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  • CLASSES

    Antileukotriene Anti-asthmatics, Systemic

    DEA CLASS

    Rx

    DESCRIPTION

    Leukotriene receptor antagonist class antiinflammatory.
    Used orally to control mild persistent asthma in patients as young as 7 years; used off-label for allergic rhinitis and to prevent exercise-induced bronchospasm.
    Inhibits hepatic metabolism of drugs like theophylline or warfarin; may result in hepatic side effects.
    Inhalational dose form under investigation.

    COMMON BRAND NAMES

    Accolate

    HOW SUPPLIED

    Accolate/Zafirlukast Oral Tab: 10mg, 20mg

    DOSAGE & INDICATIONS

    For the chronic treatment and prevention of the symptoms of asthma, either as monotherapy or as add-on therapy in patients whose persistent mild-moderate asthma is inadequately controlled with inhaled corticosteroids.
    NOTE: Zafirlukast is not a 'rescue' medication; it should not be used for the treatment of an acute asthmatic attack or acute bronchospasm. However, zafirlukast may be continued during the treatment of an acute asthmatic event.
    Oral dosage
    Adults, Adolescents and Children >= 12 years

    20 mg PO twice daily. In a randomized, double-blind study of 266 patients with moderate asthma, zafirlukast was found to be more effective than placebo in decreasing nighttime awakening, albuterol use, and daytime symptoms. Treatment with zafirlukast also increased peak expiratory flow rate and FEV-1.

    Children 5—11 years

    10 mg PO twice daily.

    Inhalation dosage (NOTE: not available in the US)
    Adults, Adolescents and Children >= 12 years

    0.2 mg via a metered-dose inhaler (frequency not established). One trial reported that zafirlukast inhibited bronchoconstriction in 16 asthmatic subjects with reproducible sensitivity to ragweed challenges. Controlled clinical trials, however, are lacking.

    For the treatment of allergic rhinitis†.
    Oral dosage
    Adults

    20 mg PO twice daily is the usual dose. The data for zafirlukast in the treatment of allergic rhinitis are limited, especially compared to the more extensive clinical study data available for montelukast. However, expert opinions regard the leukotriene receptor antagonists (LTRAs) as options in the treatment of allergic rhinitis, particularly when the patient has comorbid asthma. However, in patients with allergic rhinitis (seasonal or other) alone, intranasal corticosteroids are generally considered first-line therapy, since treatment results with LTRAs appear to be similar to standard treatments such as antihistamines, and inferior to intranasal corticosteroids.

    For exercise-induced bronchospasm prophylaxis†.
    Oral dosage
    Adults

    20 mg PO twice daily. A dose of 80 mg PO twice daily has been used in a clinical study; however, exceeding the recommended daily dose of 40 mg/day increases drug exposure which may increase the risk of elevated hepatic enzymes and hepatotoxicity. The American Thoracic Society recommends daily administration of a leukotriene receptor antagonist (LTRA) such as zafirlukast in patients who continue to have exercise-induced symptoms despite using an inhaled short-acting beta-2 agonist (SABA) before exercise, or in those who require daily (or more frequent) SABA use. In clinical practice, LTRAs may be a first-line choice for a controller agent to be added to SABAs; inhaled corticosteroids (ICS) may also be used. The choice between the 2 classes must be made on an individual basis considering patient preferences and baseline lung function. Patients with EIB associated with greater airway inflammation (e.g., asthma) may benefit more from ICS therapy. A double-blind, cross-over study in 16 adults with mild asthma and exercise-induced bronchospasm (EIB) evaluated the ability of zafirlukast to control EIB. Patients received loratadine (10 mg twice daily), zafirlukast (80 mg twice daily), the combination of loratadine with zafirlukast, or placebo for 4 different exercise challenges held 3 weeks apart. Repeated FEV1 measurements were obtained for 1 hour following exercise. The mean +/- SE maximum decreases in FEV1 were 21.6% +/- 3% (placebo), 22.8% +/- 3% (loratadine), 13.9% +/- 2% (zafirlukast, p < 0.05 vs. placebo), and 10.3% +/- 2% (the active combination, p < 0.05 vs. placebo). The mean protection afforded by zafirlukast and the combination group (expressed as area under the FEV1 percentage change vs. time curve) was 57% and 65%, respectively.

    Children >= 7 years and Adolescents

    Data are limited; 5—40 mg PO as a single dose 4 hours before an exercise challenge was studied in a double-blind, crossover study in children and adolescents 7—14 years of age. All doses of zafirlukast attenuated EIB compared with placebo; there was no difference among the doses. Safety assessments did not differ among the treatments. Patients receiving daily zafirlukast for another indication should not take an additional dose to prevent EIB. Rescue medications (i.e. albuterol) should be readily available. The American Thoracic Society recommends daily administration of a leukotriene receptor antagonist (LTRA) such as zafirlukast in patients who continue to have exercise-induced symptoms despite using an inhaled short-acting beta-2 agonist (SABA) before exercise, or in those who require daily (or more frequent) SABA use. In clinical practice, LTRAs may be a first-line choice for a controller agent to be added to SABAs; inhaled corticosteroids (ICS) may also be used. The choice between the 2 classes must be made on an individual basis considering patient preferences and baseline lung function. Patients with EIB associated with greater airway inflammation (e.g., asthma) may benefit more from ICS therapy. More study is needed in pediatrics; LTRAs do not have the same record of safety and efficacy compared to other prophylactic treatments for EIB.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO.

    Elderly

    40 mg/day PO.

    Adolescents

    40 mg/day PO.

    Children

    5—11 years: 20 mg/day PO.
    < 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use is contraindicated in patients with hepatic impairment including hepatic cirrhosis as drug exposure is increased (see Contraindications).

    Renal Impairment

    It appears that no dosage adjustments are needed, zafirlukast is not significantly eliminated via the renal route.

    ADMINISTRATION

    Oral Administration

    Administer zafirlukast on an empty stomach. Take at least 1 hour before or 2 hours after meals. The bioavailability of zafirlukast is substantially decreased when taken with food.
    Zafirlukast is for chronic administration; continue therapy even during symptom-free periods.
    Patients should be advised not to stop taking or decrease the use of other asthma treatments when starting zafirlukast unless otherwise directed by their health care prescriber.

    STORAGE

    Accolate:
    - Protect from light
    - Protect from moisture
    - Store and dispense in original container
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Zafirlukast is contraindicated in any patient with a known hypersensitivity to this agent or the inactive products in the formulation. Tablets contain povidone, lactose, titanium dioxide and cellulose derivatives.

    Acute bronchospasm, status asthmaticus

    Because of its relatively slow onset of pharmacological action (i.e., >= 24 hours), zafirlukast should not be used to treat an acute asthmatic attack, including status asthmaticus or acute bronchospasm. Zafirlukast is also not recommended to be used as monotherapy for exercise-induced bronchospasm (EIB). Thus, patients should be advised to have appropriate rescue medication (e.g., inhaled beta-agonist) available. However, zafirlukast therapy may be continued during the treatment of an acute asthmatic event. Patients should be advised not to stop taking or decrease the use of other asthma treatments when starting zafirlukast unless otherwise directed by their health care prescriber.

    Pregnancy

    Zafirlukast is classified in FDA pregnancy category B. No teratogenic effects were seen in cynomolgus monkeys at doses roughly 120 times the maximum recommended human daily dosage based on comparative drug AUCs. Higher dosages (roughly 410 times the maximum recommended human daily dosage) have resulted in maternal and/or fetal toxicity in this species. A no-effect dosage has not been established. There are no adequate or controlled trials in pregnant women. Safe use during human pregnancy has not been established. Nevertheless, the National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group lists leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy and lactation. Because animal studies are not always indicative of human response, use during pregnancy only if clearly needed. A risk-benefit assessment should be performed. The American College of Allergy, Asthma and Immunology initiated the Registry for Allergic, Asthmatic Pregnant Patients (RAAPP) in 1999 to begin to gather data from which safety of asthma medications in pregnancy can be evaluated.

    Breast-feeding

    According to the manufacturer, zafirlukast is excreted into breast milk at concentrations equal to roughly 20% of maternal plasma levels. The manufacturer recommends against breast-feeding while on this medication. Nevertheless, the National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group lists leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy and lactation. Consider the benefits of breast-feeding, the risk of potential 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, healthcare providers are encouraged to report the adverse effect to the FDA.

    Females, hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Zafirlukast is contraindicated in patients with hepatic impairment including cirrhosis (hepatic disease). Similarly, do not use in patients with hepatitis or hepatic encephalopathy. Liver dysfunction is expected to result in increased drug exposure. According to the manufacturer, study results have demonstrated a reduced drug clearance and a 50—60% greater Cmax and AUC of zafirlukast in patients with stable alcoholic cirrhosis as compared to those of normal adults. It should also be noted that cases of elevated liver enzymes, hepatitis, and life-threatening hepatic failure have been reported with the use of zafirlukast. Consider periodic serum transaminase (LFT) testing and advise patients to immediately report signs and symptoms of liver dysfunction (e.g., abdominal pain, jaundice, nausea, vomiting, dark urine). If such symptoms occur, discontinue therapy, assess liver function tests (LFTs), in particular serum ALT, and manage the patient accordingly. Do not resume zafirlukast if LFTs are consistent with hepatic dysfunction. Patients in whom zafirlukast was discontinued due to hepatic dysfunction, where no other attributable course is identified, should not be re-exposed to zafirlukast. The manufacturer states that hepatic events have occurred predominately in females.

    Geriatric

    The clearance of zafirlukast is decreased in geriatric patients. The Cmax and AUC of zafirlukast are about 50% greater than those of younger adults are. However, the manufacturer has not recommended dosage reductions in this population; clinical responses to zafirlukast are generally similar for the elderly as for younger adults at normal dosages; however, certain non-severe adverse effects, such as headache or mild infection, may occur at a higher incidence in the elderly population based on some controlled studies.

    Corticosteroid withdrawal, vasculitis

    Patients with pre-existing Churg-Strauss syndrome, a type of vasculitis, may not be good candidates for zafirlukast therapy. Although a causal relationship has not been established; in rare cases, patients taking zafirlukast have developed symptoms consistent with Churg-Strauss syndrome, a systemic eosinophilic vasculitis. Symptoms may include eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy (see Adverse Reactions). As most, though not all, patients who have developed this syndrome during zafirlukast therapy have been undergoing steroid therapy dosage reductions or withdrawal, caution is advised when oral corticosteroid withdrawal or a reduction in corticosteroid dose is being considered in patients taking zafirlukast.

    Depression, suicidal ideation

    After a 2008—2009 safety review investigating the possible association of leukotriene-modifier therapy and reported behavior/mood changes, depression, sleep disturbances, suicidal ideation, and suicides, the FDA concluded that such events may be drug-related, possibly related to the leukotriene pathway. Post-marketing report data are insufficient to characterize at-risk patients; neuropsychiatric effects have been reported in adult, adolescence, and pediatric patients on zafirlukast. Advise patients and caregivers to immediately report any neuropsychiatric events.

    Children, infants, neonates

    Children as young as 5 years old have received zafirlukast in controlled clinical trials and the effective dose for children 5—11 years has been determined (see Dosage). Zafirlukast has not been investigated in neonates, infants and children < 5 years of age. The effect of zafirlukast on growth in children has not been determined.

    ADVERSE REACTIONS

    Severe

    hepatic failure / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    suicidal ideation / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    eosinophilic pneumonia / Delayed / 0-1.0
    Churg-Strauss syndrome / Delayed / 0-1.0
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    hepatitis / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    dyspnea / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    clastogenesis / Delayed / Incidence not known

    Mild

    headache / Early / 4.5-12.9
    infection / Delayed / 3.5-3.5
    nausea / Early / 1.8-3.1
    diarrhea / Early / 1.8-2.8
    asthenia / Delayed / 1.8-1.8
    abdominal pain / Early / 1.8-1.8
    myalgia / Early / 1.6-1.6
    dizziness / Early / 1.6-1.6
    fever / Early / 1.6-1.6
    back pain / Delayed / 1.5-1.5
    vomiting / Early / 1.5-1.5
    dyspepsia / Early / 1.3-1.3
    ecchymosis / Delayed / 0-1.0
    pharyngitis / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    weakness / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    fatigue / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    insomnia / Early / Incidence not known
    tremor / Early / Incidence not known
    agitation / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    malaise / Early / Incidence not known
    irritability / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    sinusitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Acetaminophen; Hydrocodone: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: Coadministration of zafirlukast, a CYP3A4 inhibitor, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold.
    Alfentanil: Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as zafirlukast, may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Close monitoring for oversedation and respiratory depression is warranted if a CYP3A4 inhibitor is used with alfentanil.
    Aliskiren; Amlodipine: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Aliskiren; Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
    Alogliptin; Pioglitazone: It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
    Alosetron: Alosetron is metabolized by hepatic cytochrome P450 enzymes CYP2C9, CYP3A4 and CYP1A2. Inhibitors of these enzymes, such as zafirlukast, may decrease the clearance of alosetron and increase the systemic exposure of alosetron. Clinically, increased systemic exposure to alosetron may cause or worsen constipation, which might lead to serious adverse effects.
    Alprazolam: Alprazolam is metabolized by cytochrome CYP3A. Zafirlukast inhibits CYP3A isoenzymes to a significant but lesser degree, and use with alprazolam should be done with caution and consider alprazolam dose reduction up to 50%.
    Ambrisentan: In vitro studies indicate ambrisentan is a substrate of CYP3A, although in vivo studies with ketoconazole, a CYP3A4 inhibitor, did not demonstrate a clinically significant drug-drug interaction. Ambrisentan is metabolized by CYP3A4. Although data are lacking, significant CYP3A4 inhibitors, such as zafirlukast, could potentially increase ambrisentan plasma concentrations via CYP3A4 inhibition. Monitor for increased toxicity as well as increased therapeutic effect during times of coadministration.
    Amitriptyline; Chlordiazepoxide: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as chlordiazepoxide.
    Amlodipine: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Atorvastatin: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Benazepril: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan. Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Olmesartan: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Telmisartan: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amlodipine; Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan. Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Amoxicillin; Clarithromycin; Lansoprazole: Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
    Amoxicillin; Clarithromycin; Omeprazole: Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
    Aprepitant, Fosaprepitant: Use caution if zafirlukast and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of zafirlukast. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Zafirlukast is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant. Zafirlukast is also a weak in vitro CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Aripiprazole: Increased aripiprazole blood levels are expected when aripiprazole is coadministered with inhibitors of CYP3A4 such as zafirlukast since aripiprazole is partially metabolized by CYP3A4. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. 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. Adult patients 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.
    Artemether; Lumefantrine: Zafirlukast is a inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. Zafirlukast is a inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Aspirin, ASA: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Butalbital; Caffeine: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Caffeine; Dihydrocodeine: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Carisoprodol: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Carisoprodol; Codeine: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Dipyridamole: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Omeprazole: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Oxycodone: Coadministration of zafirlukast, a CYP3A4 inhibitor, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold. Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Aspirin, ASA; Pravastatin: Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
    Atazanavir: Zafirlukast is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for atazanavir toxicity.
    Atazanavir; Cobicistat: Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate. Zafirlukast is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for atazanavir toxicity.
    Avanafil: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including zafirlukast, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Axitinib: Use caution if coadministration of axitinib with zafirlukast is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Zafirlukast is a weak CYP3A4 inhibitor as well as a moderate inhibitor of CYP1A2 in vitro. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Bepridil: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease hepatic metabolism of bepridil.
    Boceprevir: Close clinical monitoring is advised when administering zafirlukast with boceprevir due to an increased potential for boceprevir-related adverse events. If zafirlukast dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of zafirlukast and boceprevir. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may be elevated.
    Bosentan: Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes by zafirlukast may increase the plasma concentration of bosentan. Monitor for potential adverse effects of bosentan during coadministration with zafirlukast. Excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
    Bromocriptine: Bromocriptine is a cytochrome P450 3A4 substrate. In theory, inhibitors of this isoenzyme like zafirlukast may decrease the metabolism of bromocriptine.
    Brompheniramine; Guaifenesin; Hydrocodone: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Bupivacaine; Lidocaine: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
    Buprenorphine: Since the metabolism of buprenorphine is mediated by the CYP3A4 isozyme, co-administration of zafirlukast, which inhibits CYP3A4 may cause decreased clearance of buprenorphine. Thus, there is a potential for excessive buprenorphine-related side effects. The buprenorphine dosage may need to be lowered for patients that receive inhibitors of CYP3A4
    Buprenorphine; Naloxone: Since the metabolism of buprenorphine is mediated by the CYP3A4 isozyme, co-administration of zafirlukast, which inhibits CYP3A4 may cause decreased clearance of buprenorphine. Thus, there is a potential for excessive buprenorphine-related side effects. The buprenorphine dosage may need to be lowered for patients that receive inhibitors of CYP3A4
    Buspirone: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as buspirone.
    Cabazitaxel: Cabazitaxel is a CYP3A4 substrate, and concomitant use of cabazitaxel with strong CYP3A4 inhibitors such as zafirlukast is expected to increase cabazitaxel concentrations. Concomitant administration of cabazitaxel and strong CYP3A4 inhibitors should be avoided. Consider alternative therapies with low enzyme induction potential.
    Caffeine; Ergotamine: Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Capecitabine: Use caution if coadministration of capecitabine with zafirlukast is necessary, and monitor for an increase in zafirlukast-related adverse reactions. Zafirlukast is a CYP2C9 substrate in vitro; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Carbamazepine: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as carbamazepine.
    Carbinoxamine; Hydrocodone; Phenylephrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Celecoxib: Celecoxib is a substrate of the cytochrome P450 2C9 isoenzyme. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 such as zafirlukast should be done with caution.
    Chlordiazepoxide: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as chlordiazepoxide.
    Chlordiazepoxide; Clidinium: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as chlordiazepoxide.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Cilostazol: Cilostazol is extensively metabolized by the cytochrome P450 CYP3A4 hepatic isoenzyme and metabolism may be inhibited by zafirlukast, an inhibitor of CYP3A4.
    Cinacalcet: Caution is recommended when coadministering cinacalcet with other CYP3A4 enzyme inhibitors, such as zafirlukast.
    Cisapride: Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Zafirlukast may have the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, is essentially considered contraindicated for use with cisapride.
    Clarithromycin: Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
    Clonazepam: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as clonazepam.
    Clopidogrel: Clopidogrel is metabolized by CYP3A isozymes to an active metabolite. As a result, drugs that inhibit CYP3A4, such as zafirlukast, theoretically may decrease the hepatic metabolism of clopidogrel to its active metabolite.
    Clorazepate: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as clorazepate.
    Clozapine: Caution is advisable during concurrent use of zafirlukast and clozapine. Zafirlukast is an inhibitor of CYP3A4 and CYP1A2, two of the isoenzymes responsible for the metabolism of clozapine. 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 or CYP1A2 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: Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate.
    Cobimetinib: If concurrent use of cobimetinib and zafirlukast is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and zafirlukast is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Conivaptan: Coadministration of conivaptan with CYP3A4 inhibitors like zafirlukast could lead to an increase in conivaptan serum concentrations.
    Conjugated Estrogens: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Corticosteroids: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as corticosteroids.
    Crizotinib: Use caution if coadministration of crizotinib with zafirlukast is necessary, due to the risk of increased crizotinib-related adverse reactions. Crizotinib is primarily metabolized by CYP3A4/5. While no formal drug interaction studies have been conducted, zafirlukast is a CYP3A4 inhibitor in vitro. Coadministration of a single dose of crizotinib with a strong CYP3A4 inhibitor increased the crizotinib AUC and Cmax by 3.2-fold and 1.4-fold, respectively; weak CYP3A4 inhibitors may also affect crizotinib exposure. The effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cyclobenzaprine: Theoretically, levels of cyclobenzaprine could rise due to inhibition at the 3A4 enzyme; however, the clinical significance of potential interactions has not been established. Observe the patient for enhanced side effects, such as CNS depression, if cyclobenzaprine and zafirlukast, a CYP3A4 inhibitor, are co-administered.
    Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with zafirlukast, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Zafirlukast is a moderate CYP2C9 inhibitor as well as a weak inhibitor of CYP3A4 in vitro; conversion of cyclophosphamide to its active metabolites may be affected. Information on the effect of CYP2C9 inhibition on cyclophosphamide activation is not available. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Cyclosporine: As cyclosporine is a CYP3A4 substrate, use with a CYP3A4 inhibitor, such as cyclosporine, may result in increased serum concentrations of cyclosporine. Monitor serum cyclosporin concentrations carefully if a CYP3A4 inhibitor is used concomitantly. Conversely, if a CYP3A4 inhibitor is discontinued, cyclosporine concentrations could decrease.
    Darifenacin: Zafirlukast inhibits CYP3A4 and may increase the serum concentration of darifenacin, a CYP3A4 substrate.
    Darunavir: Caution is warranted when darunavir is administered with zafirlukast as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat: Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate. Caution is warranted when darunavir is administered with zafirlukast as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; darunavir is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Concurrent administration of zafirlukast with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2C8; however, in vivo data do not substantiate clinically relevant CYP2C8 inhibition. Ritonavir and paritaprevir are substrates for CYP3A4, and dasabuvir is metabolized by both CYP2C8 and CYP3A4 (minor). Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
    Dasatinib: Dasatinib is metabolized by CYP3A4. Concurrent administration of inhibitors of this isoenzyme, including zafirlukast, may increase concentrations of dasatinib.
    Dextromethorphan; Quinidine: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as quinidine.
    Diazepam: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as diazepam.
    Diclofenac: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as diclofenac.
    Diclofenac; Misoprostol: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as diclofenac.
    Dienogest; Estradiol valerate: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Dihydroergotamine: Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as zafirlukast, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects).
    Diltiazem: Zafirlukast and zileuton are respiratory antiinflammatory agents which can theoretically inhibit CYP3A4 metabolism of calcium-channel blockers, CYP3A4 substrates.
    Diphenhydramine; Hydrocodone; Phenylephrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Diphenhydramine; Ibuprofen: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
    Disopyramide: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of disopyramide.
    Dofetilide: Zafirlukast, a CYP 3A4 inhibitor, may increase plasma dofetilide concentrations with potential for dofetilide toxicity.
    Doxercalciferol: Cytochrome P450 enzyme inhibitors, such as zafirlukast, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Doxorubicin: In vitro, zafirlukast is a CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of zafirlukast and doxorubicin if possible. If not possible, closely monitor increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
    Dronabinol, THC: Use caution if coadministration of dronabinol with zafirlukast 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; zafirlukast is a moderate inhibitor of CYP2C9 and a weak 3A4 inhibitor in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: Dronedarone and zafirlukast should be coadministered with caution. Dronedarone is metabolized by CYP3A. Zafirlukast is an inhibitor of CYP3A4. Concomitant use of dronedarone with zafirlukast may increase dronedarone concentrations.
    Drospirenone; Estradiol: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Dutasteride; Tamsulosin: Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as zafirlukast. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Elbasvir; Grazoprevir: 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.
    Eletriptan: Eletriptan is contraindicated for use within 72 hours of usage of zafirlukast, a potent CYP3A4 inhibitor. Eletriptan is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. The concomitant use of medications that significantly inhibit the CYP3A4 isozyme with eletriptan may result in elevations in eletriptan concentrations.
    Eltrombopag: Eltrombopag is metabolized by CYP2C8. The significance of administering inhibitors of CYP2C8, such as zafirlukast, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Enalapril; Felodipine: Zafirlukast is a CYP3A4 inhibitors which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    Ergonovine: Coadministration of certain ergot alkaloids with inhibitors of CYP3A4, such as ergonovine, may potentially increase the risk of ergot toxicity.
    Ergotamine: Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Erlotinib: Avoid the coadministration of erlotinib with zafirlukast due to the risk of increased erlotinib-related adverse reactions; if concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Zafirlukast is a moderate CYP1A2 inhibitor in vitro and a weak in vitro inhibitor of CYP3A4. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with zafirlukast may also increase erlotinib exposure.
    Erythromycin: Erythromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when erythromycin is added concurrently.
    Erythromycin; Sulfisoxazole: Erythromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when erythromycin is added concurrently.
    Estazolam: Zafirlukast is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Esterified Estrogens: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Levonorgestrel: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norethindrone: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norgestimate: As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estropipate: Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Eszopiclone: Patients should be advised of the potential for next-day psychomotor and/or memory impairment during co-administration of eszopiclone and , CYP3A4 inhibitors, such as zafirlukast. Use of these drugs together may decrease systemic clearance of eszopiclone leading to prolonged effects. If eszopiclone is to be administered concurrently with significant CYP3A4 inhibitors, a decreased dose of eszopiclone may be warranted. Subsequent dosage adjustments should be based on clinical response.
    Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with zafirlukast. In vitro, zafirlukast is a weak inhibitor of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations.
    Ezetimibe; Simvastatin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
    Famotidine; Ibuprofen: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
    Felodipine: Zafirlukast is a CYP3A4 inhibitors which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    Fentanyl: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as fentanyl.
    Fesoterodine: Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. In theory, the CYP3A4 inhibitory effects of zafirlukast may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. The need for fesoterodine doses greater than 4 mg/day should be carefully evaluated prior to increasing the dose during concurrent use of mild to moderate 3A4 inhibitors.
    Flibanserin: The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including zafirlukast, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Flurazepam: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as flurazepam.
    Fluvastatin: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as fluvastatin.
    Food: Because the bioavailability of zafirlukast is substantially decreased when taken with food, take zafirlukast on an empty stomach at least 1 hour before or 2 hours after meals. The incidence of marijuana associated adverse effects may change following coadministration with zafirlukast. Zafirlukast is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with zafirlukast the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosphenytoin: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 especially those drugs with narrow therapeutic ranges. Employ appropriate clinical monitoring. Drugs primarily metabolized by CYP2C9 include phenytoin or fosphenytoin. Dosage reduction of fosphenytoin may be warranted.
    Galantamine: Zafirlukast is a CYP3A4 inhibitor and may increase the serum concentration of galantamine, a CYP3A4 substrate.
    Gefitinib: Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and zafirlukast are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and zafirlukast is a weak CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Glimepiride: Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like zafirlukast. Monitor serum glucose concentrations if glimepiride is coadministered with zafirlukast. Dosage adjustments may be necessary.
    Glimepiride; Pioglitazone: Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like zafirlukast. Monitor serum glucose concentrations if glimepiride is coadministered with zafirlukast. Dosage adjustments may be necessary. It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
    Glimepiride; Rosiglitazone: Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like zafirlukast. Monitor serum glucose concentrations if glimepiride is coadministered with zafirlukast. Dosage adjustments may be necessary. In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as rosiglitazone, especially those drugs with narrow therapeutic ranges.
    Guaifenesin; Hydrocodone: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Halofantrine: Drugs which significantly inhibit cytochrome CYP3A4, such as zafirlukast, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and zafirlukast is warranted, it would be prudent to use caution and monitor the ECG periodically.
    Haloperidol: Zafirlukast is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Homatropine; Hydrocodone: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Hydrochlorothiazide, HCTZ; Losartan: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as losartan.
    Hydrochlorothiazide, HCTZ; Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
    Hydrocodone: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4. Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
    Hydrocodone; Phenylephrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: Monitor for respiratory depression and sedation if hydrocodone and zafirlukast are coadministered; consider dosage adjustments if necessary. Concomitant administration may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects. Hydrocodone is metabolized by CYP3A4. Zafirlukast is a weak inhibitor of CYP3A4.
    Ibrutinib: Avoid the concomitant use of ibrutinib and zafirlukast; significantly increased ibrutinib levels may occur. Consider the use of an alternate agent with less CYP3A4 inhibition. If coadministration cannot be avoided, reduce the ibrutinib dose to 140 mg PO daily and monitor patients for signs and symptoms of ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; zafirlukast is a moderate CYP3A4 inhibitor. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inhibitors may increase the ibrutinib exposure by 5- to 8-fold.
    Ibuprofen: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
    Ibuprofen; Oxycodone: Coadministration of zafirlukast, a CYP3A4 inhibitor, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold. Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
    Ibuprofen; Pseudoephedrine: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
    Irinotecan Liposomal: Use caution if irinotecan liposomal is coadministered with zafirlukast, a weak CYP3A4 inhibitor in vitro, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Isavuconazonium: Concomitant use of isavuconazonium with zafirlukast may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; zafirlukast is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isradipine: Caution should be used when CYP3A4 inhibitors are co-administered with isradipine, a CYP3A4 substrates. This combination may reduce the metabolism and lead to increased effect of isradipine.
    Ivabradine: Use caution during coadministration of ivabradine and zafirlukast as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; zafirlukast is a minor inhibitor of CYP3A, in vitro. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: Use caution when administering ivacaftor and zafirlukast concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and zafirlukast is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP2C9; zafirlukast is metabolized by CYP2C9. Coadministration may increase zafirlukast exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as zafirlukast should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Lapatinib: Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with zafirlukast, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Lesinurad: Use lesinurad and zafirlukast together with caution; zafirlukast may increase the systemic exposure of lesinurad. Zafirlukast is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Levomethadyl: Agents that inhibit hepatic cytochrome P450 3A4, such as zafirlukast, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Lidocaine: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
    Loperamide: The plasma concentration of loperamide, a CYP2C8 and CYP3A4 substrate, may be increased when administered concurrently with zafirlukast, an inhibitor of CYP2C8 and 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: The plasma concentration of loperamide, a CYP2C8 and CYP3A4 substrate, may be increased when administered concurrently with zafirlukast, an inhibitor of CYP2C8 and 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: Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
    Losartan: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as losartan.
    Lovastatin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lovastatin.
    Lovastatin; Niacin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lovastatin.
    Lumacaftor; Ivacaftor: Although the clinical significance of this interaction is unknown, concurrent use of zafirlukast and lumacaftor; ivacaftor may alter zafirlukast exposure; caution and monitoring are advised if these drugs are used together. Zafirlukast is a substrate of CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: Use caution when administering ivacaftor and zafirlukast concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and zafirlukast is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP2C9; zafirlukast is metabolized by CYP2C9. Coadministration may increase zafirlukast exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lurasidone: Zafirlukast is a minor inhibitor of CYP3A4. Because lurasidone is primarily metabolized by CYP3A4, concurrent use of zafirlukast can theoretically lead to an increased risk of lurasidone-related adverse reactions.
    Maraviroc: Use caution if coadministration of maraviroc with zafirlukast is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and zafirlukast is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: Mefloquine is metabolized by CYP3A4. Zafirlukast is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Meloxicam: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as meloxicam.
    Metformin; Pioglitazone: It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
    Metformin; Repaglinide: Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Zafirlukast has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Rosiglitazone: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as rosiglitazone, especially those drugs with narrow therapeutic ranges.
    Metformin; Saxagliptin: Monitor patients for hypoglycemia if saxagliptin and zafirlukast are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as zafirlukast.
    Methadone: The concurrent administration of methadone and inhibitors of cytochrome P450 3A4, such as zafirlukast, may result in increased concentrations of methadone. Inhibition of methadone metabolism can lead to toxicity including CNS adverse effects and potential for QT prolongation and torsades de pointes when high doses of methadone are used
    Methylergonovine: Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Methysergide: The risk of ergot toxicity, such as vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects, is potentially increased by the use of zafirlukast, a CYP3A4 inhibitors.
    Midazolam: Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as zafirlukast, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam.
    Nateglinide: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as nateglinide.
    Nebivolol; Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
    Niacin; Simvastatin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
    Nicardipine: Caution should be used when CYP3A4 inhibitors, such as zafirlukast are co-administered with nicardipine, a CYP3A4 substrate and inhibitor. Zafirlukast may inhibit the metabolism and increase the effect of nicardipine.
    Nifedipine: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate.
    Nilotinib: The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, and zafirlukast, a CYP3A4 inhibitor, may result in increased nilotinib levels. Monitor patients for nilotinib toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Nimodipine: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease hepatic metabolism of nimodipine, a CYP3A4 substrate.
    Nintedanib: Zafirlukast is a moderate inhibitor of CYP3A4 and nintedanib is a CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of zafirlukast and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nisoldipine: Because nisoldipine is metabolized by CYP3A4, zafirlukast, an inhibitor of these enzymes, has the potential to increase the bioavailability of nisoldipine.
    Olaparib: Use caution if coadministration of olaparib with zafirlukast is necessary, due to an increased risk of olaparib-related adverse reactions. Olaparib is a CYP3A4 substrate and zafirlukast is a weak CYP3A4 inhibitor. Simulations have suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2.2-fold and 1.2-fold, respectively, but data are not available with weak CYP3A4 inhibitors.
    Ombitasvir; Paritaprevir; Ritonavir: Concurrent administration of zafirlukast with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2C8; however, in vivo data do not substantiate clinically relevant CYP2C8 inhibition. Ritonavir and paritaprevir are substrates for CYP3A4, and dasabuvir is metabolized by both CYP2C8 and CYP3A4 (minor). Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
    Oritavancin: Zafirlukast is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated zafirlukast plasma concentrations. If these drugs are administered concurrently, monitor patients for zafirlukast toxicity such as headache, nausea, or diarrhea.
    Oxybutynin: Oxybutynin is metabolized by CYP3A4. Inhibitors of the CYP3A4 enzyme, such as zafirlukast, may increase the serum concentrations of oxybutynin. The manufacturer recommends caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Oxycodone: Coadministration of zafirlukast, a CYP3A4 inhibitor, and oxycodone, a CYP3A4 substrate, may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust dosage as necessary; oxycodone dosage adjustments may be needed if the CYP3A4 inhibitor is discontinued. Concurrent administration of oxycodone and voriconazole, another CYP3A4 inhibitor, increased oxycodone AUC by 3.6-fold and the Cmax by 1.7-fold.
    Paclitaxel: Published data indicate zafirlukast inhibits CYP2C8 rather potently. Until further data are available to confirm the absence of drug interactions, CYP2C8 metabolized drugs, such as paclitaxel, may require closer monitoring when used in conjunction with zafirlukast.
    Paricalcitol: Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as zafirlukast. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Pazopanib: Pazopanib is a substrate for CYP3A4 and CYP2C8. Zafirlukast is an inhibitor of CYP3A4 and CYP2C8. Concurrent administration may result in increased pazopanib concentrations. Dose reduction of pazopanib may be necessary when coadministration of pazopanib and zafirlukast is required.
    Perindopril; Amlodipine: Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
    Phenytoin: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as phenytoin.
    Pimozide: Concurrent use of pimozide and zafirlukast should be avoided. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Zafirlukast is an inhibitor of CYP3A4 and CYP1A2. Elevated pimozide concentrations occurring through inhibition of CYP3A4, CYP2D6, and/or CYP1A2 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pioglitazone: It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
    Pirfenidone: Discontinue zafirlukast prior to beginning pirfenidone because it significantly increases exposure to pirfenidone. Zafirlukast is a moderate inhibitor of CYP1A2 and CYP2C9. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
    Piroxicam: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as piroxicam.
    Propafenone: In vitro data indicate that zafirlukast inhibits CYP3A4 at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, especially those drugs, like propafenone, with narrow therapeutic ranges.
    Quazepam: Zafirlukast is a CYP3A4 inhibitor and may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Quetiapine: Zafirlukast may inhibit the CYP3A4-mediated metabolism of quetiapine, leading to increased serum concentrations of quetiapine. The manufacturer of quetiapine recommends a reduced dosage during concurrent administration of CYP3A4 inhibitors.
    Quinidine: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as quinidine.
    Ramelteon: Coadministration of ramelteon with inhibitors of CYP3A4, such as zafirlukast, may lead to increases in the serum concentrations of ramelteon.
    Ranolazine: Coadministration of ranolazine with CYP3A4 inhibitors like zafirlukast could lead to an increase in ranolazine serum concentrations, with potential to result in QTc prolongation and torsade de pointes.
    Repaglinide: Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Zafirlukast has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Ribociclib: Use caution if coadministration of ribociclib with zafirlukast is necessary, as the systemic exposure of ribociclib may be increased resulting in an increase in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4. Zafirlukast is a weak CYP3A4 inhibitor in vitro.
    Ribociclib; Letrozole: Use caution if coadministration of ribociclib with zafirlukast is necessary, as the systemic exposure of ribociclib may be increased resulting in an increase in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4. Zafirlukast is a weak CYP3A4 inhibitor in vitro.
    Rilpivirine: Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Riociguat: It is possible that an increase in the exposure of riociguat may occur when coadministered with drugs that inhibit CYP2C8 such as zafirlukast. Although in vivo data has not substantiated clinically relavent interactions with CYP2C8 substrates, patients should be monitored for hypotension if zafirlukast is coadministered with riociguat.
    Ritonavir: Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: Coadministration of rivaroxaban and zafirlukast may result in increases in rivaroxaban exposure and may increase bleeding risk. Zafirlukast is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Rofecoxib: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as rofecoxib.
    Romidepsin: Romidepsin is a substrate for CYP3A4. Zafirlukast is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Rosiglitazone: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as rosiglitazone, especially those drugs with narrow therapeutic ranges.
    Ruxolitinib: Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as zafirlukast, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Sacubitril; Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
    Saquinavir: The concurrent use of saquinavir boosted with ritonavir and zafirlukast should be used cautiously due to the potential for life threatening arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and zafirlukast are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. The use of saquinavir/ritonavir with zafirlukast may result in increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
    Saxagliptin: Monitor patients for hypoglycemia if saxagliptin and zafirlukast are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as zafirlukast.
    Sildenafil: Sildenafil is metabolized principally by the hepatic cytochrome P450 CYP 3A4 and 2C9 isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Silodosin: Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as zafirlukast may cause significant increases in silodosin plasma concentrations.
    Simeprevir: Use caution with concurrent use of simeprevir and zafirlukast. Zafirlukast is a minor inhibitor of CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
    Simvastatin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
    Simvastatin; Sitagliptin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
    Sofosbuvir; Velpatasvir: Use caution when administering velpatasvir with zafirlukast. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP3A4 substrate; zafirlukast is an inhibitor of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: Use caution when administering velpatasvir with zafirlukast. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP3A4 substrate; zafirlukast is an inhibitor of CYP3A4.
    Solifenacin: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as solifenacin.
    Sunitinib: Concurrent administration of sunitinib with inhibitors of cytochrome P450 3A4 such as zafirlukast results in increased concentrations of sunitinib and its primary active metabolite. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. If an alternative therapy is not available, monitor patients closely for increased adverse reactions to sunitinib; a reduction in the dose of sunitinib may be required.
    Suvorexant: Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Zafirlukast is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Tadalafil: Tadalafil is metabolized predominantly by the hepatic CYP3A4 isoenzyme. Inhibitors of CYP3A4, such as tadalafil, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Tamoxifen: Zafirlukast is a CYP2C9 inhibitor and, in vitro, an inhibitor of CYP3A4. Tamoxifen by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Zafirlukast may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Tamsulosin: Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as zafirlukast. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Telaprevir: Close clinical monitoring is advised when administering zafirlukast with telaprevir due to an increased potential for telaprevir-related adverse events. If zafirlukast dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of zafirlukast and telaprevir. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; telaprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of telaprevir may be elevated.
    Telithromycin: Concentrations of telithromycin may be increased with concomitant use of zafirlukast. Telithromycin is a substrate of CYP3A4 and zafirlukast is a CYP3A4 inhibitor.
    Temsirolimus: Use caution if coadministration of temsirolimus with zafirlukast is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a CYP3A4 substrate and zafirlukast is a weak CYP3A4 inhibitor in vitro; coadministration may increase plasma concentrations of sirolimus, the active metabolite of temsirolimus. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of weak inhibitors.
    Terbinafine: Due to the risk for terbinafine related adverse effects, caution is advised when coadministering zafirlukast. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2, CYP2C8, CYP2C9, and CYP3A4; zafirlukast is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Theophylline, Aminophylline: Increased theophylline levels with clinical signs and symptoms of toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. Monitor for signs and symptoms of toxicity, as well as serum aminophylline levels, when zafirlukast is used in combination with aminophylline. Increased theophylline levels with clinical signs and symptoms of toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. Monitor for signs and symptoms of toxicity, as well as serum theophylline levels, when zafirlukast is used in combination with theophylline.
    Tolbutamide: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as tolbutamide.
    Tolterodine: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as tolterodine.
    Tolvaptan: Tolvaptan is metabolized by CYP3A4. Zafirlukast is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Toremifene: Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes. Zafirlukast inhibits this isoenzyme and may decrease the metabolism of toremifen.
    Trabectedin: Use caution if coadministration of trabectedin and zafirlukast is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, zafirlukast is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Trandolapril; Verapamil: Caution should be used when CYP3A4 inhibitors are co-administered with verapamil, a CYP3A4 substrate and inhibitor. This combination may cause reduced metabolism and increased effect of verapamil.
    Treprostinil: Although pharmacokinetic drug interaction studies have not been conducted, coadministration of treprostinil and zafirlukast, a potent cytochrome P450 (CYP) 2C8 enzyme inhibitor, may result in increased treprostinil exposure. Human pharmacokinetic studies with oral treprostinil indicate that coadministration of gemfibrozil, another CYP2C8 inhibitor, results in increased exposure to treprostinil. The manufacturer of oral treprostinil recommends a reduction in the starting dose of oral treprostinil when coadministered with gemfibrozil. The clinical significance of this interaction with orally inhaled or parenteral treprostinil and other CYP2C8 inhibitors is unknown.
    Triazolam: CYP3A4 inhibitors, such as zafirlukast, may reduce the metabolism of triazolam and increase the potential for benzodiazepine toxicity.
    Ulipristal: Ulipristal is a substrate of CYP3A4 and zafirlukast is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Valdecoxib: Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as valdecoxib.
    Valsartan: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
    Vardenafil: Vardenafil is metabolized by CYP3A4. Inhibitors of CYP3A4, such as zafirlukast, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
    Vemurafenib: Concomitant use of vemurafenib and zafirlukast may result in increased concentrations of zafirlukast and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP2C9. Zafirlukast is an inhibitor of CYP3A4 and a substrate of CYP2C9. Use caution and monitor patients for toxicity.
    Verapamil: Caution should be used when CYP3A4 inhibitors are co-administered with verapamil, a CYP3A4 substrate and inhibitor. This combination may cause reduced metabolism and increased effect of verapamil.
    Vilazodone: Zafirlukast is a minor inhibitor of CYP3A4. Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, concurrent use of zafirlukast can theoretically lead to an increased risk of vilazodone-related adverse reactions. However, no dosage adjustment is recommended when vilazodone is co-administered with mild CYP3A4 inhibitors.
    Vinblastine: Zafirlukast is an inhibitor of cytochrome P450 isoenzyme 3A4. Vinblastine is a CYP3A4 substrate. Increased concentrations of vinblastine are likely if it is coadministered with zafirlukast; exercise caution.
    Vincristine Liposomal: Zafirlukast inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: Zafirlukast inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vorapaxar: Use caution during concurrent use of vorapaxar and zafirlukast. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with zafirlukast, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4 and CYP2C9, such as voriconazole.
    Warfarin: In a small study of 16 healthy male volunteers, zafirlukast increased the elimination half-life of S-warfarin by 36% and prolonged the prothrombin time by 35%. The S-isomer is the more potent of the 2 warfarin isomers and this isomer is metabolized by CYP2C9. Prothrombin times and INR should be carefully monitored in patients on warfarin therapy; the anticoagulant dosage should be adjusted as indicated by these tests and the patient's clinical status.
    Zonisamide: Zonisamide is metabolized by hepatic cytochrome P450 isoenzyme 3A4. Zafirlukast is an inhibitor of this enzyme and may decrease the clearance of zonisamide.

    PREGNANCY AND LACTATION

    Pregnancy

    Zafirlukast is classified in FDA pregnancy category B. No teratogenic effects were seen in cynomolgus monkeys at doses roughly 120 times the maximum recommended human daily dosage based on comparative drug AUCs. Higher dosages (roughly 410 times the maximum recommended human daily dosage) have resulted in maternal and/or fetal toxicity in this species. A no-effect dosage has not been established. There are no adequate or controlled trials in pregnant women. Safe use during human pregnancy has not been established. Nevertheless, the National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group lists leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy and lactation. Because animal studies are not always indicative of human response, use during pregnancy only if clearly needed. A risk-benefit assessment should be performed. The American College of Allergy, Asthma and Immunology initiated the Registry for Allergic, Asthmatic Pregnant Patients (RAAPP) in 1999 to begin to gather data from which safety of asthma medications in pregnancy can be evaluated.

    According to the manufacturer, zafirlukast is excreted into breast milk at concentrations equal to roughly 20% of maternal plasma levels. The manufacturer recommends against breast-feeding while on this medication. Nevertheless, the National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group lists leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy and lactation. Consider the benefits of breast-feeding, the risk of potential 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, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Zafirlukast is a potent, selective, and long-acting leukotriene receptor antagonist that exhibits antiinflammatory properties and mild bronchodilator effects. Zafirlukast selectively inhibits the binding of leukotriene types D4 (LTD4), and E4 (LTE4) and is 1000 to 10,000-fold more selective for leukotriene receptors (CysLT) than for alpha-receptors, beta-receptors, histamine receptors, or others. Leukotrienes are a group of arachidonic acid derivatives, created via the 5-lipoxygenase pathway, with the potential to mediate inflammatory events in asthma or other inflammatory diseases. The binding of cysteinyl leukotrienes to CysLT has been associated with asthma pathophysiology, including increased endothelial membrane permeability leading to airway edema, smooth muscle contraction, and enhanced secretion of thick, viscous mucus. When leukotriene receptors are blocked, there is a decrease in vascular leak and edema, mucus secretion, eosinophil chemotaxis and bronchial hyperresponsiveness. Blockage of the LTD4 receptors, in particular, results in bronchial relaxation. As monotherapy, zafirlukast appears to exhibit similar anti-inflammatory activity to cromolyn or nedocromil, but less than that of inhaled corticosteroids. The time to onset of zafirlukast-induced bronchodilator response is longer than that of beta-agonists and it is also less pronounced.In humans, zafirlukast inhibits inflammation and also inhibits bronchoconstriction mediated by various inhalational challenges, including: aspirin; cold-air; allergens like cat dander, ragweed and grass or mixed antigen exposures; sulfur dioxide; and exercise. In patients with asthma, the clinical outcomes (improvements in FEV1 or control of symptoms) resulting from the use of zafirlukast may exhibit large inter-patient variability.

    PHARMACOKINETICS

    Zafirlukast is administered orally and has also been studied as an inhalation. Systemically, protein-binding is > 99%. It is distributed to tissues to some degree; animal studies (rat) have demonstrated minimal distribution across the blood-brain-barrier. Zafirlukast is extensively metabolized; the hydroxylated metabolites are formed through the hepatic cytochrome P450 CYP2C9 isoenzyme. Hepatic impairment is expected to result in drug accumulation. Hydroxylated metabolites are excreted in the feces. Urinary excretion accounts for 10% of a dose, but the parent drug is not detected in the urine. The mean terminal elimination half-life in both normal controls and asthma patients is approximately 10 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C8, CYP2C9, CYP3A4
    The significance of zafirlukast-mediated effects on cytochrome P450 isoenzymes is unclear. Zafirlukast has been shown in vitro to inhibit the activity of several hepatic cytochrome isoenzymes including CYP2C8 (potent inhibitor), CYP2C9 (moderate to potent inhibitor), and CYP3A4 (minor inhibitor) ; however, in vivo data do not substantiate clinically relevant interactions with 2C8 substrates. Pharmacokinetic alterations are reported when zafirlukast and known 2C9 and 3A4 substrates are used in combination. Furthermore, while in vitro and in vivo trial data are lacking, isolated reports of CYP1A2-metabolized medication toxicity following zafirlukast initiation have been published ; the mechanism of interaction is unknown. According to the manufacturer, zafirlukast is a substrate of the isoenzyme 2C9 in vitro. It should be used cautiously in patients stabilized on drugs metabolized by CYP1A2, CYP2C8, CYP2C9, and CYP3A4, particularly when such drugs have narrow therapeutic ranges, and in patients on medications that may affect CYP2C9 function.

    Oral Route

    Peak plasma concentrations of zafirlukast are observed within 3 hours after oral dosing. The absolute bioavailability of zafirlukast is unknown. Food reduces the bioavailability of zafirlukast by roughly 40% so it should be taken either 1 hour before or 2 hours after meals. In the treatment of asthma, the peak onset of action may be noted as soon as 1 day of therapy, and usually within 2 weeks. Pharmacodynamic studies showed protective effects of zafirlukast on inhaled LTD-4 for 12—24 hours after dosing.