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    Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors

    BOXED WARNING

    Immunosuppression, infection, lymphoma, new primary malignancy, requires a specialized care setting, requires an experienced clinician, sunlight (UV) exposure

    Immunosuppression from sirolimus may lead to an increased susceptibility to infection and possible development of new primary malignancy, especially lymphoma. Instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a broad-spectrum sunscreen with a high protection factor, as patients are at increased risk for skin cancer. Use of sirolimus requires an experienced clinician, specifically only clinicians experienced in immunosuppressive therapy and management of renal transplant patients. Further, sirolimus use requires a specialized care setting that is equipped and staffed with adequate laboratory and supportive medical services. Lastly, the clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.[28610]

    Liver transplant, lung transplant

    Sirolimus is not recommended for liver transplant and lung transplant recipients; safety and efficacy of sirolimus as immunosuppressive therapy have not been established for liver or lung transplant patients. In de novo lung transplant patients, bronchial anastomotic dehiscence, including fatal cases, has been reported in patients treated with sirolimus in combination with tacrolimus and corticosteroids. In a study of de novo liver transplant recipients, use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss. Many of these patients had evidence of infection at or near the time of death. In two multicenter, randomized controlled studies in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis; most cases occurred within 30 days of transplantation and most led to graft loss or death. Further, in a study, more stable liver transplant patients converted from a calcineurin inhibitor (CNI) to sirolimus died as compared with patients who remain on CNI-based therapy. Also, more patients converted to sirolimus had adverse events (infections, specifically), biopsy-proven acute liver graft rejection at 12 months, and premature study discontinuation primarily due to adverse events or lack of efficacy as compared with those who continued on a CNI.

    DEA CLASS

    Rx

    DESCRIPTION

    Immunosuppressant; analog of tacrolimus
    Indicated for prophylaxis of organ rejection in renal transplant patients and for lymphangioleiomyomatosis
    Acts synergistically with other immunosuppressants with little overlapping toxicity; may reduce the incidence of chronic rejection

    COMMON BRAND NAMES

    Rapamune

    HOW SUPPLIED

    Rapamune/Sirolimus Oral Sol: 1mg, 1mL
    Rapamune/Sirolimus Oral Tab: 0.5mg, 1mg, 2mg

    DOSAGE & INDICATIONS

    For kidney transplant rejection prophylaxis.
    NOTE: Rapamune oral solution 2 mg has been demonstrated to be clinically equivalent to 2 mg Rapamune oral tablets and hence, are interchangeable on a mg-to-mg basis. However, it is not known if higher doses of Rapamune oral solution are clinically equivalent to higher doses of tablets on a mg-to-mg basis.
    NOTE: According to guidelines, initial calcineurin inhibitor-free therapy (e.g., use of a mammalian target of rapamycin inhibitor (m-TOR) like sirolimus with mycophenolate and steroids) is not sufficient to effectively prevent acute rejection. The safety and efficacy of de novo use of sirolimus without cyclosporine are not established in renal transplant patients. In a multi-center clinical study, de novo renal transplant patients were treated with sirolimus or cyclosporine in combination with mycophenolate (MMF), steroids, and an IL-2 receptor antagonist; patients treated with sirolimus had a significantly higher acute rejection rate and a numerically higher death rate compared to patients treated with cyclosporine. Patients treated with sirolimus versus cyclosporine did not experience improved renal function.
    NOTE: Guidelines state that a mammalian target of rapamycin inhibitor (m-TOR) like sirolimus can safely replace a calcineurin inhibitor beyond the early post-transplant period, but conversion is not advisable for patients with proteinuria higher than 800 mg/day. Further, follow a cautious and individual approach for patients with a CrCl less than 30 mL/minute. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in the maintenance renal transplant population have not been established. In a study to evaluate the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target concentrations of 12 to 20 ng/mL, chromatographic assay), enrollment was stopped for patients with a baseline glomerular filtration rate less than 40 mL/min because of a higher rate of serious adverse events including pneumonia, acute rejection, graft loss, and death in this sirolimus treatment arm. Among patients with a baseline glomerular filtration rate of more than 40 mL/min, no benefit in regard to an improvement in renal function and a greater incidence of proteinuria were noted among patients who were switched to sirolimus. Also, a 5-fold increase in the reports of tuberculosis was noted among patients who were switched to sirolimus.
    In combination with cyclosporine and corticosteroids in patients who are considered low to moderate immunologic risk.
    Oral dosage
    Adults and Adolescents who weigh >= 40 kg and without a history of an acute allograft rejection episode or the presence of chronic allograft nephropathy on a renal biopsy

    A loading dose of 6 mg PO administered as soon as possible following transplantation, and then a maintenance dose of 2 mg PO once daily. Although a loading dose of 15 mg PO and a maintenance dose of 5 mg PO were used during clinical trials, no improvement of efficacy for the 5 mg dose could be established for renal transplant patients. Patients receiving 2 mg PO daily dose demonstrated an overall better safety profile than did those patients receiving 5 mg PO daily. In patients at low to moderate immunological risk, cyclosporine should be progressively withdrawn over 4 to 8 weeks beginning 2 to 4 months following transplantation. The sirolimus dose should be titrated to obtain a whole blood trough concentration of 16 to 24 ng/mL (chromatographic method) for the first year after transplantation; a target concentration of 12 to 20 ng/mL (chromatographic method) is recommended after year 1. The safety and efficacy of withdrawing cyclosporine therapy in high-risk patients (e.g., Banff grade III acute rejection, vascular rejection before cyclosporine withdrawal, dialysis dependency, black patients, SCr greater than 4.5 mg/dL, re-transplants, multi-organ transplants, or patients with a high panel of reactive antibodies) receiving sirolimus has not been established and is not recommended. Use of cyclosporine beyond 4 months should only be considered if the benefits outweigh the risks. According to renal transplant guidelines, use of sirolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine dose is advised. Guidelines recommend that sirolimus not be started until graft function is established and surgical wounds are healed.

    Adolescents who weigh < 40 kg and without a history of an acute allograft rejection episode or the presence of chronic allograft nephropathy on a renal biopsy

    A loading dose of 3 mg/m2 PO as soon as possible following the transplantation and then maintenance dose of 1 mg/m2 PO once daily. According to renal transplant guidelines, use of sirolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine dose is advised. Guidelines recommend that sirolimus not be started until graft function is established and surgical wounds are healed.

    Following cyclosporine withdrawal in patients who are considered low to moderate immunological risk.
    NOTE: The safety and efficacy of withdrawing cyclosporine therapy in high-risk patients receiving sirolimus have not been established. High-risk patients include patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis dependent or with a creatinine higher than 4.5 mg/dL, black patients, re-transplants, multi-organ transplant recipients, and patients with a high panel of reactive antibodies.
    Oral dosage
    Adults and Adolescents

    At 2 to 4 months following transplantation, cyclosporine should be gradually tapered off over 4 to 8 weeks and the sirolimus dose should be adjusted to obtain whole blood trough concentrations within the range of 16 to 24 ng/mL (chromatographic method) for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL (chromatographic method). In most patients, dosage adjustment can be based on the following equation: new sirolimus maintenance dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough concentrations: sirolimus loading dose = 3 x (new maintenance dose - current maintenance dose). Patients should receive the new dosage regimen of sirolimus for at least 7 to 14 days before further dosage adjustment. The maximum sirolimus daily dosage should not exceed 40 mg PO. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s). The sirolimus dose will need to be approximately 4-fold higher to account for the absence of the pharmacokinetic interaction and the augmented immunosuppression requirement in the absence of cyclosporine. Clinical signs/symptoms, tissue biopsy, and laboratory parameters should be used in addition to therapeutic drug monitoring when adjusting sirolimus dosage.

    In combination with cyclosporine and corticosteroids in patients who are considered high immunologic risk.
    NOTE: The safety and efficacy of sirolimus in combination with a calcineurin inhibitor and corticosteroids have not been established in patients younger than 18 years of age with a history of an acute allograft rejection episode or the presence of chronic allograft nephropathy on a renal biopsy.
    NOTE: Black transplant recipients, repeat renal transplant recipients who lost a previous allograft for immunologic reason, or patients with high-panel reactive antibodies (PRA; peak PRA level greater than 80%) are considered high immunologic risk.
    NOTE: Sirolimus is indicated for use in combination with cyclosporine and corticosteroids for the first year after transplantation. Safety and efficacy have not been established beyond 1 year. After 1 year, adjust the immunosuppression regimen as needed based on the patient's clinical status.
    NOTE: Most (88.4%) patients also received antibody induction therapy.
    NOTE: The protocol-specified target Cmin range for sirolimus was 10 to 15 ng/mL (chromatographic method) and for cyclosporine was 200 to 300 ng/mL up to week 2, 150 to 200 ng/mL for weeks 2 to 26, and 100 to 150 ng/mL for weeks 26 to 52.
    Oral dosage
    Adults

    A loading dose of up to 15 mg PO administered on day 1 after transplantation, and then a maintenance dose of 5 mg PO once daily beginning on day 2. Obtain a sirolimus trough concentration between days 5 and 7, and adjust the daily dose as needed. The starting dose of cyclosporine should be up to 7 mg/kg/day PO in divided doses; adjust the cyclosporine dose to achieve target whole blood trough concentrations. A minimum dose of 5 mg PO daily of prednisone is also needed, and antibody induction therapy may be used. According to renal transplant guidelines, use of sirolimus in combination with cyclosporine is effective in preventing rejection but is associated with enhanced nephrotoxicity and inferior outcomes, so significant reduction in the cyclosporine dose is advised. Guidelines recommend that sirolimus not be started until graft function is established and surgical wounds are healed.

    For the treatment of lymphangioleiomyomatosis.
    Oral dosage
    Adults

    The recommended starting dose is 2 mg PO once daily. Measure trough concentration 10 to 20 days after initiation. Adjust dose using proportions [new dose = current dose x (target concentration/current concentration)] to a goal concentration between 5 to 15 ng/mL. Wait 1 to 2 weeks before further dose adjustment, which is guided by concentration monitoring. Monitor concentrations at least every 3 months after a stable dose is achieved.

    For the management of heart transplant rejection prophylaxis†.
    Oral dosage
    Adults

    10 mg PO load then 3 mg/day PO adjusted to trough of 8 to 18 ng/mL by HPLC. In a study, less acute rejection greater than or equal to 3A at month 6 was noted among recipients of sirolimus (32.4%, p = 0.027) as compared with recipients of azathioprine 3 mg/kg PO/IV load then 1 to 2.5 mg/kg/day (56.8%). All patients received dose-adjusted cyclosporine to target trough concentrations and oral prednisolone 1 mg/kg/day reduced to 0.1 mg/kg/day by month 6. Guidelines state that sirolimus or mycophenolate, as tolerated, should be included in contemporary immunosuppressive regimens because of a reduced onset and progression of cardiac allograft vasculopathy as assessed by intravascular ultrasound. Also, substitution of a calcineurin inhibitor (CNI) such as cyclosporine or tacrolimus with sirolimus may be done later than 6 months after transplantation to reduce CNI-related nephrotoxicity and cardiac allograft vasculopathy in low-risk recipients. Also, sirolimus substitution for a CNI may be beneficial for patients who continue to have seizures after CNI dosage reduction. Substitution of sirolimus for mycophenolate mofetil (MMF) for the specific purpose of lowering CNI exposure to reduce CNI-related nephrotoxicity is NOT recommended because of the interaction between sirolimus and the CNI, which enhances nephrotoxicity. Substitution of sirolimus for MMF earlier than 3 months after transplantation is also NOT recommended because of a higher risk of rejection and delayed wound healing.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO.

    Geriatric

    40 mg/day PO.

    Adolescents

    40 mg/day PO.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In patients with mild or moderate hepatic impairment, the maintenance dose of sirolimus should be reduced by approximately one-third. In patients with severe hepatic impairment, the maintenance dose of sirolimus should be reduced by approximately one-half. The loading dose does not require dosage adjustment in a patient with mild, moderate, or severe hepatic impairment. It is also recommended that sirolimus trough blood concentrations be monitored.

    Renal Impairment

    It is not necessary to modify the sirolimus loading or maintenance doses. No dosage adjustments are necessary in patients with renal impairment.
     
    Intermittent hemodialysis
    Based on poor aqueous solubility and high erythrocyte and plasma protein binding, it is anticipated that sirolimus is not dialyzable to any significant extent.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    Administer sirolimus dosage at approximately the same time each day. To minimize variations in bioavailability, administer consistently with or without food.
    To diminish the possibility of an interaction with cyclosporine, administer 4 hours after cyclosporine oral solution (modified) or oral capsules (modified).
    Do not administer concurrently with grapefruit juice.

    Oral Solid Formulations

    Do not crush, chew, or split sirolimus tablets.

    Oral Liquid Formulations

    Sirolimus in bottles may develop a slight haze when refrigerated. If this occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of a haze does not affect the quality of the product.
    Upon first use of a bottle, insert the adapter assembly (plastic tube with stopper) into the bottle until it is even with the top of the bottle. Do not remove the adapter assembly from the bottle once it has been inserted. Always keep the bottle in an upright position.
    For each use, insert one of the amber oral dosage syringes with the plunger fully depressed into the opening in the adapter.
    Use the amber oral dosage syringe to withdraw the prescribed amount of solution from the bottle by gently pulling out the plunger of the syringe.
    Once the dose is placed in the oral syringe, snap the cap into place.
    If the dose is to be taken at a later time, place the capped syringe into the carrying case provided with the sirolimus bottle. Follow the storage instructions.
    Empty the correct amount from the oral syringe into a glass or plastic container holding at least 2 ounces (60 mL) of water or orange juice. Do not dilute in any other juice, especially not grapefruit juice. Use only plastic or glass containers. Sirolimus oral solution contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). Stir vigorously for 1 minute and have the patient drink at once.
    Refill the container with an additional 4 ounces (120 mL) of water or orange juice, stir vigorously, and drink at once.
    Discard the oral syringe after use.
    If the solution comes into direct contact with the skin or mucous membranes, thoroughly wash the exposed area with soap and water. If eyes are exposed, rinse them with plain water.
    If the solution is spilled, dry the area with a dry paper towel and then wipe the area with a wet paper towel. Throw the paper towels in the garbage and thoroughly wash hands with soap and water.
    Storage: Bottles should be protected from light and refrigerated at 2 to 8 degrees C (36 to 46 degrees F). Once the bottle is open, the contents should be used within 1 month. Bottles may be stored at room temperature, if necessary, for a short period of time (e.g., not more 15 days). Sirolimus oral solution may be stored in an amber oral syringe (with the cap in place) for up to 24 hours at a room temperature up to 25 degrees C (77 degrees F) or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F); the carrying case provided with solution bottle should be used for storage. Any sirolimus solution that is diluted with water or orange juice should be used immediately.[28610]

    STORAGE

    Rapamune:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Sirolimus is contraindicated for use by patients with a hypersensitivity to sirolimus. Hypersensitivity reactions have been associated with sirolimus administration (see Adverse Reactions).

    Immunosuppression, infection, lymphoma, new primary malignancy, requires a specialized care setting, requires an experienced clinician, sunlight (UV) exposure

    Immunosuppression from sirolimus may lead to an increased susceptibility to infection and possible development of new primary malignancy, especially lymphoma. Instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a broad-spectrum sunscreen with a high protection factor, as patients are at increased risk for skin cancer. Use of sirolimus requires an experienced clinician, specifically only clinicians experienced in immunosuppressive therapy and management of renal transplant patients. Further, sirolimus use requires a specialized care setting that is equipped and staffed with adequate laboratory and supportive medical services. Lastly, the clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.[28610]

    Cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Sirolimus may worsen pre-existing hypercholesterolemia and hypertriglyceridemia. The long-term impact of sirolimus on cardiovascular mortality is unknown. Also, adverse effects from sirolimus may include atrial fibrillation, congestive heart failure, hypervolemia, and palpitations. Therefore, the risk versus benefit should be carefully considered in patients with established hyperlipidemia or cardiac disease such as coronary artery disease, cardiac arrhythmias, and heart failure before initiating sirolimus therapy, especially in renal transplant patients who have a higher prevalence of clinically significant hyperlipidemia. All patients receiving sirolimus should be monitored for sirolimus-induced hypercholesterolemia and hypertriglyceridemia. If hyperlipidemia is detected, patients should be treated with appropriate therapy and monitored for adverse effect development if treated with an HMG-CoA reductase inhibitor and/or fibrate. In clinical trials of patients who received sirolimus and cyclosporine or sirolimus after cyclosporine withdrawal, the concomitant administration of sirolimus and HMG-CoA reductase inhibitors led to adverse reactions such as CPK elevations, myalgia, and rhabdomyolysis.

    Soya lecithin hypersensitivity

    Sirolimus (Rapamune) oral solution contains soy fatty acids. Patients with soya lecithin hypersensitivity are at increased risk of an allergic reaction if given the oral solution formulation.

    Accidental exposure, ocular exposure

    Sirolimus is not absorbed through the skin and there are no special precautions regarding handling. However, if accidental exposure occurs with direct contact with skin or mucous membranes, wash the area thoroughly with soap and water. Following ocular exposure, rinse eyes with water.

    Hepatic disease

    Patients with hepatic disease require dosage adjustments of sirolimus (see Dosage and Pharmacokinetics). Monitoring of sirolimus trough concentrations is recommended for all patients, especially in patients who are likely to have altered drug metabolism such as patients with any degree of hepatic impairment or patients taking strong inhibitors or inducers of cytochrome P450 isoenzyme 3A4 (see Drug Interactions).

    Black patients, dialysis, proteinuria, renal failure, renal impairment

    Sirolimus use may delay recovery of renal function in patients with delayed graft function, and patients with proteinuria may have a worsening of the condition with sirolimus initiation (see Adverse Reactions). The sirolimus dose does not need to be adjusted for renal dysfunction; however, such patients do require close clinical monitoring. In phase III trials, mean serum creatinine was increased and mean glomerular filtration rate was decreased in patients treated with sirolimus and cyclosporine as compared to those treated with cyclosporine and placebo or azathioprine controls. Renal function should be monitored during the administration of maintenance immunosuppression regimens including sirolimus and cyclosporine, and appropriate adjustment of the regimen should be considered, including discontinuation of sirolimus and/or cyclosporine, in patients who develop renal impairment as evidenced by elevated or increasing serum creatinine concentrations. In patients at low to moderate immunological risk continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patient. The safety and efficacy of withdrawing cyclosporine therapy in high-risk patients receiving sirolimus have not been established. High-risk patients include patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis dependent (i.e., continued chronic renal failure) or with a creatinine > 4.5 mg/dl, black patients, re-transplants, multi-organ transplant recipients, and patients with a high panel of reactive antibodies. Caution should be exercised when administering sirolimus-containing maintenance regimens in combination with other agents known to impair renal function.

    Pregnancy

    Sirolimus can cause fetal harm when administered during human pregnancy. Advise pregnant women of the potential fetal risk and instruct them to use highly effective contraception before, during, and for 12 weeks after sirolimus therapy. There are limited data in pregnant women. Sirolimus crosses the placenta and is toxic to the conceptus. It is also embryo/fetotoxic in rats at subtherapeutic doses.[28610] A panel of experts from the 2002 European Best Practice Guidelines for Renal Transplant considered sirolimus contraindicated during pregnancy. In 2010, the National Transplantation Pregnancy Registry (NTPR) reported exposure of 12 pregnant kidney transplant recipients to sirolimus. Among 13 pregnancies, 3 spontaneous abortions occurred. One infant was born with cleft lip, cleft palate, and microtia (with concomitant exposure to mycophenolate). Another infant was born with tetralogy of Fallot. Two pregnancies in heart transplant recipients resulted in 1 spontaneous abortion and 1 live birth with facial abnormalities (exposure to sirolimus, cyclosporine, and mycophenolate at conception). Among 3 pregnancies in liver transplant recipients, 1 spontaneous abortion and 2 live births were reported. One spontaneous abortion was reported in a pancreas-kidney transplant recipient.[49381] [62810]

    Breast-feeding

    Use of sirolimus during breast-feeding was advised against by a panel of experts in the 2002 European Best Practice Guidelines for Renal Transplant.[49381] It is not known whether sirolimus is present in human milk. There are no data on the effects of sirolimus on the breast-fed infant or milk production. There is the potential for serious adverse effects from sirolimus in breast-fed infants based on mechanism of action. Consider the development and health benefits of breast-feeding along with the mother's clinical need for sirolimus and any potential adverse effects on the breast-fed child.[28610]

    Children, infants, neonates

    The safety and efficacy of sirolimus for organ rejection prophylaxis in neonates, infants, and children < 13 years have not been established. Also, the safety and efficacy of sirolimus in combination with a calcineurin inhibitor and corticosteroids have not been established in patients < 18 years of age with a history of an acute allograft rejection episode or the presence of chronic allograft nephropathy on a renal biopsy (high immunologic risk). As compared with patients at high immunologic risk who received calcineurin-inhibitor-based immunosuppressive therapy, a similar percentage of patients who received sirolimus with a calcineurin inhibitor and corticosteroids had a first occurrence of biopsy confirmed acute rejection, graft loss, or death (cumulative incidence of efficacy failure up to 36 months of 44% and 45.3%, respectively). All patients were 3—18 years old, received a renal transplant, and had a target sirolimus concentration of 5—15 ng/ml. In addition to an absence of benefit in regard to acute rejection, graft survival, or patient survival, patients who received sirolimus with a calcineurin inhibitor and corticosteroids had an increased risk of renal function deterioration, serum lipid abnormalities, and urinary tract infections. Monitoring of sirolimus trough concentrations is recommended for all patients, especially in patients who are likely to have altered drug metabolism such as patients at least 13 years of age who weigh less than 40 kg. The safety and efficacy of sirolimus for the treatment of lymphangioleiomyomatosis have not been established in the pediatric population.

    Vaccination

    Immunosuppressants may affect response to vaccination; therefore, vaccination may be less effective during sirolimus treatment. Avoid the use of live vaccines (e.g., MMR, oral polio, BCG, yellow fever, varicella, TY21a typhoid) during treatment with sirolimus.

    Surgery, wound dehiscence

     In vitro, sirolimus inhibits the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Impaired or delayed wound healing, lymphocele, and wound dehiscence have been reported in sirolimus recipients (see Adverse Reactions). Cautious use of sirolimus in patients with a wound or with impending surgery may be warranted.

    Liver transplant, lung transplant

    Sirolimus is not recommended for liver transplant and lung transplant recipients; safety and efficacy of sirolimus as immunosuppressive therapy have not been established for liver or lung transplant patients. In de novo lung transplant patients, bronchial anastomotic dehiscence, including fatal cases, has been reported in patients treated with sirolimus in combination with tacrolimus and corticosteroids. In a study of de novo liver transplant recipients, use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss. Many of these patients had evidence of infection at or near the time of death. In two multicenter, randomized controlled studies in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis; most cases occurred within 30 days of transplantation and most led to graft loss or death. Further, in a study, more stable liver transplant patients converted from a calcineurin inhibitor (CNI) to sirolimus died as compared with patients who remain on CNI-based therapy. Also, more patients converted to sirolimus had adverse events (infections, specifically), biopsy-proven acute liver graft rejection at 12 months, and premature study discontinuation primarily due to adverse events or lack of efficacy as compared with those who continued on a CNI.

    Diabetes mellitus

    Patients should be monitored closely for new onset diabetes mellitus or hyperglycemia. Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during sirolimus treatment. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents.

    Contraception requirements, infertility, reproductive risk

    Sirolimus may cause fetal harm when administered to a pregnant woman. Advise women of childbearing potential of the reproductive risk associated with fetal exposure to sirolimus during pregnancy. Discuss contraception requirements. Initiate highly effective contraception before, during, and for 12 weeks after sirolimus therapy. Female and male infertility may occur. Ovarian cysts and menstrual disorders (e.g., amenorrhea, menorrhagia) have been reported in females during the use of sirolimus. Azoospermia or oligospermia may be observed in males; sirolimus is an antiproliferative drug and affects rapidly dividing germ cells.[28610]

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 3.0-19.9
    thromboembolism / Delayed / 3.0-19.9
    pulmonary embolism / Delayed / 3.0-19.9
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 3.0-19.9
    hemolytic-uremic syndrome / Delayed / 3.0-19.9
    post-transplant lymphoproliferative disorder (PTLD) / Delayed / 1.0-10.0
    pancreatitis / Delayed / 0-3.0
    pleural effusion / Delayed / Incidence not known
    cardiac tamponade / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    proteinuria / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    wound dehiscence / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 45.0-57.0
    hypertension / Early / 45.0-49.0
    constipation / Delayed / 36.0-38.0
    anemia / Delayed / 23.0-33.0
    thrombocytopenia / Delayed / 14.0-30.0
    edema / Delayed / 18.0-20.0
    sinus tachycardia / Rapid / 3.0-19.9
    leukopenia / Delayed / 3.0-19.9
    impaired wound healing / Delayed / 3.0-19.9
    lymphocele / Delayed / 3.0-19.9
    hypokalemia / Delayed / 3.0-19.9
    diabetes mellitus / Delayed / 3.0-19.0
    chest pain (unspecified) / Early / 20.0
    peripheral edema / Delayed / 20.0
    hyperlipidemia / Delayed / 10.0
    hypercholesterolemia / Delayed / 20.0
    oral ulceration / Delayed / 10.0
    stomatitis / Delayed / 20.0
    cystitis / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    BK virus-associated nephropathy / Delayed / Incidence not known
    immunosuppression / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    dyspnea / Early / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    ascites / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known

    Mild

    fever / Early / 23.0-34.0
    infection / Delayed / 0-33.0
    arthralgia / Delayed / 25.0-31.0
    rash / Early / 10.0-20.0
    epistaxis / Delayed / 3.0-19.9
    amenorrhea / Delayed / 3.0-19.9
    menorrhagia / Delayed / 3.0-19.9
    pharyngitis / Delayed / 20.0
    abdominal pain / Early / 20.0
    nausea / Early / 20.0
    diarrhea / Early / 20.0
    myalgia / Early / 20.0
    headache / Early / 20.0
    dizziness / Early / 20.0
    alopecia / Delayed / 10.0
    xerosis / Delayed / 10.0
    pruritus / Rapid / 10.0
    onycholysis / Delayed / 10.0
    folliculitis / Delayed / 10.0
    acne vulgaris / Delayed / 20.0
    acneiform rash / Delayed / 10.0
    hypertrichosis / Delayed / 10.0
    gingivitis / Delayed / 10.0
    fatigue / Early / Incidence not known
    cough / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abrocitinib: (Major) Avoid coadministration of sirolimus with abrocitinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and abrocitinib is a P-gp inhibitor.
    Aliskiren; Amlodipine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Alpelisib: (Major) Avoid coadministration of alpelisib with sirolimus due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sirolimus is a BCRP inhibitor.
    Amiodarone: (Major) Avoid coadministration of sirolimus with amiodarone as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of another moderate CYP3A and P-gp inhibitor increased sirolimus overall exposure by 4.2-fold.
    Amlodipine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Amlodipine; Atorvastatin: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor. (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
    Amlodipine; Benazepril: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Amlodipine; Celecoxib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Amlodipine; Olmesartan: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Amlodipine; Valsartan: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Amobarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of sirolimus with clarithromycin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Amprenavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Angiotensin-converting enzyme inhibitors: (Moderate) Sirolimus has been associated with the development of angioedema. The use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme inhibitors may increase the risk of developing angioedema. Patients should be monitored for angioedema if any of these drugs are coadministered with sirolimus.
    Apalutamide: (Major) Avoid concomitant use of sirolimus and apalutamide due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and apalutamide is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inhibitor decreased sirolimus overall exposure by 82%.
    Aprepitant, Fosaprepitant: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with aprepitant/fosaprepitant is necessary. The dose of sirolimus may also need to be reduced with coadministration of aprepitant/fosaprepitant. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of aprepitant/fosaprepitant. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; aprepitant/fosaprepitant is a moderate CYP3A inhibitor.
    Armodafinil: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of armodafinil; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; armodafinil is a weak CYP3A inducer.
    Asciminib: (Major) Avoid coadministration of sirolimus with asciminib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and asciminib is a weak CYP3A and P-gp inhibitor.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Aspirin, ASA; Pravastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with sirolimus.
    Atazanavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of sirolimus with cobicistat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
    Atorvastatin; Ezetimibe: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
    Avacopan: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with avacopan is necessary. The dose of sirolimus may also need to be reduced with coadministration of avacopan. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of avacopan. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; avacopan is a weak CYP3A inhibitor.
    Azathioprine: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression.
    Barbiturates: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Basiliximab: (Minor) Because sirolimus is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Belumosudil: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with belumosudil is necessary. The dose of sirolimus may also need to be reduced with coadministration of belumosudil. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of belumosudil. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; belumosudil is a weak CYP3A inhibitor.
    Belzutifan: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of belzutifan; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; belzutifan is a weak CYP3A inducer.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking sirolimus. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor sirolimus whole blood trough concentrations as appropriate and watch for sirolimus-related adverse reactions as concurrent use may increase the exposure of sirolimus; the dose of sirolimus may need to be reduced. Berotralstat is a BCRP substrate and P-gp and moderate CYP3A4 inhibitor; sirolimus is a sensitive CYP3A4 and P-gp substrate and BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
    Bexarotene: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of bexarotene; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; bexarotene is a moderate CYP3A inducer.
    Bicalutamide: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with bicalutamide is necessary. The dose of sirolimus may also need to be reduced with coadministration of bicalutamide. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of bicalutamide. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; bicalutamide is a weak CYP3A inhibitor.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Although an interaction between metronidazole and sirolimus has not been studied, metronidazole has been reported to interact with tacrolimus. Specifically, a renal transplant patient reportedly had an increase in tacrolimus and cyclosporine serum concentrations when metronidazole was added to the drug regimen. A similar interaction may potentially occur with sirolimus.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Although an interaction between metronidazole and sirolimus has not been studied, metronidazole has been reported to interact with tacrolimus. Specifically, a renal transplant patient reportedly had an increase in tacrolimus and cyclosporine serum concentrations when metronidazole was added to the drug regimen. A similar interaction may potentially occur with sirolimus.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as sirolimus. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Major) Plasma concentrations of sirolimus are significantly increased when administered in combination with boceprevir. If these drugs are used together, closely monitor sirolimus concentrations and make dose reductions as required. If sirolimus dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Closely monitor the patients renal function and for sirolimus-related side effects.. Predictions about the interaction can be made based on the metabolic pathway of sirolimus. Sirolimus is a substrate of the hepatic isoenzyme CYP3A4 and the drug efflux transporter P-glycoprotein (P-gp); boceprevir inhibits both the isoenzyme and the drug efflux protein.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes including sirolimus.
    Brigatinib: (Moderate) Monitor sirolimus whole blood trough concentrations as appropriate and watch for sirolimus-related adverse reactions or changes in efficacy if coadministration with brigatinib is necessary. The dose of sirolimus may need to be changed. Sirolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate with a narrow therapeutic range. Brigatinib is a P-gp inhibitor and a weak CYP3A4 inducer.
    Butabarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Butalbital; Acetaminophen: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Butalbital; Acetaminophen; Caffeine: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Cabozantinib: (Major) Avoid coadministration of sirolimus with cabozantinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and cabozantinib is a P-gp inhibitor.
    Canakinumab: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Cannabidiol: (Major) Avoid coadministration of sirolimus with cannabidiol as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and cannabidiol is a P-gp inhibitor.
    Capmatinib: (Major) Avoid coadministration of sirolimus with capmatinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Carbamazepine: (Major) Avoid concomitant use of sirolimus and carbamazepine due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and carbamazepine is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inhibitor decreased sirolimus overall exposure by 82%.
    Carboplatin: (Minor) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Carvedilol: (Major) Avoid coadministration of sirolimus with carvedilol as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and carvedilol is a P-gp inhibitor.
    Caspofungin: (Major) Sirolimus concentrations may be reduced approximately 25% in those patients receiving concurrent caspofungin. The mechanism of this interaction has not been identified but has been reported with tacrolimus; monitor sirolimus blood concentrations and adjust sirolimus dosage as required.
    Cenobamate: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of cenobamate; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cenobamate is a moderate CYP3A4 inducer.
    Ceritinib: (Major) Avoid coadministration of sirolimus with ceritinib if possible due to increased plasma concentrations of sirolimus resulting in treatment-related adverse reactions. Sirolimus is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chlorambucil: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Chloramphenicol: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as chloramphenicol. Chloramphenicol may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cimetidine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with cimetidine is necessary. The dose of sirolimus may also need to be reduced with coadministration of cimetidine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of cimetidine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; cimetidine is a weak CYP3A inhibitor.
    Ciprofloxacin: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with ciprofloxacin is necessary. The dose of sirolimus may also need to be reduced with coadministration of ciprofloxacin. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of ciprofloxacin. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; ciprofloxacin is a moderate CYP3A inhibitor.
    Cisapride: (Major) Increased sirolimus whole blood concentrations may be observed if gastrointestinal (GI) prokinetic agents like metoclopramide or cisapride are added to therapy. Limited data indicate these agents may increase the mean bioavailability of oral sirolimus. The mechanism is thought to involve an increased rate of oral sirolimus absorption in the small bowel secondary to alterations in gut transit times. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4 and P-glycoprotein. Monitor sirolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
    Clarithromycin: (Major) Avoid coadministration of sirolimus with clarithromycin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Clobazam: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of clobazam; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; clobazam is a weak CYP3A inducer.
    Clofazimine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with clofazimine is necessary. The dose of sirolimus may also need to be reduced with coadministration of clofazimine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of clofazimine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; clofazimine is a weak CYP3A inhibitor.
    Cobicistat: (Major) Avoid coadministration of sirolimus with cobicistat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Cocaine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with cocaine is necessary. The dose of sirolimus may also need to be reduced with coadministration of cocaine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of cocaine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; cocaine is a weak CYP3A inhibitor.
    Conivaptan: (Major) Avoid coadministration of sirolimus with conivaptan as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. Concomitant use of another moderate CYP3A and P-gp inhibitor increased sirolimus overall exposure by 4.2-fold.
    Crizotinib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with crizotinib is necessary. The dose of sirolimus may also need to be reduced with coadministration of crizotinib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of crizotinib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Major) Administer sirolimus 4 hours after oral cyclosporine due to an increase in sirolimus concentrations when coadministered with cyclosporine. Use therapeutic drug monitoring to maintain sirolimus target concentrations, and monitor renal function closely during coadministration. If cyclosporine is discontinued, higher doses of sirolimus are necessary to maintain the target sirolimus trough concentration. Long-term administration of the combination has been associated with deterioration of renal function. Sirolimus is a substrate for CYP3A4 and P-gp, and cyclosporine is an inhibitor of CYP3A4 and P-gp. Simultaneous administration of sirolimus 10 mg and cyclosporine 300 mg increased sirolimus Cmax and AUC by 116% to 512% and 148% to 230%, respectively; Cmax and AUC increased by 33% to 37% and 33% to 80% when sirolimus was given 4 hours after cyclosporine.
    Dabrafenib: (Major) The concomitant use of dabrafenib and sirolimus may lead to decreased sirolimus concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor sirolimus levels and for loss of sirolimus efficacy; adjust the sirolimus dose as necessary. Dabrafenib is a moderate CYP3A4 inducer and sirolimus is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Daclatasvir: (Major) Avoid coadministration of sirolimus with daclatasvir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and daclatasvir is a P-gp inhibitor.
    Daclizumab: (Moderate) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. In a randomized trial of daclizumab for the prevention of allograft rejection in cardiac transplant patients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving daclizumab compared to those receiving placebo (7% vs. 5%, respectively, at 6 months; 10% vs. 6%, respectively, at 12 months). Some, but not all of the increased mortality appeared to be related to a higher incidence of severe infections. Concomitant use of antilymphocyte antibody therapy may also be a factor in some of the fatal infections. In renal allograft recipients treated with daclizumab and mycophenolate mofetil, no pharmacokinetic interaction between daclizumab and mycophenolic acid (the active metabolite of mycophenolate mofetil) was observed. Very limited experience exists with the use of daclizumab concomitantly with antithymocyte globulin, antilymphocyte globulin, muromonab-CD3, or tacrolimus.
    Dalfopristin; Quinupristin: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with quinupristin is necessary. The dose of sirolimus may also need to be reduced with coadministration of quinupristin. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of quinupristin. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; quinupristin is a weak CYP3A inhibitor.
    Danazol: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with danazol is necessary. The dose of sirolimus may also need to be reduced with coadministration of danazol. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of danazol. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; danazol is a moderate CYP3A inhibitor.
    Darunavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Darunavir; Cobicistat: (Major) Avoid coadministration of sirolimus with cobicistat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of sirolimus with cobicistat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Daunorubicin: (Minor) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Deferasirox: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of deferasirox; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; deferasirox is a weak CYP3A inducer.
    Delavirdine: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as delavirdine. Delavirdine may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Dexamethasone: (Major) Dexamethasone is an inducer of CYP3A4. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver. Concurrent use of sirolimus with dexamethasone may decrease patient exposure to sirolimus. Consider alternative steroid therapy. Use sirolimus and dexamethasone with caution, if at all, and monitor patients closely.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of sirolimus with quinidine as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and quinidine is a P-gp inhibitor.
    Diltiazem: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with diltiazem is necessary. The dose of sirolimus may also need to be reduced with coadministration of diltiazem. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of diltiazem. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; diltiazem is a moderate CYP3A inhibitor. Overall sirolimus exposure was increased 1.6-fold when coadministered with diltiazem.
    Doxorubicin Liposomal: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Doxorubicin: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Dronedarone: (Major) Avoid coadministration of sirolimus with dronedarone as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and dronedarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of another moderate CYP3A and P-gp inhibitor increased sirolimus overall exposure by 4.2-fold.
    Duvelisib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with duvelisib is necessary. The dose of sirolimus may also need to be reduced with coadministration of duvelisib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of duvelisib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; duvelisib is a moderate CYP3A inhibitor.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like sirolimus. Although documentation is lacking, use of echinacea with immunosuppressants is not recommended by some resources. Furthermore, sirolimus is metabolized by CYP3A4 in the liver and there are some data suggesting Echinacea affects CYP3A4 and this may lead to altered sirolimus exposure. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; the clinical significance is not yet known. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. While the overall effect on CYP3A4 substrates is not known, it may be prudent to monitor sirolimus blood concentrations if combined use is necessary.
    Efavirenz: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as sirolimus. Monitoring of serum sirolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as sirolimus. Monitoring of serum sirolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as sirolimus. Monitoring of serum sirolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Elagolix: (Moderate) Monitor for reduced therapeutic response to sirolimus if coadministered with elagolix; the dosage of sirolimus may need to be adjusted during concurrent use. Coadministration may lead to decreased sirolimus concentrations and loss of efficacy. Sirolimus is a sensitive CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for reduced therapeutic response to sirolimus if coadministered with elagolix; the dosage of sirolimus may need to be adjusted during concurrent use. Coadministration may lead to decreased sirolimus concentrations and loss of efficacy. Sirolimus is a sensitive CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with grazoprevir is necessary. The dose of sirolimus may also need to be reduced with coadministration of grazoprevir. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of grazoprevir. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; grazoprevir is a weak CYP3A inhibitor.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Avoid coadministration of sirolimus with ivacaftor as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor. (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of sirolimus. Appropriate monitoring should be used; adjust sirolimus dosage as necessary. Sirolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp.
    Eliglustat: (Major) Avoid coadministration of sirolimus with eliglustat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and eliglustat is a P-gp inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of sirolimus with cobicistat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of sirolimus with cobicistat as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Emapalumab: (Moderate) Monitor for decreased efficacy of sirolimus and adjust the dose as needed during coadministration with emapalumab. Sirolimus is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
    Enasidenib: (Major) Avoid coadministration of sirolimus with enasidenib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor.
    Encorafenib: (Moderate) Coadministration of encorafenib with sirolimus may result in increased toxicity or decreased efficacy of sirolimus. sirolimus is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enzalutamide: (Major) Avoid coadministration of sirolimus with enzalutamide due to decreased plasma concentrations of sirolimus. Sirolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Erdafitinib: (Major) Avoid coadministration of sirolimus with erdafitinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and erdafitinib is a P-gp inhibitor.
    Erythromycin: (Major) Avoid coadministration of sirolimus with erythromycin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and erythromycin is a moderate CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 4.2-fold .
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of sirolimus with erythromycin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and erythromycin is a moderate CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 4.2-fold .
    Eslicarbazepine: (Moderate) Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Agents that induce CYP3A4, such as eslicarbazepine, may affect absorption and elimination of sirolimus leading to decreased blood concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 needs to be used concomitantly.
    Etravirine: (Major) Coadministration with etravirine may result in altered sirolimus concentrations. Coadminister these drugs with caution, carefully monitoring sirolimus concentrations and making dosage adjustments as needed.
    Ezetimibe; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Fedratinib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with fedratinib is necessary. The dose of sirolimus may also need to be reduced with coadministration of fedratinib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of fedratinib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; fedratinib is a moderate CYP3A inhibitor.
    Flibanserin: (Major) Avoid coadministration of sirolimus with flibanserin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and flibanserin is a P-gp inhibitor.
    Fluconazole: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with fluconazole is necessary. The dose of sirolimus may also need to be reduced with coadministration of fluconazole. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of fluconazole. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; fluconazole is a moderate CYP3A inhibitor.
    Fluoxetine: (Moderate) Agents that inhibit CYP3A4 and/or P-glycoprotein, such as fluoxetine, may affect absorption and elimination of sirolimus leading to increased blood concentrations. Monitor sirolimus serum concentrations carefully if an inhibitor of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Fluvastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and fluvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of fluvastatin to 40 mg/day if combined with sirolimus.
    Fluvoxamine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with fluvoxamine is necessary. The dose of sirolimus may also need to be reduced with coadministration of fluvoxamine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of fluvoxamine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; fluvoxamine is a moderate CYP3A inhibitor.
    Food: (Major) Food may affect the exposure to sirolimus. As compared with the fasted state, administration of sirolimus oral solution with a high-fat meal decreased the peak blood concentration of sirolimus by 34%, increased the Tmax 3.5-fold, and increased the AUC by 35%. As compared with the fasted state, administration of sirolimus tablets with a high-fat meal increased the peak blood concentration of sirolimus by 65%, increased the Tmax by 32%, and increased the AUC by 23%. To minimize variability, sirolimus should be taken consistently with or without food.
    Fosamprenavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Fosphenytoin: (Major) Avoid concomitant use of sirolimus and fosphenytoin due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inhibitor decreased sirolimus overall exposure by 82%.
    Fostamatinib: (Major) Avoid coadministration of sirolimus with fostamatinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and fostamatinib is a weak CYP3A and P-gp inhibitor.
    Gilteritinib: (Major) Avoid coadministration of sirolimus with gilteritinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Glecaprevir; Pibrentasvir: (Major) Avoid coadministration of sirolimus with glecaprevir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and glecaprevir is a P-gp inhibitor. (Major) Avoid coadministration of sirolimus with pibrentasvir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and pibrentasvir is a P-gp inhibitor.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and sirolimus may result in decreased exposure of sirolimus. Sirolimus is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of sirolimus during coadministration.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during sirolimus treatment due to the risk of increased sirolimus exposure and adverse reactions. Sirolimus is a CYP3A and P-gp substrate and grapefruit juice is a strong CYP3A and P-gp inhibitor.
    Ibrutinib: (Major) Avoid coadministration of sirolimus with ibrutinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and ibrutinib is a P-gp inhibitor.
    Idelalisib: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as idelalisib. Idelalisib may affect absorption and elimination of sirolimus leading to increased blood concentrations. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Imatinib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with imatinib is necessary. The dose of sirolimus may also need to be reduced with coadministration of imatinib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of imatinib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; imatinib is a moderate CYP3A inhibitor.
    Indinavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Infliximab: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
    Isavuconazonium: (Major) Avoid coadministration of sirolimus with isavuconazonium as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and isavuconazonium is a moderate CYP3A and P-gp inhibitor. Concomitant use of another moderate CYP3A and P-gp inhibitor increased sirolimus overall exposure by 4.2-fold.
    Isoniazid, INH: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with isoniazid is necessary. The dose of sirolimus may also need to be reduced with coadministration of isoniazid. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of isoniazid. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; isoniazid is a weak CYP3A inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of sirolimus and rifampin due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and rifampin is a strong CYP3A and P-gp inducer. Concomitant use decreased sirolimus overall exposure by 82%. (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with isoniazid is necessary. The dose of sirolimus may also need to be reduced with coadministration of isoniazid. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of isoniazid. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; isoniazid is a weak CYP3A inhibitor.
    Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of sirolimus and rifampin due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and rifampin is a strong CYP3A and P-gp inducer. Concomitant use decreased sirolimus overall exposure by 82%. (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with isoniazid is necessary. The dose of sirolimus may also need to be reduced with coadministration of isoniazid. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of isoniazid. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; isoniazid is a weak CYP3A inhibitor.
    Istradefylline: (Major) Avoid coadministration of sirolimus with istradefylline as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and istradefylline is a weak CYP3A and P-gp inhibitor.
    Itraconazole: (Major) Avoid coadministration of sirolimus with itraconazole as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and itraconazole is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Ivacaftor: (Major) Avoid coadministration of sirolimus with ivacaftor as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of ivosidenib; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased sirolimus concentrations.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Sirolimus is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in sirolimus concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Major) Avoid coadministration of sirolimus with ketoconazole as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 10.9-fold.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of sirolimus with clarithromycin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Lapatinib: (Major) Avoid coadministration of sirolimus with lapatinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and lapatinib is a weak CYP3A and P-gp inhibitor.
    Larotrectinib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with larotrectinib is necessary. The dose of sirolimus may also need to be reduced with coadministration of larotrectinib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of larotrectinib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; larotrectinib is a weak CYP3A inhibitor.
    Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of sirolimus with ledipasvir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and ledipasvir is a P-gp inhibitor.
    Lefamulin: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with lefamulin is necessary. The dose of sirolimus may also need to be reduced with coadministration of lefamulin. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of lefamulin. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; lefamulin is a moderate CYP3A inhibitor.
    Lesinurad: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of lesinurad; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of lesinurad; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) Frequently monitor sirolimus whole blood concentrations during concurrent treatment and after discontinuation of letermovir, and adjust the sirolimus dose accordingly; sirolimus exposure may be increased. The magnitude of this interaction is expected to be greater if the patient is also receiving cyclosporine. In these patients, follow sirolimus dosing recommendations for coadministration with cyclosporine and utilize therapeutic drug monitoring to maintain sirolimus drug concentrations within therapeutic range. Concurrent use of letermovir increased the AUC and Cmax of sirolimus by 3.4-fold and 2.76-fold, respectively. Sirolimus is a sensitive substrate of CYP3A4. Both letermovir and cyclosporine are CYP3A4 inhibitors, and their combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levamlodipine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Levoketoconazole: (Major) Avoid coadministration of sirolimus with ketoconazole as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 10.9-fold.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lomitapide: (Major) Avoid coadministration of sirolimus with lomitapide as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and lomitapide is a P-gp inhibitor.
    Lonafarnib: (Major) Avoid coadministration of sirolimus with lonafarnib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and lonafarnib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Lopinavir; Ritonavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Lorlatinib: (Major) Avoid concomitant use of sirolimus and lorlatinib due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and lorlatinib is a moderate CYP3A and P-gp inducer.
    Lovastatin: (Major) Guidelines recommend avoiding coadministration of lovastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Lovastatin; Niacin: (Major) Guidelines recommend avoiding coadministration of lovastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of sirolimus with ivacaftor as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of sirolimus and lumacaftor; ivacaftor due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and lumacaftor; ivacaftor is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inhibitor decreased sirolimus overall exposure by 82%.
    Maribavir: (Major) Avoid coadministration of sirolimus with maribavir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and maribavir is a P-gp inhibitor.
    Melphalan Flufenamide: (Minor) Because sirolimus is an immunosuppressant, additive affects may be seen with antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Melphalan: (Minor) Because sirolimus is an immunosuppressant, additive affects may be seen with antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Mephobarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Methohexital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Metoclopramide: (Major) Increased sirolimus whole blood concentrations may be observed if gastrointestinal prokinetic agents like metoclopramide are added to therapy. Monitor sirolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
    Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving sirolimus, drug concentration monitoring should be performed and the sirolimus dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as sirolimus.
    Metronidazole: (Moderate) Although an interaction between metronidazole and sirolimus has not been studied, metronidazole has been reported to interact with tacrolimus. Specifically, a renal transplant patient reportedly had an increase in tacrolimus and cyclosporine serum concentrations when metronidazole was added to the drug regimen. A similar interaction may potentially occur with sirolimus.
    Micafungin: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as sirolimus concomitantly with micafungin may have additive risks for infection or other side effects. A pharmacokinetic interaction has been reported, but the mechanism of the interaction is not known, as micafungin does not interfere with CYP450 enzymes and does not inhibit P-glycoprotein (P-gp). During pharmacokinetic study in healthy volunteers, the AUC of sirolimus increased by 21% when coadministered with micafungin. Monitor patients receiving both drugs for possible sirolimus toxicity, and adjust the dose as necessary.
    Mifepristone: (Contraindicated) Coadministration of sirolimus is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome. Mifepristone, a CYP3A4 inhibitor, is likely to increase sirolimus concentrations and adverse effects, since sirolimus is a CYP3A4 substrate with a narrow therapeutic index. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Mitapivat: (Major) Avoid coadministration of sirolimus with mitapivat as concurrent use may increase sirolimus exposure and risk of toxicity or decrease sirolimus exposure leading to loss of efficacy. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp and sensitive CYP3A substrate with a narrow therapeutic range and mitapivat is a P-gp inhibitor and weak CYP3A4 inducer.
    Mitotane: (Major) Concomitant use of sirolimus and mitotane should be avoided. Mitotane may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4, and mitotane is a potent CYP3A4 inducer.
    Mobocertinib: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of mobocertinib; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; mobocertinib is a weak CYP3A inducer.
    Modafinil: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of modafinil; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; modafinil is a weak CYP3A inducer.
    Mycophenolate: (Minor) Because mycophenolate mofetil is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. Of note, tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase (UDPGT). As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated (see Mechanism of Action).
    Nafcillin: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of nafcillin; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; nafcillin is a moderate CYP3A inducer.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with sirolimus.
    Nefazodone: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as nefazodone. Nefazodone may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Nelfinavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Neratinib: (Major) Avoid coadministration of sirolimus with neratinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and neratinib is a P-gp inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with netupitant is necessary. The dose of sirolimus may also need to be reduced with coadministration of netupitant. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of netupitant. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; netupitant is a moderate CYP3A inhibitor.
    Nevirapine: (Major) Monitor sirolimus serum concentrations carefully if administered with nevirapine. Nevirapine is an inducer of the CYP3A; sirolimus is extensively metabolized by this enzyme. Concomitant administration may result in decreased sirolimus blood concentrations.
    Niacin; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Nicardipine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with nicardipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of nicardipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of nicardipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; nicardipine is a weak CYP3A inhibitor.
    Nilotinib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with nilotinib is necessary. The dose of sirolimus may also need to be reduced with coadministration of nilotinib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of nilotinib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; nilotinib is a moderate CYP3A inhibitor.
    Nirmatrelvir; Ritonavir: (Major) Avoid concurrent use of ritonavir-boosted nirmatrelvir and sirolimus. Consider use of an alternative COVID-19 therapy. Coadministration may increase sirolimus exposure resulting in increased toxicity. Sirolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Octreotide: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with octreotide is necessary. The dose of sirolimus may also need to be reduced with coadministration of octreotide. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of octreotide. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; octreotide is a moderate CYP3A inhibitor.
    Odevixibat: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of odevixibat; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; odevixibat is a weak CYP3A inducer.
    Olanzapine; Fluoxetine: (Moderate) Agents that inhibit CYP3A4 and/or P-glycoprotein, such as fluoxetine, may affect absorption and elimination of sirolimus leading to increased blood concentrations. Monitor sirolimus serum concentrations carefully if an inhibitor of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with sirolimus is contraindicated due to the potential for severe immunosuppressant-associated adverse events. When administered concurrently with ombitasvir; paritaprevir; ritonavir, the maximum plasma concentration (peak), minimum plasma concentration (trough), and systemic exposure of sirolimus are significantly increased.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of rifabutin; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rifabutin is a moderate CYP3A inducer.
    Oritavancin: (Moderate) Sirolimus is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of sirolimus may be reduced if these drugs are administered concurrently. Use sirolimus and oritavancin with caution, and monitor patients closely. Concurrent use of sirolimus with strong inducers of CYP3A4 is not recommended; however, oritavancin is a weak inducer of CYP3A4. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Osilodrostat: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with osilodrostat is necessary. The dose of sirolimus may also need to be reduced with coadministration of osilodrostat. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of osilodrostat. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; osilodrostat is a weak CYP3A inhibitor.
    Osimertinib: (Major) Avoid coadministration of sirolimus with osimertinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and osimertinib is a P-gp inhibitor.
    Oxcarbazepine: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of oxcarbazepine; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; oxcarbazepine is a weak CYP3A inducer.
    Pacritinib: (Major) Avoid coadministration of sirolimus with pacritinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and pacritinib is a weak CYP3A and P-gp inhibitor.
    Palbociclib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with palbociclib is necessary. The dose of sirolimus may also need to be reduced with coadministration of palbociclib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of palbociclib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; palbociclib is a weak CYP3A inhibitor.
    Pazopanib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with pazopanib is necessary. The dose of sirolimus may also need to be reduced with coadministration of pazopanib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of pazopanib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; pazopanib is a weak CYP3A inhibitor.
    Pentobarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Perindopril; Amlodipine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Pexidartinib: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of pexidartinib; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; pexidartinib is a moderate CYP3A4 inducer.
    Phenobarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Phentermine; Topiramate: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of topiramate; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; topiramate is a weak CYP3A inducer.
    Phenytoin: (Major) Avoid concomitant use of sirolimus and phenytoin due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and phenytoin is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inhibitor decreased sirolimus overall exposure by 82%.
    Pitavastatin: (Major) Guidelines recommend avoiding coadministration of pitavastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Pitolisant: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of pitolisant; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; pitolisant is a weak CYP3A inducer.
    Posaconazole: (Contraindicated) Coadministration of posaconazole and sirolimus is contraindicated as posaconazole significantly inhibits the CYP3A4 metabolism of sirolimus. In one study, posaconazole 400 mg PO twice daily for 16 days in combination with a single oral 2 mg sirolimus dose resulted in significant increases in the sirolimus Cmax (572% increase) and AUC (788% increase).
    Pravastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with sirolimus.
    Primidone: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Protease inhibitors: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Quinidine: (Major) Avoid coadministration of sirolimus with quinidine as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and quinidine is a P-gp inhibitor.
    Quinine: (Major) Avoid coadministration of sirolimus with quinine as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and quinine is a weak CYP3A and P-gp inhibitor.
    Ranolazine: (Major) Avoid coadministration of sirolimus with ranolazine as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ranolazine is a weak CYP3A and P-gp inhibitor.
    Ribociclib: (Major) Avoid coadministration of sirolimus with ribociclib if possible due to increased plasma concentrations of sirolimus resulting in treatment-related adverse reactions. Sirolimus is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Major) Avoid coadministration of sirolimus with ribociclib if possible due to increased plasma concentrations of sirolimus resulting in treatment-related adverse reactions. Sirolimus is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Rifabutin: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of rifabutin; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rifabutin is a moderate CYP3A inducer.
    Rifampin: (Major) Avoid concomitant use of sirolimus and rifampin due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and rifampin is a strong CYP3A and P-gp inducer. Concomitant use decreased sirolimus overall exposure by 82%.
    Rifapentine: (Major) Avoid coadministration of sirolimus with rifapentine as concurrent use may decrease the sirolimus exposure and efficacy. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rifapentine is a strong CYP3A inducer.
    Ritonavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Rolapitant: (Major) Avoid coadministration of sirolimus with rolapitant as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and rolapitant is a P-gp inhibitor.
    Rucaparib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with rucaparib is necessary. The dose of sirolimus may also need to be reduced with coadministration of rucaparib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of rucaparib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rucaparib is a weak CYP3A inhibitor.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sirolimus, may occur during concurrent use with rufinamide.
    Saquinavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Sarecycline: (Major) Avoid coadministration of sirolimus with sarecycline as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and sarecycline is a P-gp inhibitor.
    Sarilumab: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with sarilumab is necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking sirolimus, monitor sirolimus concentrations; sirolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as sirolimus. These interactions remain theoretical. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4.
    Selpercatinib: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with selpercatinib is necessary. The dose of sirolimus may also need to be reduced with coadministration of selpercatinib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of selpercatinib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; selpercatinib is a weak CYP3A inhibitor.
    Siltuximab: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Simeprevir: (Moderate) Caution is advised when administering simeprevir with sirolimus, as concurrent use may result in altered sirolimus plasma concentrations. Although no dose adjustments are recommended, routine monitoring of sirolimus plasma concentrations is advised.
    Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Simvastatin; Sitagliptin: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sirolimus with velpatasvir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and velpatasvir is a P-gp inhibitor.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sirolimus with velpatasvir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and velpatasvir is a P-gp inhibitor. (Major) Avoid coadministration of sirolimus with voxilaprevir as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and voxilaprevir is a P-gp inhibitor.
    Sorafenib: (Major) Avoid coadministration of sirolimus with sorafenib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and sorafenib is a P-gp inhibitor.
    Sotorasib: (Moderate) Monitor for loss of efficacy of sirolimus or increased toxicity during coadministration of sotorasib; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 and P-gp substrate with a narrow therapeutic range; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
    Spironolactone: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with spironolactone is necessary. The dose of sirolimus may also need to be reduced with coadministration of spironolactone. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of spironolactone. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with spironolactone is necessary. The dose of sirolimus may also need to be reduced with coadministration of spironolactone. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of spironolactone. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of sirolimus and St. John's Wort due to the risk of decreased sirolimus exposure which may reduce its efficacy. Sirolimus is a CYP3A and P-gp substrate and St. John's Wort is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inhibitor decreased sirolimus overall exposure by 82%.
    Streptogramins: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with quinupristin is necessary. The dose of sirolimus may also need to be reduced with coadministration of quinupristin. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of quinupristin. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; quinupristin is a weak CYP3A inhibitor.
    Tacrolimus: (Moderate) The concomitant use of sirolimus with a calcineurin inhibitor, such as tacrolimus, may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. In addition to a potential increased risk of thrombotic microangiopathy, sirolimus may decrease the blood concentration of tacrolimus.
    Talazoparib: (Major) Avoid coadministration of sirolimus with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and sirolimus is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Tazemetostat: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of tazemetostat; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; tazemetostat is a weak CYP3A4 inducer.
    Teduglutide: (Moderate) Teduglutide may increase absorption of sirolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of sirolimus is recommended.
    Telaprevir: (Major) Close monitoring of sirolimus serum concentrations and frequent assessments of renal function are advised when coadministering sirolimus with telaprevir. Plasma concentrations of sirolimus may be increased if administered in combination with telaprevir; thus, sirolimus dose reductions and prolongation of the dosing interval are recommended to achieve desired sirolimus concentrations. If sirolimus dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathway of sirolimus. Sirolimus is a substrate of the hepatic isoenzyme CYP3A4 and the drug efflux transporter P-glycoprotein (P-gp); telaprevir inhibits both the isoenzyme and the drug efflux protein. When used in combination, the plasma concentrations of sirolimus may be increased.
    Telithromycin: (Major) Avoid coadministration of sirolimus with telithromycin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and telithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Telmisartan; Amlodipine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with amlodipine is necessary. The dose of sirolimus may also need to be reduced with coadministration of amlodipine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of amlodipine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; amlodipine is a weak CYP3A inhibitor.
    Telotristat Ethyl: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of telotristat; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; telotristat is a weak CYP3A4 inducer.
    Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Temsirolimus: (Contraindicated) Do not use sirolimus concomitantly with temsirolimus. Temsirolimus is extensively metabolized in the liver primarily by cytochrome P450 3A4, but also by P-glycoprotein (P-gp). Five metabolites are formed, but sirolimus is the principal and active metabolite; the remainder of the metabolites account for less than 10% of radioactivity in plasma. Residual sirolimus concentrations are present up to a week after temsirolimus administration.
    Tepotinib: (Major) Avoid coadministration of sirolimus with tepotinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and tepotinib is a P-gp inhibitor.
    Tezacaftor; Ivacaftor: (Major) Avoid coadministration of sirolimus with ivacaftor as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor. (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of sirolimus. Appropriate monitoring should be used; adjust sirolimus dosage as necessary. Sirolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp.
    Thiopental: (Major) Concomitant use of sirolimus and barbiturates should be avoided. Barbiturates such as phenobarbital and primidone may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4; phenobarbital and primidone are potent CYP3A4 inducers. A similar interaction with sirolimus would be expected with all other barbiturates. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; primidone and phenobarbital may induce P-gp.
    Ticagrelor: (Major) Avoid coadministration of sirolimus with ticagrelor as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ticagrelor is a weak CYP3A and P-gp inhibitor.
    Tinidazole: (Moderate) Tinidazole may theoretically increase sirolimus serum concentrations whencoadministered. Patients should be monitored for signs of toxicity if Tinidazole is administered with sirolimus.
    Tipranavir: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Tocilizumab: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Tofacitinib: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as sirolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Topiramate: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of topiramate; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; topiramate is a weak CYP3A inducer.
    Topotecan: (Major) Avoid coadministration of sirolimus with oral topotecan due to increased topotecan exposure; sirolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and sirolimus is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Trandolapril; Verapamil: (Moderate) Monitor sirolimus concentrations during concurrent use. Sirolimus or verapamil dose adjustments may be necessary. Verapamil is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus is a substrate for both CYP3A4 and P-gp. Coadministration of sirolimus oral solution 2 mg daily and verapamil 180 mg PO every 12 hours to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased by 2.3- and 2.2-fold, respectively; both the Cmax and AUC of the active (S)-enantiomer of verapamil also increased by 1.5-fold, with a decrease in the Tmax by 1.2 hours.
    Tucatinib: (Major) Avoid coadministration of sirolimus with tucatinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and tucatinib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with sirolimus. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; sirolimus is a BCRP inhibitor.
    Upadacitinib: (Major) Avoid use of upadacitinib in combination with potent immunosuppressants such as sirolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Vemurafenib: (Major) Avoid coadministration of sirolimus with vemurafenib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and vemurafenib is a P-gp inhibitor.
    Venetoclax: (Major) Avoid coadministration of sirolimus with venetoclax as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and venetoclax is a P-gp inhibitor.
    Verapamil: (Moderate) Monitor sirolimus concentrations during concurrent use. Sirolimus or verapamil dose adjustments may be necessary. Verapamil is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus is a substrate for both CYP3A4 and P-gp. Coadministration of sirolimus oral solution 2 mg daily and verapamil 180 mg PO every 12 hours to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased by 2.3- and 2.2-fold, respectively; both the Cmax and AUC of the active (S)-enantiomer of verapamil also increased by 1.5-fold, with a decrease in the Tmax by 1.2 hours.
    Viloxazine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with viloxazine is necessary. The dose of sirolimus may also need to be reduced with coadministration of viloxazine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of viloxazine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; viloxazine is a weak CYP3A inhibitor.
    Voclosporin: (Major) Avoid coadministration of sirolimus with voclosporin as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and voclosporin is a P-gp inhibitor.
    Voriconazole: (Contraindicated) Concurrent administration of voriconazole with sirolimus is contraindicated. Voriconazole inhibits the CYP3A4 metabolism of sirolimus, resulting in significantly increased sirolimus plasma concentrations. In one study, sirolimus maximum plasma concentration and systemic exposure were increased by 7-fold and 11-fold, respectively, when administered with voriconazole.
    Voxelotor: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with voxelotor is necessary. The dose of sirolimus may also need to be reduced with coadministration of voxelotor. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of voxelotor. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; voxelotor is a moderate CYP3A inhibitor.
    Zanubrutinib: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of zanubrutinib; a sirolimus dose adjustment may be necessary. Sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; zanubrutinib is a weak CYP3A4 inducer.
    Zonisamide: (Major) Avoid coadministration of sirolimus with zonisamide as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and zonisamide is a P-gp inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    Sirolimus can cause fetal harm when administered during human pregnancy. Advise pregnant women of the potential fetal risk and instruct them to use highly effective contraception before, during, and for 12 weeks after sirolimus therapy. There are limited data in pregnant women. Sirolimus crosses the placenta and is toxic to the conceptus. It is also embryo/fetotoxic in rats at subtherapeutic doses.[28610] A panel of experts from the 2002 European Best Practice Guidelines for Renal Transplant considered sirolimus contraindicated during pregnancy. In 2010, the National Transplantation Pregnancy Registry (NTPR) reported exposure of 12 pregnant kidney transplant recipients to sirolimus. Among 13 pregnancies, 3 spontaneous abortions occurred. One infant was born with cleft lip, cleft palate, and microtia (with concomitant exposure to mycophenolate). Another infant was born with tetralogy of Fallot. Two pregnancies in heart transplant recipients resulted in 1 spontaneous abortion and 1 live birth with facial abnormalities (exposure to sirolimus, cyclosporine, and mycophenolate at conception). Among 3 pregnancies in liver transplant recipients, 1 spontaneous abortion and 2 live births were reported. One spontaneous abortion was reported in a pancreas-kidney transplant recipient.[49381] [62810]

    Use of sirolimus during breast-feeding was advised against by a panel of experts in the 2002 European Best Practice Guidelines for Renal Transplant.[49381] It is not known whether sirolimus is present in human milk. There are no data on the effects of sirolimus on the breast-fed infant or milk production. There is the potential for serious adverse effects from sirolimus in breast-fed infants based on mechanism of action. Consider the development and health benefits of breast-feeding along with the mother's clinical need for sirolimus and any potential adverse effects on the breast-fed child.[28610]

    MECHANISM OF ACTION

    Sirolimus inhibits T-cell activation and proliferation. Unlike cyclosporine or tacrolimus, which inhibit the first phase of T-cell activation, sirolimus inhibits the second phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early gene products (e.g., interleukin (IL)-2, IL-3, IL-4, tumor necrosis factor (TNF) alpha, and interferon gamma) that allow T-cells to progress from the G0- to G1-phase. The second phase involves signal transduction and clonal proliferation of T-cells. Sirolimus and tacrolimus both bind to the same immunophilin, known as intracellular FK-binding protein (FKBP) 12. But unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin, the sirolimus-FKBP complex binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR). The sirolimus-FKBP complex does not affect calcineurin activity, which is also the target of cyclosporine. Sirolimus is synergistic with cyclosporine both in vitro and in vivo. The inhibition of mTOR prevents activation of one or more phosphatases or kinases and blocks signal transduction pathways critical to cell cycle progression. Inactivation of the mTOR pathway inhibits the proliferation of smooth muscle-like cells (LAM cells) in the lung. Sirolimus inhibits interleukin (IL)-2, IL-4, IL-7, IL-15, and IL-17 induced proliferation of T-cells resulting in cell cycle arrest in the late G1-phase and preventing progression to the S-phase. Sirolimus also prevents B-cell differentiation into antibody-producing cells, decreasing the levels of IgM, IgG, and IgA. The inhibition of antibody production contributes to the potent immunoregulatory effects of sirolimus. The sirolimus-FKBP-mTOR complex indirectly inhibits the activation of 70-kd S6 protein kinase (p70sk6), which blocks the synthesis of proteins necessary for the accelerated protein synthesis associated with the progression of T-cells to the S-phase. Other effects include reduction of the kinase activity of the cdk4/cyclin D and cdk2/cyclin E complexes and inhibition of the expression of bcl-2 and BAG-1 without effecting the expression of c-fos/c-jun and c-myc. Sirolimus also affects the proliferation of cells outside the immune system including non-lymphoid tumor cells, smooth muscle cells, hepatocytes, and fibroblasts.

    PHARMACOKINETICS

    Sirolimus is administered orally as either a tablet or an oral solution. It is insoluble in aqueous media, and the oral solution is formulated in an oil base. Sirolimus is a substrate and inhibitor of P-glycoprotein (P-gp), an energy-dependent drug-efflux pump located in intestinal epithelium and the blood brain barrier. There appears to be overlap between inhibitors and/or substrates of cytochrome P450 (CYP) 3A4 and P-gp. The P-gp efflux of sirolimus from intestinal cells back into the gut lumen allows for CYP3A4 metabolism prior to absorption, thus limiting sirolimus availability. When administered with inhibitors of both CYP3A4 and P-gp (e.g., diltiazem, erythromycin, or ketoconazole) increased sirolimus bioavailability leads to increased concentrations. Trough concentrations appear to be related to the immunosuppressive effects and toxicity of the drug, and should be monitored in all patients, especially in patients likely to have altered drug metabolism, patients who weigh < 40 kg, patients with hepatic impairment, during administration of strong CYP3A4 inducers or inhibitors, and/or if the cyclosporine dose is markedly reduced or discontinued.
     
    Sirolimus is extensively distributed into erythrocytes with a blood to plasma ratio of 36 in stable renal transplant patients. The distribution among cellular components is red blood cells 95%, plasma 3%, lymphocytes 1%, and granulocytes 1%. The high binding of sirolimus within erythrocytes may be due to high intracellular levels of FKBP12. In man, sirolimus is approximately 92% bound to plasma proteins. Sirolimus is a substrate for CYP3A4. It is extensively metabolized by O-demethylation and/or hydroxylation. Seven major metabolites are identifiable in whole blood including hydroxy, desmethyl, and hydroxydemethyl metabolites. These metabolites are a small component of whole blood concentrations and contribute < 10% of the immunosuppressive activity. The mean elimination half-life in stable renal transplant patients appears to be about 62 +/- 16 hours. The major route of excretion appears to be via the feces with only 2.2% of the dose excreted in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, P-gp
    Sirolimus is a substrate of CYP3A4 and P-glycoprotein (P-gp).
     

    Oral Route

    Following administration, sirolimus oral solution is rapidly absorbed with a Tmax of about 2 hours. The bioavailability is about 14% after administration of the oral solution. The mean bioavailability of the tablet is about 27% higher relative to the oral solution. The tablets and oral solution are not bioequivalent; however, clinical equivalence has been demonstrated at the 2-mg dose level. Food may alter the bioavailability. Compared to fasting, a 34% decrease in Cmax, a 3.5-fold increase in Tmax, and 35% increase in AUC were observed in healthy volunteers following administration of the oral solution after a high-fat breakfast. After administration of the tablets and a high-fat meal in healthy volunteers, Cmax, Tmax, and AUC showed increases of 65%, 32%, and 23%, respectively. To minimize variability, administer both tablets and oral solution consistently with or without food. 
     
    After administration of the oral solution to renal transplant patients, sirolimus concentrations are dose proportional between 3 and 12 mg/m2. In renal transplant patients, whole blood trough concentrations are significantly correlated with AUC (r2= 0.96). Mean whole blood trough concentrations following sirolimus 2 mg/day and 5 mg/day are 8.59 +/- 4.01 ng/ml and 17.3 +/- 7.4 ng/ml, respectively. Upon repeated twice daily administration without an initial loading dose in a multiple-dose study, the average trough concentration increases approximately 2- to 3-fold over the initial 6 days of therapy at which time steady state is reached. Administration of a loading dose of 3-times the maintenance dose will provide near steady state concentrations within 1 day in most patients. The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state require approximately 6 weeks.
     
    In 37 lymphangioleiomyomatosis patients, median whole blood trough concentration following 3 weeks of treatment with 2 mg/day was 6.8 ng/mL (range 4.6—9 ng/mL).