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  • CLASSES

    Selective Immunosuppressants

    BOXED WARNING

    Immunosuppression, infection, lymphoma, neoplastic disease, 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 neoplastic disease, especially lymphoma. Instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a 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.

    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 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.
    In renal transplant patients, administer 4 hours after cyclosporine oral solution or capsules.
    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. For each use, insert one of the syringes with the plunger fully depressed into the opening in the adapter.
    Always keep the bottle in an upright position. 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 in the oral syringe, the solution may be kept for a maximum of 24 hours at temperatures up to 25 degrees C (77 degrees F) or under refrigeration (2—8 degrees C). Discard the oral syringe after use.
    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 drink at once.
    Refill the container with additional 4 ounces (120 ml) of water or orange juice, stir vigorously, and drink at once.
    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.

    STORAGE

    Rapamune:
    - Store at controlled room temperature (between 68 and 77 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, neoplastic disease, 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 neoplastic disease, especially lymphoma. Instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a 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.

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

    Sirolimus may worsen pre-existing hypercholesterolemia and hypertriglyceridemia (see Adverse Reactions). 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. In clinical trials, the concomitant administration of sirolimus and HMG-CoA reductase inhibitors and/or fibrates appears to be well tolerated.

    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 is a FDA pregnancy risk category C agent. There are no adequate and well-controlled trials in pregnant humans, and its ability to cause fetal harm or affect reproductive capacity is unknown. In 2004, the National Transplantation Pregnancy Registry (NTPR) reported exposure of four pregnant kidney transplant recipients to sirolimus (in combination with other immunosuppressants). Pregnancy outcomes for these four women included 3 live births and 1 spontaneous abortion at gestational week 8; of the 3 live births, 1 infant was born with a cleft lip/palate and microtia. The manufacturer recommends use of the drug during pregnancy only if the potential benefit to the mother justifies the potential risk to the infant; however, a panel of experts from the 2002 European Best Practice Guidelines for Renal Transplant considers sirolimus contraindicated during pregnancy. Inform females of childbearing potential of the pregnancy risks associated with sirolimus and instruct them to use effective contraception before, during, and for 12 weeks following therapy.

    Breast-feeding

    Data are limited regarding use of sirolimus during breast-feeding and its excretion in human milk is unknown. However, presence in breast milk is considered likely due to the drugs low molecular weight (914) and prolonged elimination half-life (62 hours). The manufacturer recommends a decision be made to discontinue either breast-feeding or use of the drug because of the potential for serious adverse reactions in a nursing infant. Use of sirolimus during breast-feeding was also advised against by a panel of experts in the 2002 European Best Practice Guidelines for Renal Transplant. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA. 

    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

    Patients receiving any vaccination during immunosuppressive therapy with sirolimus or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. Those undergoing immunosuppressive therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts of immunocompromised patients, including health care professionals. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of or in addition to vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    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.

    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
    nephrotic syndrome / Delayed / Incidence not known
    proteinuria / 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
    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
    secondary malignancy / Delayed / 1.0-10.0
    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
    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 (unspecified) / 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

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (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.
    Acetaminophen; 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.
    Acetaminophen; 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.
    Amiodarone: (Moderate) Agents that inhibit CYP3A4 and/or P-glycoprotein, such as amiodarone, may affect absorption and elimination of sirolimus leading to increased blood concentrations. Monitor sirolimus serum concentrations carefully if these drugs need to be coadministered.
    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; Lansoprazole: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as clarithromycin. Clarithromycin 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 (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Additionally, sirolimus is a substrate for P-gp, and clarithromycin is a P-gp inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as clarithromycin. Clarithromycin 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 (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Additionally, sirolimus is a substrate for P-gp, and clarithromycin is a P-gp inhibitor.
    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.
    Aprepitant, Fosaprepitant: (Major) Use caution if sirolimus and aprepitant, fosaprepitant are used concurrently and monitor for an increase in sirolimus-related adverse effects for several days after administration of a multi-day aprepitant regimen. Sirolimus is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of sirolimus. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    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.
    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 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. (Moderate) Sirolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated sirolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of sirolimus. These drugs used in combination may result in elevated sirolimus plasma concentrations, causing an increased risk for sirolimus-related adverse events.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    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.
    Azithromycin: (Moderate) Sirolimus is a substrate of P-glycoprotein (P-gp) and azithromycin is a P-gp inhibitor; therefore, sirolimus concentrations could be increased with coadministration. Monitor patients for increased side effects if these drugs are given together.
    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.
    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 trough concentrations and watch for decreased efficacy of sirolimus if coadministration with brigatinib is necessary. Sirolimus is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration with a strong CYP3A4 inducer decreased the AUC and Cmax of a single dose of sirolimus by approximately 82% and 71%, respectively; brigatinib may also decrease sirolimus exposure.
    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.
    Cabozantinib: (Moderate) Monitor for an increase in sirolimus-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of sirolimus may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and sirolimus is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Concomitant use of sirolimus and carbamazepine should be avoided. Carbamazepine 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 CYP3A, and carbamazepine is a potent CYP3A inducer. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate, and carbamazepine induces P-gp.
    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: (Moderate) Increased concentrations of sirolimus may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and sirolimus is a P-gp substrate.
    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.
    Ceritinib: (Major) Avoid coadministration of ceritinib with sirolimus due to increased sirolimus exposure. If coadministration is unavoidable, monitor sirolimus trough concentrations and watch for sirolimus-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and sirolimus is a CYP3A4 substrate with a narrow therapeutic index.
    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.
    Cimetidine: (Moderate) Coadministration of cimetidine with sirolimus may result in increased sirolimus plasma concentrations increasing the risk for nephrotoxicity. Sirolimus is a CYP3A4 substrate; cimetidine is a CYP3A43 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 the use of sirolimus with potent CYP3A4 inhibitors, such as clarithromycin. Clarithromycin 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 (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Additionally, sirolimus is a substrate for P-gp, and clarithromycin is a P-gp inhibitor.
    Cobicistat: (Moderate) Sirolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated sirolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of sirolimus. These drugs used in combination may result in elevated sirolimus plasma concentrations, causing an increased risk for sirolimus-related adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Sirolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated sirolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of sirolimus. These drugs used in combination may result in elevated sirolimus plasma concentrations, causing an increased risk for sirolimus-related adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Sirolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated sirolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of sirolimus. These drugs used in combination may result in elevated sirolimus plasma concentrations, causing an increased risk for sirolimus-related adverse events.
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and sirolimus, a CYP3A4/P-gp substrate. Concurrent use may result in elevated sirolimus serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as sirolimus, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sirolimus. Treatment with sirolimus may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions if coadministration with crizotinib is necessary. The dose of sirolimus may need to be reduced. Sirolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate with a narrow therapeutic range. Crizotinib is a moderate CYP3A4 inhibitor, as well as an inhibitor of P-gp at clinically relevant concentrations. Coadministration with another moderate CYP3A4/P-gp increased the AUC of sirolimus by 2.2-fold.
    Cyclosporine: (Major) Concomitant administration of sirolimus and cyclosporine may result in increased concentrations of sirolimus. The combination may also lead to an increase in nephrotoxic and immunosuppressant effects.
    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 74%.
    Daclatasvir: (Moderate) Systemic exposure of sirolimus, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sirolimus; monitor patients for potential adverse effects.
    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) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as dalfopristin; quinupristin. Dalfopristin; quinupristin 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.
    Danazol: (Major) Agents that inhibit CYP3A4 and/or P-glycoprotein, such as danazol, may affect absorption and elimination of sirolimus leading to increased blood concentrations. Monitor sirolimus serum concentrations carefully if these drugs need to be coadministered.
    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 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. (Moderate) Sirolimus therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated sirolimus serum concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of sirolimus. These drugs used in combination may result in elevated sirolimus plasma concentrations, causing an increased risk for sirolimus-related adverse events.
    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.
    Dasatinib: (Moderate) Dasatinib is a time-dependent, weak inhibitor of CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme like sirolimus are administered concurrently with dasatinib as increased adverse reactions may occur.
    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.
    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.
    Diltiazem: (Moderate) The simultaneous administration of sirolimus and diltiazem may significantly increase the bioavailability of sirolimus. This may be due to inhibition of sirolimus metabolism through the CYP3A pathway. Sirolimus blood trough concentrations should be monitored and dose adjustments may be necessary.
    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: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Sirolimus is a substrate for CYP3A4 and P-gp. concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    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.
    Elbasvir; Grazoprevir: (Moderate) Administering sirolimus with elbasvir; grazoprevir may result in elevated sirolimus plasma concentrations. Sirolimus is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Coadministration of sirolimus and eliglustat may result in increased plasma concentrations of sirolimus. Exercise caution when using these agents together; monitor therapeutic sirolimus concentrations and adjust the dosage as appropriate. Sirolimus is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor. Although specific recommendations are not available, when eliglustat is given in combination with digoxin, another narrow therapeutic index P-gp substrate, an empiric digoxin dosage reduction of 30% followed by careful monitoring is recommended.
    Eluxadoline: (Major) Although the CYP3A4 inhibitory effects of eluxadoline have not been definitively established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index, such as sirolimus. Closely monitor sirolimus drug concentrations and for increased sirolimus-related side effects when initiating or discontinuing eluxadoline therapy. Sirolimus dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
    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.
    Erythromycin: (Major) Avoid the use of sirolimus with strong CYP3A4 inhibitors, such as erythromycin. Erythromycin 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 (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. In 24 healthy volunteers, sirolimus Cmax and AUC were increased by 4.4- and 4.2-fold respectively, with simultaneous oral administration of sirolimus oral solution (2 mg PO) and erythromycin ethylsuccinate tablets (800 mg every 8 hours). Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold. Additionally, sirolimus is a substrate for P-gp, and erythromycin is a P-gp inhibitor.
    Erythromycin; Sulfisoxazole: (Major) Avoid the use of sirolimus with strong CYP3A4 inhibitors, such as erythromycin. Erythromycin 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 (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. In 24 healthy volunteers, sirolimus Cmax and AUC were increased by 4.4- and 4.2-fold respectively, with simultaneous oral administration of sirolimus oral solution (2 mg PO) and erythromycin ethylsuccinate tablets (800 mg every 8 hours). Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold. Additionally, sirolimus is a substrate for P-gp, and erythromycin is a P-gp inhibitor.
    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.
    Flibanserin: (Major) The concomitant use of flibanserin, a P-glycoprotein (P-gp) inhibitor, and sirolimus, a P-gp substrate, can increase sirolimus concentrations, which may lead to sirolimus toxicity. Close monitoring is recommended. Patients should be instructed to contact their healthcare provider if they experience symptoms of increased sirolimus exposure such as rash, difficulty sleeping, fever, or signs of infection.
    Fluconazole: (Major) Plasma concentrations of sirolimus, a CYP3A4 substrate, are increased when administered in combination with fluconazole, an inibitor of CYP3A4. When these drugs are used together, monitor sirolimus plasma concentration and adjust dosage based on clinical effect and concentration measurement.
    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.
    Fluoxetine; Olanzapine: (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.
    Fluvoxamine: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as fluvoxamine. Fluvoxamine 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.
    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) Concomitant use of sirolimus and fosphenytoin should be avoided. Fosphenytoin 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 fosphenytoin is a potent CYP3A4 inducer.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and sirolimus as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Sirolimus is a substrate of P-glycoprotein (P-gp); glecaprevir is an inhibitor of P-gp. Additionally, glecaprevir is a substrate of breast cancer resistance protein (BCRP) while sirolimus is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and sirolimus as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Sirolimus is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp. Additionally, pibrentasvir is a substrate of breast cancer resistance protein (BCRP) while sirolimus is an inhibitor of BCRP.
    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: (Severe) 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. Grapefruit juice inhibits the cytochrome P-450 3A4 isozyme in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level. According to the manufacturer, because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, grapefruit juice should not be used to dilute sirolimus or taken concurrently with sirolimus.
    Ibrutinib: (Moderate) Use ibrutinib and sirolimus together with caution; plasma concentrations of sirolimus may increase resulting in increased toxicity. Monitor sirolimus levels and adjust the dose as necessary. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; sirolimus is a P-gp substrate with a narrow therapeutic index.
    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.
    Ifosfamide: (Minor) Concurrent use of ifosfamide with other agents which cause bone marrow or immune suppression such as immunosuppressives like sirolimus may result in additive effects.
    Imatinib: (Minor) Imatinib is a potent inhibitor of cytochrome P450 CYP3A4 and may increase concentrations of other drugs metabolized by this enzyme including sirolimus.
    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: (Moderate) Use caution and closely monitor sirolimus serum concentrations when administered concurrently with isavuconazonium. Use of these drugs together results in elevated sirolimus serum concentrations and an increased risk for adverse reactions. Sirolimus dose adjustments may be necessary and should be guided by serum concentrations during coadministration. Isavuconazole, the active moiety of isavuconazonium, is a inhibitor of hepatic isoenzyme CYP3A4 as well as the drug transporter P-glycoprotein (P-gp); sirolimus is a substrate of CYP3A4 and P-gp.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of sirolimus with strong inducers of CYP3A4 and/or P-glycoprotein, such as rifampin, should be avoided. 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 and/or P-glycoprotein may affect absorption and elimination of sirolimus leading to decreased blood concentrations. In patients where rifampin is indicated, alternative agents with less enzyme induction should be considered (e.g., rifapentine). When sirolimus was given to patients receiving rifampin, the clearance of sirolimus increased 5.5-fold, which represents mean decreases in AUC and Cmax of about 82% and 71%, respectively. Enzyme induction may still occur with the alternative agents (e.g., rifapentine); however, the degree should be less. Rifapentine is known to decrease sirolimus concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Isoniazid, INH; Rifampin: (Major) Concurrent use of sirolimus with strong inducers of CYP3A4 and/or P-glycoprotein, such as rifampin, should be avoided. 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 and/or P-glycoprotein may affect absorption and elimination of sirolimus leading to decreased blood concentrations. In patients where rifampin is indicated, alternative agents with less enzyme induction should be considered (e.g., rifapentine). When sirolimus was given to patients receiving rifampin, the clearance of sirolimus increased 5.5-fold, which represents mean decreases in AUC and Cmax of about 82% and 71%, respectively. Enzyme induction may still occur with the alternative agents (e.g., rifapentine); however, the degree should be less. Rifapentine is known to decrease sirolimus concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Itraconazole: (Major) Avoid sirolimus use during and for 2 weeks after discontinuation of itraconazole treatment. Itraconazole, a potent CYP3A4 inhibitor, 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. Itraconazole is also an inhibitor of P-gp.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and sirolimus concurrently; careful monitoring of sirolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as sirolimus, can increase sirolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
    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: (Severe) Avoid coadministration of ketoconazole with sirolimus. Ketoconazole may inhibit the CYP3A4 metabolism of sirolimus, leading to potential toxicity. Multiple-dose ketoconazole significantly increased sirolimus Cmax by 4.3-fold, Tmax by 38%, and AUC 10.9-fold. The terminal half-life of sirolimus is not affected. Single doses of sirolimus did not affect steady-state 12-hour ketoconazole serum concentrations.
    Lapatinib: (Moderate) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Lapatinib is also a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Sirolimus is a substrate of both CYP3A4 and P-glycoprotein. As increased sirolimus concentrations are likely, cautious coadministration is recommended, and consider a sirolimus dose reduction. In addition, because sirolimus is an immunosuppressant, additive affects may be seen with antineoplastic agents such as lapatinib. 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.
    Ledipasvir; Sofosbuvir: (Major) Caution and close monitoring of sirolimus-associated adverse reactions is advised with concomitant administration of ledipasvir. Sirolimus is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase sirolimus plasma concentrations. Monitor sirolimus serum concentrations carefully if these drugs need to be coadministered.
    Lomitapide: (Moderate) Concomitant use of lomitapide and sirolimus may result in increased serum concentrations of sirolimus. According to the manufacturer of lomitapide, dose reduction of sirolimus should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and sirolimus is a P-gp substrate.
    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.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of sirolimus and lumacaftor; ivacaftor should be avoided. Lumacaftor; ivacaftor 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 lumacaftor is a potent CYP3A4 inducer. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to inhibit and induce P-gp.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and sirolimus concurrently; careful monitoring of sirolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as sirolimus, can increase sirolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
    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, RU-486: (Severe) Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum concentrations of drugs that are CYP3A4 substrates and that have a narrow therapeutic index, such as sirolimus. Coadministration is contraindicated when the drug is used chronically, such as in the treatment of Cushing's syndrome. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    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.
    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).
    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: (Moderate) Monitor sirolimus concentrations if coadministration with neratinib is necessary; sirolimus concentrations may be increased. Adjust the sirolimus dose as clinically appropriate. Sirolimus is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates.
    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.
    Nicardipine: (Major) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including sirolimus.
    Nilotinib: (Major) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with sirolimus, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased sirolimus levels. A sirolimus dose reduction may be necessary if these drugs are used together.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) 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.
    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.
    Oxcarbazepine: (Moderate) Sirolimus is extensively metabolized by CYP3A4 and concurrent use of sirolimus with agents that induce CYP3A4 and/or P-glycoprotein, such as oxcarbazepine, may affect absorption and elimination of sirolimus leading to decreased blood concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Palbociclib: (Moderate) Monitor sirolimus concentrations and watch for an increase in sirolimus-related adverse reactions if coadministration with palbociclib is necessary. The dose of sirolimus may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A and sirolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and sirolimus, a CYP3A4 substrate, may cause an increase in systemic concentrations of sirolimus. Use caution when administering these drugs concomitantly. Additive immunosuppression may occur possibly resulting in an increased risk of infection or other side effects.
    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.
    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.
    Phenytoin: (Major) Concomitant use of sirolimus and phenytoin should be avoided. Phenytoin 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 phenytoin is a potent CYP3A4 inducer.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sirolimus, a P-gp substrate, may increase the exposure of sirolimus. Use caution when sirolimus is used in combination with P-gp inhibitors. If these agents are used together, the sirolimus dosage may need to be adjusted. 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.
    Posaconazole: (Severe) 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).
    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.
    Ranolazine: (Major) Coadministration of ranolazine and sirolimus may impair the absorption and elimination of sirolimus. In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as sirolimus, potentially leading to adverse reactions, especially for drugs with a narrow therapeutic index. In addition, ranolazine may decrease the absorption of sirolimus via P-glycoprotein inhibition.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with sirolimus is necessary, as the systemic exposure of sirolimus may be increased resulting in an increase in sirolimus-related adverse reactions. Monitor sirolimus trough concentrations and adjust the dose if necessary. Ribociclib is a moderate CYP3A4 inhibitor and sirolimus is a CYP3A4 substrate with a narrow therapeutic window.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with sirolimus is necessary, as the systemic exposure of sirolimus may be increased resulting in an increase in sirolimus-related adverse reactions. Monitor sirolimus trough concentrations and adjust the dose if necessary. Ribociclib is a moderate CYP3A4 inhibitor and sirolimus is a CYP3A4 substrate with a narrow therapeutic window.
    Rifabutin: (Major) Concurrent use of sirolimus with strong inducers of CYP3A4 and/or P-glycoprotein, such as rifabutin, should be avoided. 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 and/or P-glycoprotein may affect absorption and elimination of sirolimus leading to decreased blood concentrations. In patients where rifabutin is indicated, alternative agents with less enzyme induction should be considered (e.g., rifapentine). Enzyme induction may still occur with the alternative agents (e.g., rifapentine); however, the degree should be less. Rifapentine is known to decrease sirolimus concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Rifampin: (Major) Concurrent use of sirolimus with strong inducers of CYP3A4 and/or P-glycoprotein, such as rifampin, should be avoided. 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 and/or P-glycoprotein may affect absorption and elimination of sirolimus leading to decreased blood concentrations. In patients where rifampin is indicated, alternative agents with less enzyme induction should be considered (e.g., rifapentine). When sirolimus was given to patients receiving rifampin, the clearance of sirolimus increased 5.5-fold, which represents mean decreases in AUC and Cmax of about 82% and 71%, respectively. Enzyme induction may still occur with the alternative agents (e.g., rifapentine); however, the degree should be less. Rifapentine is known to decrease sirolimus concentrations. Monitor sirolimus serum concentrations carefully if an inducer of CYP3A4 or P-glycoprotein needs to be used concomitantly.
    Rifapentine: (Major) Rifapentine is known to decrease sirolimus concentrations. However, if treatment with a rifamycin antibiotic is required, rifapentine is the drug of choice. While enzyme induction and altered sirolimus concentrations occur with rifapentine, it is less than seen with other rifamycins. Monitor sirolimus serum concentrations carefully if these drugs are coadministered.
    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: (Moderate) Use caution if sirolimus and rolapitant are used concurrently, and monitor sirolimus levels and watch for sirolimus-related adverse effects. Sirolimus is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase concentrations and adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    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.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and sirolimus as coadministration may result in increased systemic exposure of sirolimus. Sirolimus is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of sirolimus.
    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.
    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.
    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.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with sirolimus. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); sirolimus is a potent inhibitor of BCRP. Sirolimus is also a substrate for P-glycoprotein (P-gp); while velpatasvir is a P-gp inhibitor.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of sirolimus, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with sirolimus. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); sirolimus is a potent inhibitor of BCRP. Sirolimus is also a substrate for P-glycoprotein (P-gp); while velpatasvir is a P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort in all formuations should be avoided in patients treated with sirolimus. St. John's Wort may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. Sirolimus is a substrate of CYP3A4, and St. John's Wort is a potent CYP3A4 inducer. In addition, the exposure of sirolimus may be altered via P-glycoprotein (P-gp) transport. Sirolimus is P-gp substrate, and St. John's Wort induces P-gp.
    Streptogramins: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as dalfopristin; quinupristin. Dalfopristin; quinupristin 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.
    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.
    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 the use of sirolimus with potent CYP3A4 inhibitors, such as telithromycin. Telithromycin 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 (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Additionally, sirolimus is a substrate for P-gp, and telithromycin is a weak P-gp inhibitor.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and sirolimus is necessary, as the systemic exposure of sirolimus may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of sirolimus; consider increasing the dose of sirolimus if necessary. Sirolimus is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    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: (Severe) 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.
    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.
    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) Closely observe patients for signs of infection, altered clinical response, or drug toxicity. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as sirolimus. If tocilizumab is initiated or discontinued in a patient taking sirolimus, check the drug concentration; sirolimus dose adjustment may be needed.
    Topotecan: (Major) Avoid the concomitant use of sirolimus, a potent inhibitor of Breast Cancer Resistance Protein (BCRP) inhibitor, with oral topotecan, a BCRP substrate. When oral topotecan was administered concomitantly with escalating doses of a dual BCRP and P-gp inhibitor, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control.
    Trandolapril; Verapamil: (Moderate) Monitor sirolimus concentrations during co-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 26 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.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as sirolimus may increase sirolimus concentrations; use caution. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with sirolimus is necessary, due to a possible increase in sirolimus-related adverse reactions; this may be more pronounced in patients taking a concomitant CYP3A4 inhibitor. Sirolimus is a substrate of CYP3A4 and P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vemurafenib: (Major) Concomitant use of vemurafenib and sirolimus may result in altered concentrations of sirolimus. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Sirolimus is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and sirolimus as sirolimus levels may be increased. If concomitant use of these drugs is required, administer sirolimus at least 6 hours before venetoclax. Monitor patients for signs and symptoms of sirolimus toxicity. Venetoclax is an inhibitor of P-glycoprotein (P-gp) and sirolimus is a P-gp substrate with a narrow therapeutic index; these agents may interact in the gastrointestinal tract.
    Verapamil: (Moderate) Monitor sirolimus concentrations during co-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 26 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.
    Voriconazole: (Severe) 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.
    Zileuton: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates including sirolimus.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sirolimus is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Sirolimus is a FDA pregnancy risk category C agent. There are no adequate and well-controlled trials in pregnant humans, and its ability to cause fetal harm or affect reproductive capacity is unknown. In 2004, the National Transplantation Pregnancy Registry (NTPR) reported exposure of four pregnant kidney transplant recipients to sirolimus (in combination with other immunosuppressants). Pregnancy outcomes for these four women included 3 live births and 1 spontaneous abortion at gestational week 8; of the 3 live births, 1 infant was born with a cleft lip/palate and microtia. The manufacturer recommends use of the drug during pregnancy only if the potential benefit to the mother justifies the potential risk to the infant; however, a panel of experts from the 2002 European Best Practice Guidelines for Renal Transplant considers sirolimus contraindicated during pregnancy. Inform females of childbearing potential of the pregnancy risks associated with sirolimus and instruct them to use effective contraception before, during, and for 12 weeks following therapy.

    Data are limited regarding use of sirolimus during breast-feeding and its excretion in human milk is unknown. However, presence in breast milk is considered likely due to the drugs low molecular weight (914) and prolonged elimination half-life (62 hours). The manufacturer recommends a decision be made to discontinue either breast-feeding or use of the drug because of the potential for serious adverse reactions in a nursing infant. Use of sirolimus during breast-feeding was also advised against by a panel of experts in the 2002 European Best Practice Guidelines for Renal Transplant. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA. 

    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).