Rapamune

Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors

For storage information, see specific product information within the How Supplied section.
Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Oral Administration

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

Oral Solid Formulations

Do not crush, chew, or split sirolimus tablets.

Oral Liquid Formulations

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

Topical Administration Other Topical Formulations

Topical Gel (Hyftor)
For topical use only. Do not administer via oral, ophthalmic, or vaginal routes.
Wash hands before and after applying.
Apply to affected areas of the face in the morning and at bedtime.
Do not cover with occlusive dressing.
Minimize or avoid exposing treated skin to natural or artificial sunlight.

Severe

osteonecrosis / Delayed / 3.0-20.0
thrombotic thrombocytopenic purpura (TTP) / Delayed / 3.0-19.9
hemolytic-uremic syndrome / Delayed / 3.0-19.9
pulmonary embolism / Delayed / 3.0-19.9
thrombosis / Delayed / 3.0-19.9
thromboembolism / Delayed / 3.0-19.9
proteinuria / Delayed / 9.2-14.1
post-transplant lymphoproliferative disorder (PTLD) / Delayed / 1.0-10.0
pancreatitis / Delayed / 0-3.0
nephrotic syndrome / Delayed / 2.2-2.2
pericardial effusion / Delayed / Incidence not known
cardiac tamponade / Delayed / Incidence not known
pleural effusion / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
nephrotoxicity / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
leukoencephalopathy / Delayed / Incidence not known
wound dehiscence / Delayed / Incidence not known
pulmonary hypertension / Delayed / Incidence not known
bronchiolitis obliterans / Delayed / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
lymphoma / 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
hypokalemia / Delayed / 3.0-19.9
diabetes mellitus / Delayed / 3.0-19.0
erythema / Early / 7.0-7.0
contact dermatitis / Delayed / 0-5.0
conjunctival hyperemia / Early / 3.0-3.0
chest pain (unspecified) / Early / 20.0
peripheral edema / Delayed / 20.0
hypercholesterolemia / Delayed / 20.0
hyperlipidemia / Delayed / 10.0
stomatitis / Delayed / 20.0
oral ulceration / Delayed / 10.0
neutropenia / Delayed / Incidence not known
immunosuppression / Delayed / Incidence not known
BK virus-associated nephropathy / Delayed / Incidence not known
lymphocele / Delayed / Incidence not known
dyspnea / Early / Incidence not known
interstitial lung disease / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
infertility / Delayed / Incidence not known
ovarian cyst / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known
ascites / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
encephalopathy / Delayed / Incidence not known

Mild

acneiform rash / Delayed / 3.0-46.0
xerosis / Delayed / 28.0-40.0
fever / Early / 23.0-34.0
infection / Delayed / 0-33.0
arthralgia / Delayed / 25.0-31.0
acne vulgaris / Delayed / 7.0-22.0
rash / Early / 10.0-20.0
epistaxis / Delayed / 3.0-19.9
amenorrhea / Delayed / 3.0-19.9
menorrhagia / Delayed / 3.0-19.9
pruritus / Rapid / 9.0-17.0
ocular irritation / Rapid / 9.0-9.0
skin irritation / Early / 0-3.0
petechiae / Delayed / 3.0-3.0
photosensitivity / Delayed / 1.0-1.0
myalgia / Early / 20.0
dizziness / Early / 20.0
musculoskeletal pain / Early / 10.0
headache / Early / 20.0
nausea / Early / 20.0
abdominal pain / Early / 20.0
diarrhea / Early / 20.0
folliculitis / Delayed / 10.0
alopecia / Delayed / 10.0
hypertrichosis / Delayed / 10.0
onycholysis / Delayed / 10.0
pharyngitis / Delayed / 20.0
gingivitis / Delayed / 10.0
cough / Delayed / Incidence not known
azoospermia / Delayed / Incidence not known
oligospermia / Delayed / Incidence not known

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

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

Liver transplant, lung transplant

Oral 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, cases of bronchial anastomotic dehiscence, most fatal, have 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, graft loss, and hepatic artery thrombosis. 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. In another clinical study in stable liver transplant patients 6 to 144 months post transplant converted from a calcineurin inhibitor (CNI) to sirolimus, the number of patient deaths was higher among those converted to sirolimus compared to those that remained on a CNI-based regimen. 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.

HYFTOR, Rapamune

Rx

Immunosuppressant; analog of tacrolimus
Oral formulations for prophylaxis of organ rejection in renal transplant patients and for lymphangioleiomyomatosis; topical gel for facial angiofibroma associated with tuberous sclerosis
Acts synergistically with other immunosuppressants with little overlapping toxicity; may reduce the incidence of chronic rejection

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 treatment of facial angiofibroma associated with tuberous sclerosis complex.

 

Topical dosage (Hyftor only) Adults

Apply the gel topically to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime. Reevaluate the need for continued dosing if symptoms do not improved within 12 weeks.

Children and Adolescents 6 years and older

Apply the gel topically to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime. Reevaluate the need for continued dosing if symptoms do not improved within 12 weeks.

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.

For the treatment of graft-versus-host disease (GVHD)†. For the treatment of acute GVHD†. Oral dosage Adults

2 to 8 mg PO once daily for 5 days, initially. Adjust dose based on serum sirolimus trough concentration to target 4 to 12 ng/mL. Usual maintenance dose: 1 to 4 mg/day.  Guidelines suggest sirolimus as a second-line treatment option for steroid-refractory acute GVHD.

For the treatment of chronic GVHD†. Oral dosage Adults

0.25 to 0.5 mg PO once daily, initially. Adjust dose based on serum sirolimus trough concentration to target 4 to 8 ng/mL. A loading dose of sirolimus should be avoided in salvage therapy of chronic GVHD, and initial dosing should be rather low given its long half-life. 6 or 10 mg PO loading dose, followed by 2 or 5 mg PO once daily has been reported. Guidelines suggest sirolimus as a second-line treatment option for refractory chronic GVHD.

†Indicates off-label use

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh Class A or B): Reduce maintenance oral dose by approximately one-third.
Severe hepatic impairment (Child-Pugh Class C): Reduce maintenance oral dose 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 closely monitored during sirolimus use in these patients.

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.

Abrocitinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of abrocitinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and abrocitinib is a P-gp inhibitor.
Adagrasib: (Major) Avoid concomitant use of sirolimus and adagrasib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Amiodarone: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amiodarone. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of other moderate CYP3A and P-gp inhibitors increased sirolimus overall exposure by 2.2- to 4.2-fold.
Amlodipine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Amlodipine; Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Amlodipine; Benazepril: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor. (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.
Amlodipine; Celecoxib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Amlodipine; Olmesartan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Amlodipine; Valsartan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Amobarbital: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Angiotensin-converting enzyme inhibitors: (Moderate) Sirolimus has been associated with the development of angioedema. The use of sirolimus with other drugs known to cause angioedema, such as angiotensin-converting enzyme inhibitors may increase the risk of developing angioedema. Patients should be monitored for angioedema if any of these drugs are coadministered with sirolimus.
Apalutamide: (Major) Avoid concomitant use of sirolimus and apalutamide as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and apalutamide is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Aprepitant, Fosaprepitant: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of aprepitant/fosaprepitant. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and aprepitant/fosaprepitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Armodafinil: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of armodafinil. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and armodafinil is a weak CYP3A inducer.
Asciminib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of asciminib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and asciminib is a weak CYP3A and P-gp inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Atazanavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
Avacopan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of avacopan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Barbiturates: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Belumosudil: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of belumosudil. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and belumosudil is a weak CYP3A inhibitor.
Belzutifan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of belzutifan. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Benazepril: (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.
Benazepril; Hydrochlorothiazide, HCTZ: (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.
Berotralstat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of berotralstat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Bexarotene: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of bexarotene. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and bexarotene is a moderate CYP3A inducer.
Bicalutamide: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of bicalutamide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and bicalutamide is a weak CYP3A inhibitor.
Bosentan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of bosentan. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Brigatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of brigatinib. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and brigatinib is a weak CYP3A inducer and P-gp inhibitor.
Bromocriptine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of bromocriptine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Cabozantinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of cabozantinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and cabozantinib is a P-gp inhibitor.
Cannabidiol: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of cannabidiol. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and cannabidiol is a P-gp inhibitor.
Capivasertib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of capivasertib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and capivasertib is a weak CYP3A inhibitor.
Capmatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of capmatinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and capmatinib is a P-gp inhibitor.
Captopril: (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.
Captopril; Hydrochlorothiazide, HCTZ: (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.
Carbamazepine: (Major) Avoid concomitant use of sirolimus and carbamazepine as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and carbamazepine is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Carvedilol: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of carvedilol. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and carvedilol is a P-gp inhibitor.
Cenobamate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of cenobamate. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Ceritinib: (Major) Avoid concomitant use of sirolimus and ceritinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor.
Chikungunya Vaccine, Live: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Chloramphenicol: (Major) Avoid concomitant use of sirolimus and chloramphenicol. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of cimetidine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and cimetidine is a weak CYP3A inhibitor.
Ciprofloxacin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ciprofloxacin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Cisapride: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of cisapride. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Clarithromycin: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Clobazam: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of clobazam. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and clobazam is a weak CYP3A inducer.
Clofazimine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of clofazimine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and clofazimine is a weak CYP3A inhibitor.
Cobicistat: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Cocaine: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with cocaine is necessary. The dose of sirolimus may also need to be reduced with coadministration of cocaine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of cocaine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; cocaine is a weak CYP3A inhibitor.
Conivaptan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of conivaptan. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. Concomitant use of other moderate CYP3A and P-gp inhibitors increased sirolimus overall exposure by 2.2- to 4.2-fold.
Crizotinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of crizotinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Cyclosporine: (Moderate) Administer oral sirolimus 4 hours after oral cyclosporine. Simultaneous oral coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. While the effect of this interaction is diminished when administered separately, additional sirolimus dosage reductions may be required in some patients. Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate. Simultaneous coadministration has been observed to increase sirolimus overall exposure by 148% to 230%; separating administration by 4 hours has been observed to increase sirolimus overall exposure by 33% to 80%.
Dabrafenib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of dabrafenib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer.
Daclatasvir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of daclatasvir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and daclatasvir is a P-gp inhibitor.
Dalfopristin; Quinupristin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of quinupristin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and quinupristin is a weak CYP3A inhibitor.
Danazol: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of danazol. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Daridorexant: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of daridorexant. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and daridorexant is a weak CYP3A and P-gp inhibitor.
Darunavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Darunavir; Cobicistat: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Deferasirox: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of deferasirox. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and deferasirox is a weak CYP3A inducer.
Delavirdine: (Major) Avoid concomitant use of sirolimus and delavirdine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of dexamethasone. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and dexamethasone is a weak CYP3A inducer.
Dextromethorphan; Quinidine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of quinidine. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and quinidine is a P-gp inhibitor.
Diltiazem: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of diltiazem. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Concomitant use increased sirolimus overall exposure 1.6-fold in a drug interaction study.
Dronedarone: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of dronedarone. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and dronedarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of other moderate CYP3A and P-gp inhibitors increased sirolimus overall exposure by 2.2- to 4.2-fold.
Duvelisib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of duvelisib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Efavirenz: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of efavirenz. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of efavirenz. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of efavirenz. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Elacestrant: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of elacestrant. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and elacestrant is a P-gp inhibitor.
Elagolix: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of elagolix. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and elagolix is a moderate CYP3A inducer and P-gp inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of elagolix. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and elagolix is a moderate CYP3A inducer and P-gp inhibitor.
Elbasvir; Grazoprevir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of grazoprevir. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and grazoprevir is a weak CYP3A inhibitor.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivacaftor. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
Eliglustat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of eliglustat. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and eliglustat is a P-gp inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Enalapril, Enalaprilat: (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.
Enalapril; Hydrochlorothiazide, HCTZ: (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.
Enasidenib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of enasidenib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor.
Encorafenib: (Major) Avoid concomitant use of sirolimus and encorafenib as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Enzalutamide: (Major) Avoid concomitant use of sirolimus and enzalutamide as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and enzalutamide is a strong CYP3A inducer.
Erdafitinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of erdafitinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and erdafitinib is a P-gp inhibitor.
Erythromycin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of erythromycin. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and erythromycin is a moderate CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 4.2-fold in a drug interaction study.
Eslicarbazepine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of eslicarbazepine. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer.
Etravirine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of etravirine. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and etravirine is a weak CYP3A inducer and P-gp inhibitor.
Ezetimibe; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
Fedratinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fedratinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Fexinidazole: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fexinidazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fexinidazole is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Flibanserin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of flibanserin. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and flibanserin is a P-gp inhibitor.
Fluconazole: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fluconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Fluvastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and fluvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of fluvastatin to 40 mg/day if combined with sirolimus.
Fluvoxamine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fluvoxamine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
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 concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Fosinopril: (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.
Fosinopril; Hydrochlorothiazide, HCTZ: (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.
Fosphenytoin: (Major) Avoid concomitant use of sirolimus and phenytoin/fosphenytoin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Fostamatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fostamatinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and fostamatinib is a weak CYP3A and P-gp inhibitor.
Futibatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of futibatinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and futibatinib is a P-gp inhibitor.
Gilteritinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of gilteritinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor.
Glecaprevir; Pibrentasvir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of glecaprevir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and glecaprevir is a P-gp inhibitor. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pibrentasvir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and pibrentasvir is a P-gp inhibitor.
Glycerol Phenylbutyrate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of glycerol phenylbutyrate. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during sirolimus treatment due to the risk of increased sirolimus exposure and adverse reactions. Sirolimus is a CYP3A and P-gp substrate and grapefruit juice is a strong CYP3A and P-gp inhibitor.
Hydrochlorothiazide, HCTZ; Moexipril: (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.
Ibrutinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ibrutinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and ibrutinib is a P-gp inhibitor.
Idelalisib: (Major) Avoid concomitant use of sirolimus and idelalisib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor.
Imatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of imatinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Indinavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Isavuconazonium: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of isavuconazonium. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and isavuconazonium is a moderate CYP3A and P-gp inhibitor. Concomitant use of other moderate CYP3A and P-gp inhibitors increased sirolimus overall exposure by 2.2- to 4.2-fold.
Isoniazid, INH: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of isoniazid. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and isoniazid is a weak CYP3A inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of sirolimus and rifampin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and rifampin is a strong CYP3A and P-gp inducer. Concomitant use decreased sirolimus overall exposure by 82% in a drug interaction study. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of isoniazid. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and isoniazid is a weak CYP3A inhibitor.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of sirolimus and rifampin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and rifampin is a strong CYP3A and P-gp inducer. Concomitant use decreased sirolimus overall exposure by 82% in a drug interaction study. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of isoniazid. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and isoniazid is a weak CYP3A inhibitor.
Istradefylline: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of istradefylline. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and istradefylline is a weak CYP3A and P-gp inhibitor.
Itraconazole: (Major) Avoid concomitant use of sirolimus and itraconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and itraconazole is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Ivacaftor: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivacaftor. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
Ivosidenib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivosidenib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and ivosidenib is a weak CYP3A inducer.
Ketoconazole: (Major) Avoid concomitant use of sirolimus and ketoconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 10.9-fold in a drug interaction study.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Lapatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lapatinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and lapatinib is a weak CYP3A and P-gp inhibitor.
Larotrectinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of larotrectinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and larotrectinib is a weak CYP3A inhibitor.
Lasmiditan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lasmiditan. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ledipasvir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and ledipasvir is a P-gp inhibitor.
Lefamulin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lefamulin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and lefamulin is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Lenacapavir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lenacapavir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor. Concomitant use of other moderate CYP3A and P-gp inhibitors increased sirolimus overall exposure by 2.2- to 4.2-fold.
Lesinurad: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lesinurad. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lesinurad. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of letermovir. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Concomitant use has been observed to increase sirolimus overall exposure by 3.4-fold.
Levamlodipine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Levoketoconazole: (Major) Avoid concomitant use of sirolimus and ketoconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 10.9-fold in a drug interaction study.
Lisinopril: (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.
Lisinopril; Hydrochlorothiazide, HCTZ: (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.
Live Vaccines: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Lomitapide: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lomitapide. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and lomitapide is a P-gp inhibitor.
Lonafarnib: (Major) Avoid concomitant use of sirolimus and lonafarnib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and lonafarnib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Lorlatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of lorlatinib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and lorlatinib is a moderate CYP3A and P-gp inducer.
Lovastatin: (Major) Guidelines recommend avoiding coadministration of lovastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of sirolimus and lumacaftor; ivacaftor as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and lumacaftor is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivacaftor. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of sirolimus and lumacaftor; ivacaftor as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and lumacaftor is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Maribavir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of maribavir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and maribavir is a weak CYP3A and P-gp inhibitor.
Mavacamten: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of mavacamten. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Mefloquine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of mefloquine. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and mefloquine is a P-gp inhibitor.
Meropenem: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of meropenem. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and meropenem is a weak CYP3A and P-gp inducer.
Meropenem; Vaborbactam: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of meropenem. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and meropenem is a weak CYP3A and P-gp inducer.
Methohexital: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Metoclopramide: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of metoclopramide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Micafungin: (Moderate) Monitor for an increase in sirolimus-related adverse effects and adjust sirolimus dosage as appropriate based on response if concomitant use with micafungin is required. Concomitant use has been observed to increase sirolimus overall exposure by 21% without an effect on sirolimus peak.
Mifepristone: (Contraindicated) Concomitant use of sirolimus

and mifepristone is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor.
Mitapivat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of mitapivat. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and mitapivat is a weak CYP3A inducer and P-gp inhibitor.
Mitotane: (Major) Avoid concomitant use of sirolimus and mitotane as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and mitotane is a strong CYP3A inducer.
Mobocertinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of mobocertinib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and mobocertinib is a weak CYP3A inducer.
Modafinil: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of modafinil. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and modafinil is a weak CYP3A inducer.
Moexipril: (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.
Nafcillin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nafcillin. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and nafcillin is a moderate CYP3A inducer.
Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with sirolimus.
Nefazodone: (Major) Avoid concomitant use of sirolimus and nefazodone. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor.
Nelfinavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Neratinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of neratinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and neratinib is a P-gp inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of netupitant. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Nevirapine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nevirapine. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nicardipine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nicardipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nicardipine is a weak CYP3A inhibitor.
Nilotinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nilotinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving sirolimus, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase sirolimus exposure resulting in increased toxicity. Sirolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Nirogacestat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nirogacestat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Odevixibat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of odevixibat. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Olutasidenib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of olutasidenib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and olutasidenib is a weak CYP3A inducer.
Omaveloxolone: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of omaveloxolone. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and omaveloxolone is a weak CYP3A inducer.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of rifabutin. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Oritavancin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of oritavancin. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and oritavancin is a weak CYP3A inducer.
Osilodrostat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of osilodrostat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and osilodrostat is a weak CYP3A inhibitor.
Osimertinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of osimertinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and osimertinib is a P-gp inhibitor.
Oxcarbazepine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of oxcarbazepine. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and oxcarbazepine is a weak CYP3A inducer.
Pacritinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pacritinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and pacritinib is a weak CYP3A and P-gp inhibitor.
Palbociclib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of palbociclib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor.
Pazopanib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pazopanib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and pazopanib is a weak CYP3A inhibitor.
Pentobarbital: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Perindopril: (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.
Perindopril; Amlodipine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor. (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.
Pexidartinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pexidartinib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer.
Phenobarbital: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Phentermine; Topiramate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of topiramate. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and topiramate is a weak CYP3A inducer.
Phenytoin: (Major) Avoid concomitant use of sirolimus and phenytoin/fosphenytoin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Pirtobrutinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pirtobrutinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and pirtobrutinib is a weak CYP3A and P-gp inhibitor.
Pitavastatin: (Major) Guidelines recommend avoiding coadministration of pitavastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
Pitolisant: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pitolisant. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Posaconazole: (Contraindicated) Coadministration of posaconazole and sirolimus is contraindicated. Concomitant use has been observed to increase overall sirolimus exposure by approximately 9-fold which may increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor.
Pravastatin: (Moderate) Carefully weigh the benefits of combined use of sirolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with sirolimus.
Pretomanid: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pretomanid. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and pretomanid is a P-gp inhibitor.
Primidone: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Propafenone: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of propafenone. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and propafenone is a P-gp inhibitor.
Protease inhibitors: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Quinapril: (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.
Quinapril; Hydrochlorothiazide, HCTZ: (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.
Quinidine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of quinidine. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and quinidine is a P-gp inhibitor.
Quinine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of quinine. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and quinine is a weak CYP3A and P-gp inhibitor.
Ramipril: (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.
Ranolazine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ranolazine. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ranolazine is a weak CYP3A and P-gp inhibitor.
Repotrectinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of repotrectinib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribociclib: (Major) Avoid concomitant use of sirolimus and ribociclib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor.
Ribociclib; Letrozole: (Major) Avoid concomitant use of sirolimus and ribociclib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor.
Rifabutin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of rifabutin. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Rifampin: (Major) Avoid concomitant use of sirolimus and rifampin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and rifampin is a strong CYP3A and P-gp inducer. Concomitant use decreased sirolimus overall exposure by 82% in a drug interaction study.
Rifapentine: (Major) Avoid concomitant use of sirolimus and rifapentine as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and rifapentine is a strong CYP3A inducer.
Ritlecitinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ritlecitinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Ritonavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Rolapitant: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of rolapitant. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and rolapitant is a P-gp inhibitor.
Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Rucaparib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of rucaparib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and rucaparib is a weak CYP3A inhibitor.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sirolimus, may occur during concurrent use with rufinamide.
Saquinavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Sarecycline: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of sarecycline. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and sarecycline is a P-gp inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid concomitant use of sirolimus and barbiturates as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and barbiturates are strong CYP3A and P-gp inducers. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Selpercatinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of selpercatinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and selpercatinib is a weak CYP3A and P-gp inhibitor.
Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of taurursodiol. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and taurursodiol is a weak CYP3A inducer and P-gp inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of velpatasvir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and velpatasvir is a P-gp inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of velpatasvir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and velpatasvir is a P-gp inhibitor. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of voxilaprevir. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and voxilaprevir is a P-gp inhibitor.
Sorafenib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of sorafenib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and sorafenib is a P-gp inhibitor.
Sotorasib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of sotorasib. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Sparsentan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of sparsentan. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and sparsentan is a P-gp inhibitor.
Spironolactone: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of spironolactone. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of spironolactone. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of sirolimus and St. John's wort as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Stiripentol: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of stiripentol. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and stiripentol is a weak CYP3A inducer and P-gp inhibitor.
Streptogramins: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of quinupristin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and quinupristin is a weak CYP3A inhibitor.
Tacrolimus: (Moderate) The concomitant use of sirolimus with a calcineurin inhibitor, such as tacrolimus, may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. In addition to a potential increased risk of thrombotic microangiopathy, sirolimus may decrease the blood concentration of tacrolimus.
Tazemetostat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of tazemostat. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and tazemostat is a weak CYP3A inducer.
Tecovirimat: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of tecovirimat. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and tecovirimat is a weak CYP3A inducer.
Teduglutide: (Moderate) Teduglutide may increase absorption of sirolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of sirolimus is recommended.
Telmisartan; Amlodipine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Telotristat Ethyl: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of telotristat. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and telotristat is a weak CYP3A inducer.
Temsirolimus: (Contraindicated) Do not use sirolimus concomitantly with temsirolimus. Temsirolimus is extensively metabolized in the liver primarily by cytochrome P450 3A4, but also by P-glycoprotein (P-gp). Five metabolites are formed, but sirolimus is the principal and active metabolite; the remainder of the metabolites account for less than 10% of radioactivity in plasma. Residual sirolimus concentrations are present up to a week after temsirolimus administration.
Tepotinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of tepotinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and tepotinib is a P-gp inhibitor.
Tezacaftor; Ivacaftor: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivacaftor. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
Ticagrelor: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ticagrelor. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ticagrelor is a weak CYP3A and P-gp inhibitor.
Tipranavir: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Tofacitinib: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as sirolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Topiramate: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of topiramate. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and topiramate is a weak CYP3A inducer.
Trandolapril: (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.
Trandolapril; Verapamil: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of verapamil. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and verapamil is a moderate CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 2.2-fold in a drug interaction study. (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.
Trofinetide: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of trofinetide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Tucatinib: (Major) Avoid concomitant use of sirolimus and tucatinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and tucatinib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Upadacitinib: (Major) Avoid use of upadacitinib in combination with potent immunosuppressants such as sirolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Vemurafenib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vemurafenib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and vemurafenib is a P-gp inhibitor.
Venetoclax: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of venetoclax. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and venetoclax is a P-gp inhibitor.
Verapamil: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of verapamil. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and verapamil is a moderate CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 2.2-fold in a drug interaction study.
Viloxazine: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of viloxazine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and viloxazine is a weak CYP3A inhibitor.
Voclosporin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of voclosporin. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and voclosporin is a P-gp inhibitor.
Vonoprazan: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Voriconazole: (Contraindicated) Concomitant use of voriconazole with sirolimus is contraindicated; use may increase sirolimus exposure and risk for adverse effects. Sirolimus is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration has been observed to increase sirolimus peak and overall exposure by 7- and 11-fold, respectively
Voxelotor: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of voxelotor. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to sirolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving sirolimus. At least 2 weeks before initiation of sirolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Sirolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Zafirlukast: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of zafirlukast. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and zafirlukast is a weak CYP3A inhibitor.
Zanubrutinib: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of zanubrutinib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and zanubrutinib is a weak CYP3A inducer.
Zonisamide: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of zonisamide. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and zonisamide is a P-gp inhibitor.

HYFTOR Topical Gel: 0.2%
Rapamune/Sirolimus Oral Sol: 1mg, 1mL
Rapamune/Sirolimus Oral Tab: 0.5mg, 1mg, 2mg

Adults

40 mg per day PO; 800 mg (2.5 cm) per day for topical gel.

Geriatric

40 mg per day PO; 800 mg (2.5 cm) per day for topical gel.

Adolescents

40 mg per day PO; 800 mg (2.5 cm) per day for topical gel.

Children

12 years: 800 mg (2.5 cm) per day for topical gel; safety and efficacy of oral formulations have not been established.
6 to 11 years: 600 mg (2 cm) per day for topical gel; safety and efficacy of oral formulations have not been established.
1 to 5 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

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.
 
The mechanism by which sirolimus treats angiofibroma associated with tuberous sclerosis is unknown; however, tuberous sclerosis is associated with genetic defects in tuberous sclerosis 1 (TSC1) and TSC2 which leads to the activation of mTOR. As stated above, sirolimus inhibits mTOR activation.

Sirolimus is administered orally as either a tablet or an oral solution and topically as a gel. It is insoluble in aqueous media, and the oral solution is formulated in an oil base. Sirolimus is extensively distributed into erythrocytes with a mean blood to plasma ratio of 36 +/- 18 in stable renal transplant patients. The mean volume of distribution is 12 +/- 8 L/kg. Sirolimus is approximately 92% bound to plasma proteins, primarily albumin (97%), alpha1-acid glycoprotein, and lipoproteins. Sirolimus is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). Sirolimus undergoes extensive metabolism in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestines into the gut lumen. 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. It is extensively metabolized by O-demethylation and/or hydroxylation. Seven major metabolites are identifiable in whole blood including hydroxy, desmethyl, and hydroxydemethyl metabolites; however, sirolimus is the major component in human blood and accounts for more than 90% of its immunosuppressant activity. These metabolites are a small component of whole blood concentrations and contribute less than 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 (91%) with only 2.2% of the dose excreted in the urine.
 
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 less than 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.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
Sirolimus is a substrate of CYP3A4 and p-glycoprotein (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. Coadministration with inhibitors of both CYP3A4 and P-gp (e.g., diltiazem, erythromycin, or ketoconazole) increases sirolimus concentrations. Concurrent use of sirolimus with CYP3A4 and P-gp inducers decreases sirolimus concentrations.

Oral Route

The tablets and oral solution are not bioequivalent; however, clinical equivalence has been demonstrated at the 2-mg dose level. In a multi-dose study the average trough sirolimus concentration was found to increase approximately 2- to 3-fold over the initial 6 days, at which time steady-state was achieved, following repeated twice daily administration without an initial loading dose. In comparison, a loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients. Food affects bioavailability and sirolimus must be taken consistently with or without food. In healthy patients, a high-fate meal increased the mean total systemic exposure of sirolimus by 23 to 35% as compared with values after fasting. The effect of food on Cmax was inconsistent depending on dosage form.
 
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, given concomitantly with cyclosporine, in patients at low to moderate risk are 7.2 (3.6 to 11) and 14 (8 to 22), respectively. In another study involving patients at low to moderate risk, mean sirolimus whole blood trough concentrations were 8.6 ng/mL (5 to 13) with sirolimus plus cyclosporine compared to 19 ng/mL (14 to 22) with sirolimus alone. Among high risk patients, the mean whole blood trough concentrations were 15.7 ng/mL (5.4 to 27.3), 11.8 ng/mL (6.2 to 16.9), and 11.5 ng/mL (6.3 to 17.3) at up to 2 weeks, 2 to 6 weeks, and 26 to 52 weeks, respectively, of combination sirolimus and cyclosporine therapy. The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state require approximately 6 weeks.
 
Solution
Following administration of multiple doses of sirolimus oral solution 2 mg daily with cyclosporine and corticosteroids in adult renal transplant patients at low to moderate immunologic risk, the Tmax was 2.1 +/- 0.8 hours, Cmax was 14.4 +/- 5.3 ng/mL, Cmin was 7.1 +/- 3.5 ng/mL, and AUC was 194 +/- 78 ng x hour/mL. The bioavailability is about 14% after administration of the oral solution. After administration of the oral solution to renal transplant patients, sirolimus concentrations are dose proportional between 3 and 12 mg/m2.
 
Tablets
Following administration of multiple doses of sirolimus oral tablet 2 mg daily with cyclosporine and corticosteroids in adult renal transplant patients at low to moderate immunologic risk, the Tmax was 3.5 +/- 2.4 hours, Cmax was 15 +/- 4.9 ng/mL, Cmin was 7.6 +/- 3.1 ng/mL, and AUC was 230 +/- 67 ng x hour/mL. In healthy patients, the mean bioavailability of the tablet is about 27% higher relative to the oral solution. In 37 lymphangioleiomyomatosis patients, median whole blood trough concentration following 3 weeks of treatment with sirolimus tablets 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9 ng/mL).

Topical Route

Following 12 weeks of treatment with sirolimus topical gel in adults and pediatric patients (6 years and older), sirolimus blood concentrations ranged from undetectable to 0.5 ng/mL. Periodic blood samples were also obtained in the 52-week trial. In this trial, the maximum sirolimus concentration measured at any time in adults was 3.27 ng/mL and the maximum concentration at any time in pediatric subjects was 1.8 ng/mL. Based on blood concentrations, there was no evidence that sirolimus accumulates systemically upon topical application in patients with tuberous sclerosis for periods of up to 1 year.

Pregnancy

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

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