleukin, IL-2 increases IL-6 concentrations; IL-6 is a mild CYP3A inhibitor. Both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Alfentanil: (Major) Administering alfentanil with grazoprevir may result in elevated alfentanil plasma concentrations. Alfentanil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Alfuzosin: (Moderate) Administering alfuzosin with elbasvir; grazoprevir may result in elevated alfuzosin plasma concentrations. Alfuzosin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Aliskiren; Amlodipine: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Almotriptan: (Moderate) Administering almotriptan with elbasvir; grazoprevir may result in elevated almotriptan plasma concentrations. Almotriptan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Alogliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Alogliptin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Alogliptin; Pioglitazone: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Alpelisib: (Major) Avoid coadministration of alpelisib with elbasvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and elbasvir is a BCRP inhibitor. (Major) Avoid coadministration of alpelisib with grazoprevir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and grazoprevir is a BCRP inhibitor.
Alprazolam: (Major) Avoid coadministration of alprazolam and grazoprevir due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with grazoprevir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and grazoprevir is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amiodarone: (Moderate) Administering elbasvir; grazoprevir with amiodarone may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amiodarone is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amitriptyline: (Moderate) Administering perphenazine; amitriptyline with elbasvir; grazoprevir may result in elevated amitriptyline plasma concentrations. Amitriptyline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Amlodipine: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with grazoprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor. (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amlodipine; Benazepril: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amlodipine; Celecoxib: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amlodipine; Olmesartan: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amlodipine; Valsartan: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Amobarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Concurrent administration of elbasvir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of clarithromycin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Antidiabetic Agents: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Apalutamide: (Contraindicated) Concurrent administration of apalutamide with elbasvir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. Apalutamide is a strong CYP3A inducer and elbasvir is a substrate of CYP3A. (Contraindicated) Concurrent administration of apalutamide with grazoprevir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Apalutamide is a strong CYP3A inducer and grazoprevir is a substrate of CYP3A.
Aripiprazole: (Moderate) Administering aripiprazole with grazoprevir may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and grazoprevir is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
Armodafinil: (Major) Concurrent administration of elbasvir with armodafinil should be avoided if possible. Armodafinil is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with armodafinil should be avoided if possible. Armodafinil is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Artemether; Lumefantrine: (Moderate) Administering artemether; lumefantrine with elbasvir; grazoprevir may result in elevated artemether; lumefantrine plasma concentrations. Artemether; lumefantrine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Asenapine: (Moderate) Administering asenapine with elbasvir; grazoprevir may result in elevated asenapine plasma concentrations. Asenapine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Aspirin, ASA; Butalbital; Caffeine: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response. (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with grazoprevir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of grazoprevir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If grazoprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Grazoprevir is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like grazoprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If grazoprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with atazanavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Atazanavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Contraindicated) Concurrent administration of elbasvir; grazoprevir with atazanavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Atazanavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP1B1). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Atazanavir; Cobicistat: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with atazanavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Atazanavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Contraindicated) Concurrent administration of elbasvir; grazoprevir with atazanavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Atazanavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP1B1). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with grazoprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with grazoprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Avanafil: (Major) Administering avanafil with grazoprevir may result in elevated avanafil plasma concentrations. Avanafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Azelastine; Fluticasone: (Moderate) Administering fluticasone with elbasvir; grazoprevir may result in elevated fluticasone plasma concentrations. Fluticasone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Barbiturates: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Basiliximab: (Moderate) Administering elbasvir; grazoprevir with basiliximab may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Basiliximab is a mild CYP3A inhibitor. Both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Bedaquiline: (Moderate) Administering bedaquiline with elbasvir; grazoprevir may result in elevated bedaquiline plasma concentrations. Bedaquiline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Belladonna Alkaloids; Ergotamine; Phenobarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with grazoprevir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of grazoprevir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If grazoprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Grazoprevir is a weak inhibitor of CYP3A4.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking elbasvir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and elbasvir is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%. (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking grazoprevir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and grazoprevir is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
Bexarotene: (Major) If possible, avoid concurrent administration of elbasvir with bexarotene. Bexarotene is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir. (Major) If possible, avoid concurrent administration of grazoprevir with bexarotene. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Bexarotene is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A.
Boceprevir: (Major) Concurrent administration of elbasvir with boceprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Boceprevir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with boceprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Boceprevir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of boceprevir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Bosentan: (Major) Concurrent administration of elbasvir with bosentan should be avoided if possible. Bosentan is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with bosentan should be avoided if possible. Bosentan is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Bosutinib: (Major) Administering bosutinib with grazoprevir may result in elevated bosutinib plasma concentrations. Bosutinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Brentuximab vedotin: (Moderate) Administering brentuximab vedotin with elbasvir; grazoprevir may result in elevated brentuximab vedotin plasma concentrations. Monomethyl auristatin E (MMAE) is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Brexpiprazole: (Moderate) Administering brexpiprazole with grazoprevir may result in elevated brexpiprazole plasma concentrations. Brexpiprazole is a substrate of CYP3A4 and grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Budesonide: (Minor) Administering budesonide with grazoprevir may result in elevated budesonide plasma concentrations. Budesonide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Budesonide; Formoterol: (Minor) Administering budesonide with grazoprevir may result in elevated budesonide plasma concentrations. Budesonide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Administering budesonide with grazoprevir may result in elevated budesonide plasma concentrations. Budesonide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Bupivacaine Liposomal: (Moderate) Administering bupivacaine with elbasvir; grazoprevir may result in elevated bupivacaine plasma concentrations. Bupivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Bupivacaine: (Moderate) Administering bupivacaine with elbasvir; grazoprevir may result in elevated bupivacaine plasma concentrations. Bupivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Bupivacaine; Epinephrine: (Moderate) Administering bupivacaine with elbasvir; grazoprevir may result in elevated bupivacaine plasma concentrations. Bupivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Bupivacaine; Lidocaine: (Moderate) Administering bupivacaine with elbasvir; grazoprevir may result in elevated bupivacaine plasma concentrations. Bupivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Administering lidocaine with elbasvir; grazoprevir may result in elevated lidocaine plasma concentrations. Lidocaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Bupivacaine; Meloxicam: (Moderate) Administering bupivacaine with elbasvir; grazoprevir may result in elevated bupivacaine plasma concentrations. Bupivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Administering meloxicam with elbasvir; grazoprevir may result in elevated meloxicam plasma concentrations. Meloxicam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Buprenorphine: (Moderate) Administering buprenorphine with elbasvir; grazoprevir may result in elevated buprenorphine plasma concentrations. Buprenorphine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Buprenorphine; Naloxone: (Moderate) Administering buprenorphine with elbasvir; grazoprevir may result in elevated buprenorphine plasma concentrations. Buprenorphine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Buspirone: (Moderate) Administering buspirone with elbasvir; grazoprevir may result in elevated buspirone plasma concentrations. Buspirone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Butabarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Butalbital; Acetaminophen: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Butalbital; Acetaminophen; Caffeine: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Butalbital; Acetaminophen; Caffeine; Codeine: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response. (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Canagliflozin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Canagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Carbamazepine: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with carbamazepine is contraindicated. Carbamazepine is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cariprazine: (Moderate) Administering cariprazine with elbasvir; grazoprevir may result in elevated cariprazine plasma concentrations. Cariprazine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Celecoxib; Tramadol: (Moderate) Administering acetaminophen; tramadol with elbasvir; grazoprevir may result in elevated tramadol plasma concentrations. Tramadol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Cenobamate: (Major) Coadministration of elbasvir with cenobamate is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Major) Coadministration of grazoprevir with cenobamate is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with ceritinib is necessary. Elbasvir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased elbasvir exposure by 3-fold. (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with ceritinib is necessary. Grazoprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold.
Chloramphenicol: (Major) Concurrent administration of elbasvir with chloramphenicol should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Chloramphenicol is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with chloramphenicol should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Chloramphenicol is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Chlordiazepoxide: (Moderate) Administering chlordiazepoxide with elbasvir; grazoprevir may result in elevated chlordiazepoxide plasma concentrations. Chlordiazepoxide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Chlordiazepoxide; Amitriptyline: (Moderate) Administering chlordiazepoxide with elbasvir; grazoprevir may result in elevated chlordiazepoxide plasma concentrations. Chlordiazepoxide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Administering perphenazine; amitriptyline with elbasvir; grazoprevir may result in elevated amitriptyline plasma concentrations. Amitriptyline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Chlordiazepoxide; Clidinium: (Moderate) Administering chlordiazepoxide with elbasvir; grazoprevir may result in elevated chlordiazepoxide plasma concentrations. Chlordiazepoxide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Chlorpheniramine; Codeine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with grazoprevir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of grazoprevir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If grazoprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Grazoprevir is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with grazoprevir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of grazoprevir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If grazoprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Grazoprevir is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpropamide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Cilostazol: (Major) Administering cilostazol with grazoprevir may result in elevated cilostazol plasma concentrations. Cilostazol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Cinacalcet: (Moderate) Administering cinacalcet with elbasvir; grazoprevir may result in elevated cinacalcet plasma concentrations. Cinacalcet is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ciprofloxacin: (Moderate) Administering elbasvir; grazoprevir with ciprofloxacin may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ciprofloxacin is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Cisapride: (Major) Administering cisapride with grazoprevir may result in elevated cisapride plasma concentrations. Cisapride is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Clarithromycin: (Major) Concurrent administration of elbasvir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of clarithromycin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Clobazam: (Moderate) Monitor for a reduced virologic response if elbasvir is coadministered with clobazam. Use of these drugs together may result in reduced concentrations of elbasvir. Clobazam is a weak inducer of CYP3A, while elbasvir is a CYP3A substrate. (Moderate) Monitor for a reduced virologic response if grazoprevir is coadministered with clobazam. Use of these drugs together may result in reduced concentrations of grazoprevir. Clobazam is a weak inducer of CYP3A, while grazoprevir is a CYP3A substrate.
Clomipramine: (Moderate) Administering clomipramine with elbasvir; grazoprevir may result in elevated clomipramine plasma concentrations. Clomipramine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Clonazepam: (Moderate) Administering clonazepam with elbasvir; grazoprevir may result in elevated clonazepam plasma concentrations. Clonazepam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Clorazepate: (Major) Administering clorazepate with grazoprevir may result in elevated clorazepate plasma concentrations. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by 2C19 and 3A4. Grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Clozapine: (Moderate) Administering clozapine with grazoprevir may result in elevated clozapine plasma concentrations. Clozapine is a substrate of CYP3A4 and grazoprevir is a weak CYP3A inhibitor. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Cobimetinib: (Moderate) Administering cobimetinib with elbasvir; grazoprevir may result in elevated cobimetinib plasma concentrations. Cobimetinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Cocaine: (Moderate) Administering elbasvir; grazoprevir with cocaine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Cocaine is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Codeine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Codeine; Guaifenesin: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Codeine; Phenylephrine; Promethazine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Codeine; Promethazine: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Colchicine: (Moderate) Administering colchicine with elbasvir; grazoprevir may result in elevated colchicine plasma concentrations. Colchicine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Administering medroxyprogesterone with elbasvir; grazoprevir may result in elevated medroxyprogesterone plasma concentrations. Medroxyprogesterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Cyclosporine: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with cyclosporine is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Cyclosporine is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP1B1). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Dabrafenib: (Major) If possible, avoid concurrent administration of elbasvir with dabrafenib. Dabrafenib is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with dabrafenib. Dabrafenib is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of dabrafenib (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Daclatasvir: (Contraindicated) Concurrent administration of grazoprevir with daclatasvir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Daclatasvir is an inhibitor of the organic anion transporting polypeptide (OATP1B1/3). Grazoprevir is a substrate of OATP1B1/3.
Danazol: (Moderate) Administering elbasvir; grazoprevir with danazol may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Danazol is a moderate CYP3A inhibitor. Both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Dapagliflozin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Dapagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Dapagliflozin; Saxagliptin: (Moderate) Administering metformin; saxagliptin with elbasvir; grazoprevir may result in elevated saxagliptin plasma concentrations. Saxagliptin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Dapsone: (Minor) Administering dapsone with grazoprevir may result in elevated dapsone plasma concentrations. Dapsone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Darifenacin: (Moderate) Administering darifenacin with elbasvir; grazoprevir may result in elevated darifenacin plasma concentrations. Darifenacin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Darolutamide: (Contraindicated) Concomitant use of grazoprevir and darolutamide is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; darolutamide is an inhibitor of OATP1B1/3.
Darunavir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with darunavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Darunavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Darunavir; Cobicistat: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with darunavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Darunavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with darunavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Darunavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concurrent administration of grazoprevir with paritaprevir is contraindicated. Use of these drugs together is expected to significantly increase grazoprevir plasma concentrations, and may result in adverse effects (i.e., elevated ALT concentrations). Paritaprevir is an inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Dasatinib: (Moderate) Administering elbasvir; grazoprevir with dasatinib may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Dasatinib is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Daunorubicin: (Moderate) Administering daunorubicin with elbasvir; grazoprevir may result in elevated daunorubicin plasma concentrations. Daunorubicin is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Deferasirox: (Major) If possible, avoid concurrent administration of elbasvir with deferasirox. Deferasirox is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response.
Delavirdine: (Major) Concurrent administration of elbasvir with delavirdine should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Delavirdine is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with delavirdine should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Delavirdine is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of delavirdine (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Dexamethasone: (Major) If possible, avoid concurrent administration of elbasvir with dexamethasone. Dexamethasone is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with dexamethasone. Dexamethasone is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of dexamethasone (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Dextromethorphan; Quinidine: (Moderate) Administering quinidine with elbasvir; grazoprevir may result in elevated quinidine plasma concentrations. Quinidine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Diazepam: (Moderate) Administering diazepam with elbasvir; grazoprevir may result in elevated diazepam plasma concentrations. At high concentrations, diazepam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Diclofenac: (Moderate) Administering diclofenac with elbasvir; grazoprevir may result in elevated diclofenac plasma concentrations. Diclofenac is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Diclofenac; Misoprostol: (Moderate) Administering diclofenac with elbasvir; grazoprevir may result in elevated diclofenac plasma concentrations. Diclofenac is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with grazoprevir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of grazoprevir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If grazoprevir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Grazoprevir is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Diltiazem: (Moderate) Administering elbasvir; grazoprevir with diltiazem may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Diltiazem is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Disopyramide: (Moderate) Administering disopyramide with elbasvir; grazoprevir may result in elevated disopyramide plasma concentrations. Disopyramide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Disulfiram: (Moderate) Administering disulfiram with elbasvir; grazoprevir may result in elevated disulfiram plasma concentrations. Disulfiram is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Docetaxel: (Moderate) Administering docetaxel with elbasvir; grazoprevir may result in elevated docetaxel plasma concentrations. Docetaxel is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Dolasetron: (Minor) Administering dolasetron with grazoprevir may result in elevated dolasetron plasma concentrations. Dolasetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Donepezil: (Moderate) Administering donepezil with elbasvir; grazoprevir may result in elevated donepezil plasma concentrations. Donepezil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Donepezil; Memantine: (Moderate) Administering donepezil with elbasvir; grazoprevir may result in elevated donepezil plasma concentrations. Donepezil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Doxorubicin Liposomal: (Moderate) Administering doxorubicin with elbasvir; grazoprevir may result in elevated doxorubicin plasma concentrations. Doxorubicin is a substrate of CYP3A and the drug transporter breast cancer resistance protein (BCRP). Elbasvir and grazoprevir are inhibitors of BCRP, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Doxorubicin: (Moderate) Administering doxorubicin with elbasvir; grazoprevir may result in elevated doxorubicin plasma concentrations. Doxorubicin is a substrate of CYP3A and the drug transporter breast cancer resistance protein (BCRP). Elbasvir and grazoprevir are inhibitors of BCRP, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with elbasvir; grazoprevir is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; grazoprevir is a weak inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Moderate) Administering elbasvir; grazoprevir with dronedarone may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Dronedarone is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Droperidol: (Moderate) Administering droperidol with elbasvir; grazoprevir may result in elevated droperidol plasma concentrations. Droperidol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Dulaglutide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Dutasteride; Tamsulosin: (Moderate) Administering tamsulosin with elbasvir; grazoprevir may result in elevated tamsulosin plasma concentrations. Tamsulosin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Efavirenz: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with efavirenz is contraindicated. Efavirenz is a CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Efavirenz; Emtricitabine; Tenofovir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with efavirenz is contraindicated. Efavirenz is a CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with efavirenz is contraindicated. Efavirenz is a CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Elagolix: (Major) Concurrent administration of elbasvir with elagolix should be avoided if possible. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. Elagolix is a weak to moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. (Major) If possible, avoid concurrent administration of grazoprevir with elagolix. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Elagolix is a weak to moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concurrent administration of elbasvir with elagolix should be avoided if possible. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. Elagolix is a weak to moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. (Major) If possible, avoid concurrent administration of grazoprevir with elagolix. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Elagolix is a weak to moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A.
Eletriptan: (Major) Administering eletriptan with grazoprevir may result in elevated eletriptan plasma concentrations. Eletriptan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for grazoprevir-related adverse reactions during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of grazoprevir. Grazoprevir is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of grazoprevir and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Administering eliglustat with grazoprevir may result in elevated eliglustat plasma concentrations and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Eliglustat is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Empagliflozin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Empagliflozin; Linagliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Empagliflozin; Linagliptin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Empagliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Enalapril; Felodipine: (Moderate) Administering felodipine with elbasvir; grazoprevir may result in elevated felodipine plasma concentrations. Felodipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Enasidenib: (Contraindicated) Concomitant use of grazoprevir and enasidenib is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; enasidenib is an inhibitor of OATP1B1/3.
Enzalutamide: (Contraindicated) Concurrent administration of enzalutamide with elbasvir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. Enzalutamide is a strong CYP3A inducer, while elbasvir is a substrate of CYP3A. (Contraindicated) Concurrent administration of enzalutamide with grazoprevir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Enzalutamide is a strong CYP3A inducer, while grazoprevir is a substrate of CYP3A.
Ergot alkaloids: (Moderate) Administering ergot alkaloids with elbasvir; grazoprevir may result in elevated plasma concentrations of the ergot alkaloids. Ergot alkaloids are substrates of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ertugliflozin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Ertugliflozin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Ertugliflozin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Erythromycin: (Moderate) Administering elbasvir; grazoprevir with erythromycin may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Erythromycin is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Erythromycin; Sulfisoxazole: (Moderate) Administering elbasvir; grazoprevir with erythromycin may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Erythromycin is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Escitalopram: (Moderate) Administering escitalopram with elbasvir; grazoprevir may result in elevated escitalopram plasma concentrations. Escitalopram is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eslicarbazepine: (Major) If possible, avoid concurrent administration of elbasvir with eslicarbazepine. Eslicarbazepine is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with eslicarbazepine. Eslicarbazepine is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Estazolam: (Moderate) Administering estazolam with elbasvir; grazoprevir may result in elevated estazolam plasma concentrations. Estazolam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Estradiol Cypionate; Medroxyprogesterone: (Moderate) Administering medroxyprogesterone with elbasvir; grazoprevir may result in elevated medroxyprogesterone plasma concentrations. Medroxyprogesterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eszopiclone: (Moderate) Administering eszopiclone with elbasvir; grazoprevir may result in elevated eszopiclone plasma concentrations. Eszopiclone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ethosuximide: (Moderate) Administering ethosuximide with elbasvir; grazoprevir may result in elevated ethosuximide plasma concentrations. Ethosuximide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Etravirine: (Major) Concurrent administration of elbasvir with etravirine should be avoided if possible. Etravirine is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with etravirine should be avoided if possible. Etravirine is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Exenatide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Ezetimibe; Simvastatin: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Felbamate: (Moderate) Caution is advised when administering elbasvir; grazoprevir with felbamate. Felbamate is a mild CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together may decrease the plasma concentrations of both elbasvir and grazoprevir, and could result in decreased virologic response.
Felodipine: (Moderate) Administering felodipine with elbasvir; grazoprevir may result in elevated felodipine plasma concentrations. Felodipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If grazoprevir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or grazoprevir; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and grazoprevir is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) Administering flibanserin with elbasvir; grazoprevir may result in elevated flibanserin plasma concentrations. Flibanserin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Fluconazole: (Moderate) Administering elbasvir; grazoprevir with fluconazole may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluconazole is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Fluoxetine: (Moderate) Administering elbasvir; grazoprevir with fluoxetine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluoxetine is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Flurazepam: (Moderate) Administering flurazepam with elbasvir; grazoprevir may result in elevated flurazepam plasma concentrations. Flurazepam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Flutamide: (Major) If possible, avoid concurrent administration of elbasvir with flutamide. Flutamide is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with flutamide. Flutamide is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of flutamide (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Fluticasone: (Moderate) Administering fluticasone with elbasvir; grazoprevir may result in elevated fluticasone plasma concentrations. Fluticasone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Fluticasone; Salmeterol: (Moderate) Administering fluticasone with elbasvir; grazoprevir may result in elevated fluticasone plasma concentrations. Fluticasone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Administering fluticasone with elbasvir; grazoprevir may result in elevated fluticasone plasma concentrations. Fluticasone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Administering vilanterol with elbasvir; grazoprevir may result in elevated vilanterol plasma concentrations. Vilanterol is a primary substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Fluticasone; Vilanterol: (Moderate) Administering fluticasone with elbasvir; grazoprevir may result in elevated fluticasone plasma concentrations. Fluticasone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Administering vilanterol with elbasvir; grazoprevir may result in elevated vilanterol plasma concentrations. Vilanterol is a primary substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Fluvastatin: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with fluvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated fluvastatin plasma concentrations. Use the lowest effective fluvastatin dose and monitor patients for statin-related adverse events (such as myopathy).
Fluvoxamine: (Moderate) Administering elbasvir; grazoprevir with fluvoxamine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluvoxamine is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Fosamprenavir: (Major) If possible, avoid concurrent administration of elbasvir with fosamprenavir. Use of these drugs together may cause changes in the plasma concentrations of elbasvir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Fosamprenavir is a strong inhibitor and moderate inducer of CYP3A; elbasvir is a substrate of CYP3A. (Major) If possible, avoid concurrent administration of grazoprevir with fosamprenavir. Use of these drugs together may cause changes in the plasma concentrations of grazoprevir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Fosamprenavir is a strong inhibitor and moderate inducer of CYP3A; grazoprevir is a substrate of CYP3A. In addition, concentrations of fosamprenavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Fosphenytoin: (Contraindicated) Concurrent administration of elbasvir with fosphenytoin (a prodrug of phenytoin) is contraindicated. Phenytoin is a strong CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentration of elbasvir, and may result in decreased virologic response. (Contraindicated) Concurrent administration of grazoprevir with fosphenytoin (a prodrug of phenytoin) is contraindicated. Phenytoin is a strong CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentration of grazoprevir, and may result in decreased virologic response.
Fostemsavir: (Contraindicated) Concomitant use of grazoprevir and fostemsavir is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Gemfibrozil: (Contraindicated) Concurrent administration of grazoprevir with gemfibrozil is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Gemfibrozil is an inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and elbasvir as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of breast cancer resistance protein (BCRP); elbasvir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of glecaprevir and grazoprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Grazoprevir is a substrate of organic anion transporting polypeptide (OATP) 1B1/3; glecaprevir is an inhibitor of OATP1B1/3. Additionally, glecaprevir is a substrate of BCRP and grazoprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and elbasvir as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of breast cancer resistance protein (BCRP); elbasvir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and grazoprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Grazoprevir is a substrate of organic anion transporting polypeptide (OATP) 1B1/3 and an inhibitor of breast cancer resistance protein (BCRP); pibrentasvir is a substrate of BCRP and an inhibitor of OATP1B1/3.
Glimepiride: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Glimepiride; Rosiglitazone: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Glipizide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Glipizide; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Glyburide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Glyburide; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Granisetron: (Minor) Administering granisetron with grazoprevir may result in elevated granisetron plasma concentrations. Granisetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Grapefruit juice: (Major) Concurrent administration of elbasvir with grapefruit juice should be avoided if possible. Giving elbasvir with grapefruit juice is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Grapefruit is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with grapefruit juice should be avoided if possible. Giving grazoprevir with grapefruit juice is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Grapefruit is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Haloperidol: (Moderate) Administering haloperidol with elbasvir; grazoprevir may result in elevated haloperidol plasma concentrations. Haloperidol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxyprogesterone: (Moderate) Administering hydroxyprogesterone with elbasvir; grazoprevir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ibrutinib: (Moderate) Administering ibrutinib with elbasvir; grazoprevir may result in elevated ibrutinib plasma concentrations. Ibrutinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like grazoprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If grazoprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Concurrent administration of elbasvir with idelalisib should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Idelalisib is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with idelalisib should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Idelalisib is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of idelalisib (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Imatinib: (Moderate) Administering elbasvir; grazoprevir with imatinib, STI-571 may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Imatinib is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. In addition, imatinib is a substrate for the breast cancer resistance protein (BCRP), while both elbasvir and grazoprevir are BCRP inhibitors. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Imipramine: (Moderate) Administering imipramine with elbasvir; grazoprevir may result in elevated imipramine plasma concentrations. Imipramine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Indinavir: (Major) Concurrent administration of elbasvir with indinavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Indinavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with indinavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Indinavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of indinavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Insulin Aspart: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Degludec; Liraglutide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Detemir: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Glargine: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Glargine; Lixisenatide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Glulisine: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Lispro: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Insulin, Inhaled: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Isavuconazonium: (Moderate) Administering elbasvir; grazoprevir with isavuconazonium may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Isavuconazonium is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with rifampin is contraindicated. Rifampin is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Isoniazid, INH; Rifampin: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with rifampin is contraindicated. Rifampin is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Isradipine: (Moderate) Administering isradipine with elbasvir; grazoprevir may result in elevated isradipine plasma concentrations. Isradipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Itraconazole: (Major) Elbasvir is not recommended for use during and for 2 weeks after itraconazole therapy. Inhibition of CYP3A4 by itraconazole may significantly increase the plasma concentrations of elbasvir, resulting in adverse effects. Itraconazole is a strong inhibitor of CYP3A4; elbasvir is a CYP3A4 substrate. (Major) Grazoprevir is not recommended for use during and for 2 weeks after itraconazole therapy. Inhibition of CYP3A4 by itraconazole may significantly increase the plasma concentrations of grazoprevir, resulting in adverse effects. Itraconazole is a strong inhibitor of CYP3A4; grazoprevir is a CYP3A4 substrate.
Ivabradine: (Moderate) Administering ivabradine with elbasvir; grazoprevir may result in elevated ivabradine plasma concentrations. Ivabradine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ixabepilone: (Moderate) Administering ixabepilone with elbasvir; grazoprevir may result in elevated ixabepilone plasma concentrations. Ixabepilone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ketoconazole: (Major) Concurrent administration of elbasvir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ketoconazole is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ketoconazole is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concurrent administration of elbasvir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of clarithromycin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Ledipasvir; Sofosbuvir: (Major) Administering ledipasvir with elbasvir may result in elevated ledipasvir plasma concentrations. Ledipasvir is a substrate for the breast cancer resistance protein (BCRP); elbasvir is a BCRP inhibitor. (Major) Administering ledipasvir with grazoprevir may result in elevated ledipasvir plasma concentrations. Ledipasvir is a substrate for the breast cancer resistance protein (BCRP);grazoprevir is a BCRP inhibitor.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with grazoprevir as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; grazoprevir is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lente Insulin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Letermovir: (Moderate) An increase in the plasma concentration of elbasvir may occur during concurrent administration with letermovir; closely monitor for elbasvir-related adverse events, such as liver toxicity. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Elbasvir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. (Moderate) An increase in the plasma concentration of grazoprevir may occur during concurrent administration with letermovir; closely monitor for grazoprevir-related adverse events, such as liver toxicity. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Grazoprevir is a substrate of CYP3A4and the organic anion-transporting polypeptides (OATP1B1/3). Both letermovir and cyclosporine are CYP3A4 inhibitors and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Levamlodipine: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Levoketoconazole: (Major) Concurrent administration of elbasvir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ketoconazole is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ketoconazole is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Levomilnacipran: (Moderate) Administering levomilnacipran with elbasvir; grazoprevir may result in elevated levomilnacipran plasma concentrations. Levomilnacipran is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Lidocaine: (Moderate) Administering lidocaine with elbasvir; grazoprevir may result in elevated lidocaine plasma concentrations. Lidocaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Lidocaine; Epinephrine: (Moderate) Administering lidocaine with elbasvir; grazoprevir may result in elevated lidocaine plasma concentrations. Lidocaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Lidocaine; Prilocaine: (Moderate) Administering lidocaine with elbasvir; grazoprevir may result in elevated lidocaine plasma concentrations. Lidocaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Linagliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Linagliptin; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Liraglutide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Lixisenatide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Lomitapide: (Moderate) Administering lomitapide with elbasvir; grazoprevir may result in elevated lomitapide plasma concentrations. Lomitapide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and grazoprevir; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing grazoprevir. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; grazoprevir is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with lonafarnib is necessary. Elbasvir is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased elbasvir exposure by 3-fold.
Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with grazoprevir, an inhibitor of CYP3A4. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with grazoprevir, an inhibitor of CYP3A4. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
Lopinavir; Ritonavir: (Contraindicated) Concurrent administration of grazoprevir with lopinavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Lopinavir is an inhibitor of the organic anion transporting protein (OATP1B1). Grazoprevir is also a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Lorlatinib: (Major) Coadministration of elbasvir with lorlatinib is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. (Major) Coadministration of grazoprevir with lorlatinib is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
Losartan: (Minor) Administering losartan with grazoprevir may result in elevated losartan plasma concentrations. Losartan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Administering losartan with grazoprevir may result in elevated losartan plasma concentrations. Losartan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Lovastatin: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with lovastatin. Although this interaction has not been studied, use of these drugs together may result in elevated lovastatin plasma concentrations. Use the lowest effective lovastatin dose and monitor patients for statin-related adverse events (such as myopathy). Lovastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Lovastatin; Niacin: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with lovastatin. Although this interaction has not been studied, use of these drugs together may result in elevated lovastatin plasma concentrations. Use the lowest effective lovastatin dose and monitor patients for statin-related adverse events (such as myopathy). Lovastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Lurasidone: (Moderate) Administering lurasidone with elbasvir; grazoprevir may result in elevated lurasidone plasma concentrations. Lurasidone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Macitentan: (Moderate) Administering macitentan with elbasvir; grazoprevir may result in elevated macitentan plasma concentrations. Macitentan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Maprotiline: (Moderate) Administering maprotiline with elbasvir; grazoprevir may result in elevated maprotiline plasma concentrations. Maprotiline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Maraviroc: (Minor) Use caution if coadministration of maraviroc with grazoprevir is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and grazoprevir is a weak CYP3A inhibitor. Monitor for an increase in adverse effects with concomitant use.
Medroxyprogesterone: (Moderate) Administering medroxyprogesterone with elbasvir; grazoprevir may result in elevated medroxyprogesterone plasma concentrations. Medroxyprogesterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Mefloquine: (Moderate) Administering mefloquine with elbasvir; grazoprevir may result in elevated mefloquine plasma concentrations. Mefloquine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Meloxicam: (Moderate) Administering meloxicam with elbasvir; grazoprevir may result in elevated meloxicam plasma concentrations. Meloxicam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Mephobarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Metformin; Repaglinide: (Moderate) Administering repaglinide with elbasvir; grazoprevir may result in elevated repaglinide plasma concentrations. Repaglinide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Metformin; Rosiglitazone: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Metformin; Saxagliptin: (Moderate) Administering metformin; saxagliptin with elbasvir; grazoprevir may result in elevated saxagliptin plasma concentrations. Saxagliptin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Metformin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Methohexital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Methotrexate: (Moderate) Administering methotrexate with elbasvir; grazoprevir may result in elevated methotrexate plasma concentrations. Methotrexate is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors. (Minor) Administering methotrexate with elbasvir; grazoprevir may result in elevated methotrexate plasma concentrations. Methotrexate is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Midazolam: (Moderate) Administering midazolam with elbasvir; grazoprevir may result in elevated midazolam plasma concentrations. Midazolam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Midostaurin: (Contraindicated) Concomitant use of grazoprevir and midostaurin is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; midostaurin is an inhibitor of OATP1B1.
Mifepristone: (Moderate) Administering elbasvir; grazoprevir with mifepristone may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Mifepristone is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity. (Moderate) Administering elbasvir; grazoprevir with mifepristone, RU-486 may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Mifepristone is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Miglitol: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Mirtazapine: (Moderate) Administering mirtazapine with elbasvir; grazoprevir may result in elevated mirtazapine plasma concentrations. Mirtazapine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Mitotane: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with mitotane is contraindicated due to potential decreased concentrations of both elbasvir and grazoprevir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer, while both elbasvir and grazoprevir are substrates of CYP3A.
Mitoxantrone: (Moderate) Administering mitoxantrone with elbasvir; grazoprevir may result in elevated mitoxantrone plasma concentrations. Mitoxantrone is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Modafinil: (Major) Concurrent administration of elbasvir with modafinil should be avoided if possible. Modafinil is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with modafinil should be avoided if possible. Modafinil is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Nafcillin: (Major) Concurrent administration of elbasvir with nafcillin should be avoided if possible. Nafcillin is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with nafcillin should be avoided if possible. Nafcillin is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with grazoprevir is necessary. The dose of sirolimus may also need to be reduced with coadministration of grazoprevir. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of grazoprevir. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; grazoprevir is a weak CYP3A inhibitor.
Nateglinide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Nefazodone: (Major) Concurrent administration of elbasvir with nefazodone should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvirr, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nefazodone is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with nefazodone should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentration grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nefazodone is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of nefazodone (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Nelfinavir: (Major) Concurrent administration of elbasvir with nelfinavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nelfinavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with nelfinavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nelfinavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of nelfinavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Administering elbasvir; grazoprevir with netupitant; palonosetron may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Netupitant; palonosetron is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity. (Moderate) Administering palonosetron with elbasvir; grazoprevir may result in elevated palonosetron plasma concentrations. Palonosetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Nevirapine: (Major) If possible, avoid concurrent administration of elbasvir with nevirapine. Nevirapine is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with nevirapine. Nevirapine is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of nevirapine (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Niacin; Simvastatin: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Nicardipine: (Moderate) Administering elbasvir; grazoprevir with nicardipine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nicardipine is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity. (Moderate) Administering elbasvir; grazoprevir with nicardipine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nicardipine is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Nifedipine: (Moderate) Administering nifedipine with elbasvir; grazoprevir may result in elevated nifedipine plasma concentrations. Nifedipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Nilotinib: (Moderate) Administering elbasvir; grazoprevir with nilotinib may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nilotinib is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Nimodipine: (Moderate) Administering nimodipine with elbasvir; grazoprevir may result in elevated nimodipine plasma concentrations. Nimodipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Nirmatrelvir; Ritonavir: (Major) Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Nisoldipine: (Moderate) Administering nisoldipine with elbasvir; grazoprevir may result in elevated nisoldipine plasma concentrations. Nisoldipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Nortriptyline: (Moderate) Administering nortriptyline with elbasvir; grazoprevir may result in elevated nortriptyline plasma concentrations. Nortriptyline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Obeticholic Acid: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with obeticholic acid is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Obeticholic acid is an inhibitor of the organic anion transporting polypeptide (OATP1B1/3) in vitro; grazoprevir is an OATP1B1/3 substrate.
Octreotide: (Moderate) Administering elbasvir; grazoprevir with octreotide may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Octreotide is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Olanzapine; Fluoxetine: (Moderate) Administering elbasvir; grazoprevir with fluoxetine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluoxetine is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concurrent administration of grazoprevir with paritaprevir is contraindicated. Use of these drugs together is expected to significantly increase grazoprevir plasma concentrations, and may result in adverse effects (i.e., elevated ALT concentrations). Paritaprevir is an inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Omeprazole; Amoxicillin; Rifabutin: (Major) If possible, avoid concurrent administration of elbasvir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of rifabutin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Ondansetron: (Moderate) Administering ondansetron with elbasvir; grazoprevir may result in elevated ondansetron plasma concentrations. Ondansetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Oritavancin: (Moderate) Caution is advised when administering elbasvir; grazoprevir with oritavancin. Oritavancin is a mild CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together may decrease the plasma concentrations of both elbasvir and grazoprevir, and could result in decreased virologic response.
Oxybutynin: (Moderate) Administering oxybutynin with elbasvir; grazoprevir may result in elevated oxybutynin plasma concentrations. Oxybutynin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like grazoprevir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If grazoprevir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) Administering paclitaxel with elbasvir; grazoprevir may result in elevated paclitaxel plasma concentrations. Paclitaxel is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Palonosetron: (Moderate) Administering palonosetron with elbasvir; grazoprevir may result in elevated palonosetron plasma concentrations. Palonosetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Panobinostat: (Major) Administering panobinostat with grazoprevir may result in elevated panobinostat plasma concentrations. Panobinostat is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Paricalcitol: (Moderate) Administering paricalcitol with elbasvir; grazoprevir may result in elevated paricalcitol plasma concentrations. Paricalcitol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Pazopanib: (Moderate) Administering elbasvir; grazoprevir with pazopanib may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Pazopanib is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. In addition, pazopanib is a substrate for the breast cancer resistance protein (BCRP), while both elbasvir and grazoprevir are BCRP inhibitors. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Pentobarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Perampanel: (Moderate) Caution is advised when administering elbasvir; grazoprevir with perampanel. Perampanel is a mild CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together may decrease the plasma concentrations of both elbasvir and grazoprevir, and could result in decreased virologic response. Conversely, concentrations of perampanel (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Perindopril; Amlodipine: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Perphenazine; Amitriptyline: (Moderate) Administering perphenazine; amitriptyline with elbasvir; grazoprevir may result in elevated amitriptyline plasma concentrations. Amitriptyline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Pexidartinib: (Major) Coadministration of elbasvir with pexidartinib is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. (Major) Coadministration of grazoprevir with pexidartinib is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Phentermine; Topiramate: (Moderate) Caution is advised when administering elbasvir with topiramate. Topiramate is a mild CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of elbasvir and could result in decreased virologic response. (Moderate) Caution is advised when administering elbasvir; grazoprevir with topiramate. Topiramate is a mild CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of grazoprevir and could result in decreased virologic response.
Phenytoin: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with phenytoin is contraindicated. Phenytoin is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Pimozide: (Major) Administering pimozide with grazoprevir may result in elevated pimozide plasma concentrations. Pimozide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Pioglitazone: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Pioglitazone; Glimepiride: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Pioglitazone; Metformin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Pirfenidone: (Moderate) Administering elbasvir; grazoprevir with pirfenidone may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Pirfenidone is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Posaconazole: (Major) Concurrent administration of elbasvir with posaconazole should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Posaconazole is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with posaconazole should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Posaconazole is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Pramlintide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Primidone: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Probenecid; Colchicine: (Moderate) Administering colchicine with elbasvir; grazoprevir may result in elevated colchicine plasma concentrations. Colchicine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Propafenone: (Moderate) Administering propafenone with elbasvir; grazoprevir may result in elevated propafenone plasma concentrations. Propafenone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Quazepam: (Moderate) Administering quazepam with grazoprevir may result in elevated quazepam plasma concentrations. Quazepam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Quetiapine: (Moderate) Administering quetiapine with elbasvir; grazoprevir may result in elevated quetiapine plasma concentrations. Quetiapine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Quinidine: (Moderate) Administering quinidine with elbasvir; grazoprevir may result in elevated quinidine plasma concentrations. Quinidine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Quinine: (Major) If possible, avoid concurrent administration of elbasvir with quinine. Use of these drugs together may cause changes in the plasma concentrations of elbasvir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Quinine is an inhibitor and inducer of CYP3A; elbasvir is a substrate of CYP3A. (Major) If possible, avoid concurrent administration of grazoprevir with quinine. Use of these drugs together may cause changes in the plasma concentrations of grazoprevir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Quinine is an inhibitor and inducer of CYP3A; grazoprevir is a substrate of CYP3A. In addition, concentrations of quinine (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Ramelteon: (Moderate) Administering ramelteon with elbasvir; grazoprevir may result in elevated ramelteon plasma concentrations. Ramelteon is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ranolazine: (Moderate) Administering elbasvir; grazoprevir with ranolazine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ranolazine is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Regular Insulin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Regular Insulin; Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Repaglinide: (Moderate) Administering repaglinide with elbasvir; grazoprevir may result in elevated repaglinide plasma concentrations. Repaglinide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Ribociclib: (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with ribociclib is necessary. Grazoprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Use caution if ribociclib is coadministered with elbasvir, as the systemic exposure of elbasvir may be increased resulting in adverse reactions. Ribociclib is a strong CYP3A4 inhibitor, and elbasvir is a CYP3A4 substrate.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with ribociclib is necessary. Grazoprevir is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Use caution if ribociclib is coadministered with elbasvir, as the systemic exposure of elbasvir may be increased resulting in adverse reactions. Ribociclib is a strong CYP3A4 inhibitor, and elbasvir is a CYP3A4 substrate.
Rifabutin: (Major) If possible, avoid concurrent administration of elbasvir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) If possible, avoid concurrent administration of grazoprevir with rifabutin; consider use of an alternative hepatitis C treatment regimen. Rifabutin is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response. Conversely, concentrations of rifabutin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Rifampin: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with rifampin is contraindicated. Rifampin is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Rifapentine: (Contraindicated) Concomitant use of grazoprevir and rifapentine is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of grazoprevir, which may result in decreased virologic response. Grazoprevir is a substrate of CYP34A and rifapentine is a strong CYP3A4 inducer. (Contraindicated) Concurrent administration of rifapentine with elbasvir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of elbasvir and may result in decreased virologic response. Elbasvir is a substrate of CYP3A and rifapentine is a strong CYP3A inducer.
Riociguat: (Moderate) Administering riociguat with elbasvir; grazoprevir may result in elevated riociguat plasma concentrations. Riociguat is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Risperidone: (Moderate) Administering risperidone with elbasvir; grazoprevir may result in elevated risperidone plasma concentrations. Risperidone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ritonavir: (Major) Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Rivaroxaban: (Minor) Administering rivaroxaban with grazoprevir may result in elevated rivaroxaban plasma concentrations. Rivaroxaban is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Roflumilast: (Moderate) Administering roflumilast with elbasvir; grazoprevir may result in elevated roflumilast plasma concentrations. Roflumilast is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Rolapitant: (Major) Administering rolapitant with grazoprevir may result in elevated rolapitant plasma concentrations. Rolapitant is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Romidepsin: (Moderate) Administering romidepsin with elbasvir; grazoprevir may result in elevated romidepsin plasma concentrations. Romidepsin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ropivacaine: (Moderate) Administering ropivacaine with elbasvir; grazoprevir may result in elevated ropivacaine plasma concentrations. Ropivacaine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Rosiglitazone: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Rosuvastatin: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with elbasvir; grazoprevir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Rosuvastatin; Ezetimibe: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with elbasvir; grazoprevir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Ruxolitinib: (Moderate) Administering ruxolitinib with elbasvir; grazoprevir may result in elevated ruxolitinib plasma concentrations. Ruxolitinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Saquinavir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with saquinavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Saquinavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Saxagliptin: (Moderate) Administering metformin; saxagliptin with elbasvir; grazoprevir may result in elevated saxagliptin plasma concentrations. Saxagliptin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Secobarbital: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Selexipag: (Major) Administering selexipag with elbasvir may result in elevated selexipag plasma concentrations. Selexipag is a substrate of CYP3A and the active metabolite is a substrate for breast cancer resistance protein (BCRP). Elbasvir is an inhibitor of BCRP. If these drugs are used together, closely monitor for signs of adverse events. (Major) Administering selexipag with grazoprevir may result in elevated selexipag plasma concentrations. Selexipag is a substrate of CYP3A and the active metabolite is a substrate for breast cancer resistance protein (BCRP). Grazoprevir is an inhibitor of BCRP, and also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Semaglutide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Sertraline: (Moderate) Administering sertraline with elbasvir; grazoprevir may result in elevated sertraline plasma concentrations. Sertraline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Sibutramine: (Moderate) Administering sibutramine with elbasvir; grazoprevir may result in elevated sibutramine plasma concentrations. Sibutramine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Sildenafil: (Moderate) Administering sildenafil with elbasvir; grazoprevir may result in elevated sildenafil plasma concentrations. Sildenafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Simeprevir: (Major) Concurrent administration of elbasvir with simeprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations). Simeprevir is a substrate and inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with simeprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Simeprevir is a substrate and inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, simeprevir is a weak inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3.
Simvastatin: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Simvastatin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir. (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with grazoprevir is necessary. The dose of sirolimus may also need to be reduced with coadministration of grazoprevir. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of grazoprevir. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; grazoprevir is a weak CYP3A inhibitor.
Sitagliptin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with grazoprevir. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Velpatasvir is a substrate for the Breast Cancer Resistance Protein (BCRP). Grazoprevir is a BCRP inhibitor. Grazoprevir is also a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4. Additionally, velpatasvir is an inhibitor of the organic anion transporting polypeptides OATP1B1 and OATP1B3. grazoprevir is an OATP1B1/3 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with grazoprevir. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Velpatasvir is a substrate for the Breast Cancer Resistance Protein (BCRP). Grazoprevir is a BCRP inhibitor. Grazoprevir is also a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4. Additionally, velpatasvir is an inhibitor of the organic anion transporting polypeptides OATP1B1 and OATP1B3. grazoprevir is an OATP1B1/3 substrate.
Solifenacin: (Moderate) Administering solifenacin with elbasvir; grazoprevir may result in elevated solifenacin plasma concentrations. Solifenacin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Sonidegib: (Moderate) Administering sonidegib with elbasvir; grazoprevir may result in elevated sonidegib plasma concentrations. Sonidegib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Sotorasib: (Major) Coadministration of elbasvir with sotorasib is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Major) Concomitant use of grazoprevir and sotorasib is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with St. John's Wort, Hypericum perforatum is contraindicated. St. John's Wort is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if grazoprevir must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like grazoprevir can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If grazoprevir is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfasalazine: (Moderate) Administering sulfasalazine with elbasvir; grazoprevir may result in elevated sulfasalazine plasma concentrations. Sulfasalazine is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Suvorexant: (Moderate) Administering suvorexant with elbasvir; grazoprevir may result in elevated suvorexant plasma concentrations. Suvorexant is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Tacrolimus: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as elbasvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Studies have shown plasma concentrations of tacrolimus are increased when administered concurrently with elbasvir; grazoprevir. If these drugs are use together, frequently monitor for changes in tacrolimus whole blood concentrations, renal function, and for tacrolimus-associated adverse events. Tacrolimus is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Tadalafil: (Moderate) Administering tadalafil with elbasvir; grazoprevir may result in elevated tadalafil plasma concentrations. Tadalafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Talazoparib: (Major) Avoid coadministration of elbasvir with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and elbasvir is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure. (Major) Avoid coadministration of grazoprevir with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and grazoprevir is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
Tamsulosin: (Moderate) Administering tamsulosin with elbasvir; grazoprevir may result in elevated tamsulosin plasma concentrations. Tamsulosin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Tasimelteon: (Moderate) Administering tasimelteon with elbasvir; grazoprevir may result in elevated tasimelteon plasma concentrations. Tasimelteon is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Telithromycin: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with telithromycin is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Telithromycin is a strong inhibitor of the hepatic enzyme CYP3A and the organic anion transporting polypeptide (OATP1B1/3). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Telmisartan; Amlodipine: (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Teniposide: (Moderate) Administering teniposide with elbasvir; grazoprevir may result in elevated teniposide plasma concentrations. Teniposide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Terbinafine: (Moderate) Administering terbinafine with elbasvir; grazoprevir may result in elevated terbinafine plasma concentrations. Terbinafine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Teriflunomide: (Contraindicated) Concurrent administration of grazoprevir with teriflunomide is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Grazoprevir is a substrate of the organic anion-transporting peptide (OATP1B1/1B3); teriflunomide is an in vitro inhibitor of OATP.
Theophylline, Aminophylline: (Moderate) Administering theophylline, aminophylline with elbasvir; grazoprevir may result in elevated theophylline plasma concentrations. Theophylline is a minor substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Thiopental: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Tiagabine: (Moderate) Administering tiagabine with elbasvir; grazoprevir may result in elevated tiagabine plasma concentrations. Tiagabine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ticagrelor: (Moderate) Administering elbasvir; grazoprevir with ticagrelor may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ticagrelor is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Tinidazole: (Moderate) Administering tinidazole with elbasvir; grazoprevir may result in elevated tinidazole plasma concentrations. Tinidazole is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Tipranavir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with tipranavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Tipranavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Tolazamide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Tolbutamide: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Tolterodine: (Moderate) Administering tolterodine with elbasvir; grazoprevir may result in elevated tolterodine plasma concentrations. Tolterodine is a substrate of CYP3A in people who are poor CYP2D6 metabolizers; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Topiramate: (Moderate) Caution is advised when administering elbasvir with topiramate. Topiramate is a mild CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of elbasvir and could result in decreased virologic response. (Moderate) Caution is advised when administering elbasvir; grazoprevir with topiramate. Topiramate is a mild CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of grazoprevir and could result in decreased virologic response.
Topotecan: (Major) Avoid coadministration of elbasvir with oral topotecan due to increased topotecan exposure; elbasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and elbasvir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. (Major) Avoid coadministration of grazoprevir with oral topotecan due to increased topotecan exposure; grazoprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and grazoprevir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Tramadol: (Moderate) Administering acetaminophen; tramadol with elbasvir; grazoprevir may result in elevated tramadol plasma concentrations. Tramadol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Tramadol; Acetaminophen: (Moderate) Administering acetaminophen; tramadol with elbasvir; grazoprevir may result in elevated tramadol plasma concentrations. Tramadol is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Trandolapril; Verapamil: (Moderate) Administering elbasvir; grazoprevir with verapamil may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Verapamil is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Trazodone: (Moderate) Administering trazodone with elbasvir; grazoprevir may result in elevated trazodone plasma concentrations. Trazodone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with elbasvir; grazoprevir and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and grazoprevir is a weak CYP3A inhibitor.
Tucatinib: (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with tucatinib is necessary. Elbasvir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased elbasvir exposure by 3-fold. (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase grazoprevir exposure. Grazoprevir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with elbasvir. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; elbasvir is a BCRP inhibitor. (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with grazoprevir. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and BCRP substrate; grazoprevir is a weak CYP3A4 inhibitor and a BCRP inhibitor.
Ultralente Insulin: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Umeclidinium; Vilanterol: (Moderate) Administering vilanterol with elbasvir; grazoprevir may result in elevated vilanterol plasma concentrations. Vilanterol is a primary substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Valproic Acid, Divalproex Sodium: (Major) If possible, avoid concurrent administration of elbasvir with valproic acid, divalproex sodium. Use of these drugs together may cause changes in the plasma concentrations of elbasvir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Valproic acid is an inhibitor and inducer of CYP3A; elbasvir is a substrate of CYP3A. (Major) If possible, avoid concurrent administration of grazoprevir with valproic acid, divalproex sodium. Use of these drugs together may cause changes in the plasma concentrations of grazoprevir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Valproic acid is an inhibitor and inducer of CYP3A; grazoprevir is a substrate of CYP3A.
Vemurafenib: (Moderate) Caution is advised when administering elbasvir; grazoprevir with vemurafenib. Use of these drugs together may cause the plasma concentration of vemurafenib to increase. Elbasvir and grazoprevir are inhibitors of the breast cancer resistance protein (BCRP), while grazoprevir is also a weak inhibitor of CYP3A. Vemurafenib is a substrate for both BCRP and CYP3A. If these drugs are administered concurrently, closely monitor for adverse reactions.
Venlafaxine: (Moderate) Administering venlafaxine with elbasvir; grazoprevir may result in elevated venlafaxine plasma concentrations. Venlafaxine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Verapamil: (Moderate) Administering elbasvir; grazoprevir with verapamil may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Verapamil is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Vilazodone: (Minor) Administering vilazodone with grazoprevir may result in elevated vilazodone plasma concentrations. Vilazodone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Vincristine Liposomal: (Moderate) Administering vincristine with elbasvir; grazoprevir may result in elevated vincristine plasma concentrations. Vincristine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Vincristine: (Moderate) Administering vincristine with elbasvir; grazoprevir may result in elevated vincristine plasma concentrations. Vincristine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with grazoprevir is necessary. Vinorelbine is a CYP3A4 substrate and grazoprevir is a weak CYP3A4 inhibitor.
Voclosporin: (Contraindicated) Concomitant use of grazoprevir and voclosporin is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1; voclosporin is an inhibitor of OATP1B1.
Vorapaxar: (Moderate) Administering vorapaxar with elbasvir; grazoprevir may result in elevated vorapaxar plasma concentrations. Vorapaxar is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Voriconazole: (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with voriconazole is necessary. Grazoprevir is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Use caution if voriconazole is coadministered with elbasvir, as the systemic exposure of elbasvir may be increased resulting in adverse reactions. Voriconazole is a strong CYP3A4 inhibitor, and elbasvir is a CYP3A4 substrate.
Warfarin: (Moderate) Closely monitor patients receiving warfarin in combination with elbasvir for changes in International Normalized Ratio (INR) both during and after discontinuation of the hepatitis C virus (HCV) treatment regimen. One study found that when adding an elbasvir containing regimen to patients stable on warfarin anticoagulation, warfarin sensitivity decreased significantly during treatment and returned to baseline after discontinuation of the HCV therapy. More specifically, the mean INR decreased from 2.4 to 1.96 during treatment and recovered to 2.59 after elbasvir treatment. (Moderate) Closely monitor the INR if coadministration of warfarin with grazoprevir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Grazoprevir is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Yohimbine: (Moderate) Administering yohimbine with elbasvir; grazoprevir may result in elevated yohimbine plasma concentrations. Yohimbine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Zafirlukast: (Moderate) Administering elbasvir; grazoprevir with zafirlukast may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Zafirlukast is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Zileuton: (Moderate) Administering zileuton with elbasvir; grazoprevir may result in elevated zileuton plasma concentrations. Zileuton is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Ziprasidone: (Major) Administering ziprasidone with grazoprevir may result in elevated ziprasidone plasma concentrations. Ziprasidone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Zolmitriptan: (Moderate) Administering zolmitriptan with elbasvir; grazoprevir may result in elevated zolmitriptan plasma concentrations. Zolmitriptan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Zolpidem: (Moderate) The primary isoenzyme responsible for the metabolism of zolpidem is CYP3A4. The effect of weak CYP3A4 inhibitors, such as elbasvir; grazoprevir, on zolpidem exposure is not known. Until further information is available, it is advisable to monitor for zolpidem-related CNS effects when this combination is administered. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
Zonisamide: (Moderate) Administering zonisamide with elbasvir; grazoprevir may result in elevated zonisamide plasma concentrations. Zonisamide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.

PREGNANCY AND LACTATION

No adequate, well-controlled studies have been conducted in pregnant humans, and it is unknown whether elbasvir; grazoprevir poses a risk to the developing fetus. In animal studies, adverse effects on embryo-fetal development and pre/postnatal development were not identified in rats and rabbits exposed to doses higher than the recommended human dose. However, in both rats and rabbits, elbasvir and grazoprevir were shown to cross the placenta. For elbasvir, drug concentrations in fetal plasma at gestation day 20 were up to 0.8% (rabbits) and 2.2% (rats) of those observed in the mother. Grazoprevir fetal concentrations at gestation day 20 were 7% (rabbit) and 89% (rats) of the maternal concentration. In certain patient populations, elbasvir; grazoprevir must be administered with ribavirin. Use of elbasvir; grazoprevir in combination with ribavirin is contraindicated in pregnant women. Ribavirin may cause birth defects and death of the exposed fetus; thus, the drug is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

In certain patient populations, elbasvir; grazoprevir must be administered with ribavirin. Use of elbasvir; grazoprevir in combination with ribavirin is contraindicated in male partners of women who are pregnant. Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use in men whose female partners are pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. Patients and their partners are required use 2 reliable forms of effective contraception during treatment and for 6 months after use of the combination therapy. Patients who are not willing to practice strict contraception should not receive elbasvir; grazoprevir with ribavirin. Females must also undergo pregnancy testing immediately prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

MECHANISM OF ACTION

Elbasvir; grazoprevir is active against chronic infections caused by hepatitis C virus (HCV) genotypes 1 and 4. Elbasvir is an inhibitor of the HCV NS5A protein. Grazoprevir is an HCV NS3/4A protease inhibitor.
 
Elbasvir: Elbasvir prevents hepatitis C viral replication by inhibiting the HCV NS5A protein. Although the exact mechanism is unknown, data suggest NS5A inhibitors may prevent replication by blocking viral hyperphosphorylation. It has been proposed that tight control of phosphorylation versus hyperphosphorylation is needed for efficient viral function (i.e., RNA replication and virion assembly).
 
Hepatitis C viral resistance to elbasvir has been demonstrated in both cell cultures and during clinical studies. An evaluation of cell cultures found viruses containing amino acid substitutions in the NS5A domain display reduced susceptibility to elbasvir. For HCV genotype 1a replicons, susceptibility to elbasvir was reduced by 1.5- to 2,000-fold in the presence of a single NS5A substitution at M28A/G/T, Q30D/E/H/K/R, L31M/V, H58D, and Y93C/H/N. For genotype 1b replicons, a single NS5A substitution at L28M, L31F, and Y93H reduced susceptibility by 2- to 17-fold. Finally, a single NS5A substitution at L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold in genotype 4 replicons. Further decreases in antiviral activity are expected in viruses with multiple NS5A substitutions. Resistance analyses were conducted on 50 patients who experienced treatment failure during clinical trials (6 on-treatment failures, 44 post-treatment relapse). Treatment-emergent NS5A substitutions were identified in 81% of genotype 1a, 88% of genotype 1b, and 100% of genotype 4 infected patients. The most common substitutions in genotype 1a were at Q30. Cross-resistance is expected among NS5A protease inhibitors (i.e., ledipasvir).
 
The presence of 1 or more pretreatment HCV NS5A amino acid polymorphisms (M28, Q30, L31, and Y93) has been associated with reduced elbasvir; grazoprevir efficacy in genotype 1a infected patients. Specifically, the sustained virologic response at week 12 (SVR12) following treatment with 12 weeks of elbasvir; grazoprevir is 88% for patients with M28V/T/L polymorphisms, 40% for patients with Q30H/R/L polymorphisms, 38% for patients with L31M polymorphism, and 63% for patients with Y93C/H/N/S polymorphisms. However, limited data suggest the SVR12 may be increased when elbasvir; grazoprevir is administered in combination with ribavirin and the treatment duration was extended to 16 weeks. In 1 small clinical trial, 100% (n = 6/6) of genotype 1a infected patients with baseline NS5A polymorphisms who received elbasvir; grazoprevir plus ribavirin for 16 weeks achieved SVR12. Further, in 2 postmarket observational studies, SVR12 was achieved by 93% (n = 27/29) and 81% (n = 75/93) of genotype 1a infected patients with 1 or more baseline NS5A polymorphisms who received 16 weeks of treatment with the combination regimen.
 
Grazoprevir: Grazoprevir prevents viral replication by blocking the proteolytic activity of HCV NS3/4A protease. Hepatitis C virus NS3/4A protease is an enzyme responsible for the conversion of HCV encoded polyproteins to mature/functioning viral proteins. These mature proteins (NS3, NS4A, NS4B, NS5A, and NS5B) are essential for viral replication.
 
Hepatitis C viral resistance to grazoprevir has been demonstrated in both cell cultures and during clinical studies. An evaluation of cell cultures found viruses containing amino acid substitutions in the NS3 domain display reduced susceptibility to grazoprevir. For HCV genotype 1a replicons, susceptibility to grazoprevir was reduced by 2- to 81-fold in the presence of a single NS3 substitution at Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y. For genotype 1b replicons, a single NS3 substitution at F43S, Y56F, V107I, A156S/T/V, and D168A/G/V reduced susceptibility by 1.5- to 375-fold. Finally, a single NS3 substitution at D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold in genotype 4 replicons. Further decreases in antiviral activity are expected in viruses with multiple NS3 substitutions. Resistance analyses were conducted on 50 patients who experienced treatment failure during clinical trials (6 on-treatment failures, 44 post-treatment relapse). Treatment-emergent NS3 substitutions were identified in 78% of genotype 1a, 25% of genotype 1b, and 40% of genotype 4 infected patients. The most common substitutions in genotype 1a were at D168. Cross-resistance is expected among NS3/4A protease inhibitors (i.e., boceprevir, simeprevir).

PHARMACOKINETICS

Elbasvir; grazoprevir is administered orally.
 
Elbasvir: Following systemic absorption, greater than 99.9% of circulating elbasvir is bound to human plasma proteins (i.e., albumin and alpha 1-acid glycoprotein). The drug distributes into most tissues, with an estimated volume of distribution of approximately 680 L. Elbasvir undergoes oxidative metabolism, primarily by CYP3A enzymes. Excretion occurs primarily through the feces (greater than 90%), with less than 1% being eliminated in the urine. In HCV infected patients, the geometric mean terminal half-life for 50 mg of elbasvir is approximately 24 hours.
Grazoprevir: Following systemic absorption, more than 98.8% of circulating grazoprevir is bound to human plasma proteins (i.e., albumin and alpha 1-acid glycoprotein). Grazoprevir has an estimated volume of distribution of approximately 1,250 L, with the majority of the drug being actively transported into the liver via the OATP1B1/3 uptake transporters. Grazoprevir undergoes oxidative metabolism, primarily by CYP3A enzymes. Excretion occurs primarily through the feces (greater than 90%), with less than 1% being eliminated in the urine. In HCV infected patients, the geometric mean terminal half-life for 100 mg of grazoprevir is approximately 31 hours.
 
Affected enzymes and drug transporters: CYP3A, P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP)
Elbasvir and grazoprevir are substrates for the hepatic enzyme CYP3A and the intestinal drug transporter P-gp; however, the effects of P-gp inducers and inhibitors on their absorption appear to be minimal. Elbasvir has been shown to inhibit P-gp in vitro, but its effect on plasma concentrations of P-gp substrates is also considered clinically irrelevant. Grazoprevir is a weak CYP3A inhibitor and a substrate for the liver uptake transporters OATP1B1/3. Coadministration with inducers and inhibitors of CYP3A or inhibitors of OATP1B1/3 are expected to alter the plasma concentrations of elbasvir and grazoprevir. Elbasvir and grazoprevir are also inhibitors of the intestinal drug transporter BCRP, and may increase concentrations of concurrently administered BCRP substrates.