Version October 2024
Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression.
Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving sirolimus should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near the time of death. In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis; most cases of hepatic artery thrombosis occurred within 30 days post transplantation, and most led to graft loss or death. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.
Note: Refer to the Sirolimus (Protein Bound) monograph for dosing and information related to the IV sirolimus protein-bound formulation. Patient should be under the care of a clinician experienced in immunosuppressive therapy and management of the specific indication.
Chordoma, advanced: Oral: 2 mg once daily adjusted to maintain a trough level between 15 and 20 ng/mL (in combination with imatinib) until disease progression or unacceptable toxicity (Ref).
Graft-versus-host disease (off-label use):
Graft-versus-host disease, prevention:
Note: Typically used in combination with other immunosuppressive therapies; refer to study protocols for further information.
Oral: 2 mg once daily initially starting 3 days prior to allogeneic hematopoietic cell transplant and adjusted to maintain trough levels between 3 and 12 ng/mL through day 150, followed by a taper through day 180 (Ref) or through day 180, followed by a taper through day 365 (Ref) in the absence of graft-versus-host disease (GVHD) (in combination with cyclosporine and mycophenolate mofetil) (Ref) or 12 mg loading dose starting 3 days prior to allogeneic hematopoietic cell transplant, followed by 4 mg daily (target sirolimus trough level: 3 to 12 ng/mL; in combination with tacrolimus ± methotrexate); taper off after 6 to 9 months (Ref).
Graft-versus-host disease, acute, treatment:
Newly diagnosed standard-risk acute graft-versus-host disease: Oral: 6 mg loading dose, followed by maintenance dosing to maintain a target trough between 10 to 14 ng/mL until resolution of acute GVHD, then titrate dose to a target trough of 5 to 10 ng/mL after resolution of acute GVHD until at least day 56, then taper to discontinue by 3 months from day 56 (Ref).
Refractory acute graft-versus-host disease: Oral: 4 to 5 mg/m2 for 14 days (no loading dose) (Ref).
Graft-versus-host disease, chronic treatment: Oral: 6 mg loading dose, followed by 2 mg daily (target trough level: 7 to 12 ng/mL) for 6 to 9 months (Ref).
Heart transplantation, prophylaxis of rejection and allograft vasculopathy (off-label use):
Note: Avoid use in the immediate post–heart transplant period (eg, ≤30 days post transplant) due to risk for adverse effects (eg, impaired wound healing, infection) (Ref). Dose and target sirolimus trough concentrations must be highly individualized based on time from transplant, assay method, and concurrent therapies. The following are examples of dosing regimens based on the available literature; refer also to institutional protocols:
Calcineurin inhibitor minimization:
Note: With this approach, the antiproliferative (eg, mycophenolate) is typically discontinued. The calcineurin inhibitor (CNI) dose and target trough concentration should be reduced when sirolimus is initiated to reduce the risk of kidney toxicity (Ref).
Oral: Upon discontinuation of antiproliferative, administer sirolimus 6 mg loading dose followed by 2 mg once daily titrated to target trough concentrations between 4 and 12 ng/mL (Ref).
Calcineurin inhibitor avoidance:
Note: Conversion from a CNI to sirolimus may be undertaken >1 month post transplant in carefully selected individuals with compelling indications for mTOR inhibitor therapy (eg, CNI toxicity or intolerance) (Ref).
Immediate calcineurin inhibitor dose reduction approach: Oral: Reduce cyclosporine by 25 mg twice daily or tacrolimus by 1 mg twice daily, followed by initiation of sirolimus 1 mg once daily. Adjust sirolimus dose to target trough concentrations between 8 and 14 ng/mL; once target trough concentrations achieved, withdraw CNI and repeat biopsy 2 weeks after CNI withdrawal (Ref).
Delayed calcineurin inhibitor dose reduction approach: Oral: Initiate sirolimus 1 mg once daily for 1 week, then adjust sirolimus to target trough concentrations between 10 and 15 ng/mL over the following 2 weeks. Once sirolimus target trough concentrations achieved, reduce CNI dose to achieve 50% of initial CNI target concentrations, then after 2 weeks evaluate for rejection. If no rejection, continue same regimen for an additional month, then reduce CNI further to achieve 25% of initial CNI target concentrations. Repeat biopsy 2 weeks later and if no rejection, may discontinue CNI after 2 additional weeks. Continue to maintain sirolimus trough concentrations between 10 and 15 ng/mL after CNI discontinuation (usual doses required to maintain target levels: 1 to 8 mg daily) (Ref).
Kidney transplantation, rejection prophylaxis: Note: Use generally avoided in patients with hyperlipidemia (ie, serum cholesterol >300 mg/dL, triglycerides >400 mg/dL), serum creatinine >4 mg/dL, or proteinuria >1 g/day (Ref). Dose and target sirolimus trough concentrations must be highly individualized based on time from transplant, assay method, and concurrent therapies. The following are examples of dosing regimens based on the available literature; refer also to institutional protocols:
Initial dosage:
Calcineurin inhibitor minimization: Oral: 6 mg loading dose on day 1, followed by 2 mg once daily (per manufacturer) in combination with calcineurin inhibitor (CNI) and corticosteroids; adjust dose to maintain trough concentrations between 3 and 8 ng/mL (Ref).
Calcineurin inhibitor avoidance : Oral: 12 to 15 mg loading dose between 4 and 24 hours after last CNI dose, followed by 4 to 8 mg once daily thereafter (in combination with adjunctive agents and corticosteroids); adjust dose to maintain trough concentrations between 8 and 12 ng/mL (Ref).
Dosage adjustment: Adjust dose at 7- to 14-day intervals (due to long half-life) to maintain 24-hour trough concentrations within desired range based on risk and concomitant therapy (Ref).
Liver transplantation, rejection prophylaxis (off-label use): Note: Sirolimus should not be used until >30 days post transplant to mitigate the risk of hepatic artery thrombosis (Ref). Dose and target sirolimus trough concentrations must be highly individualized based on time from transplant, assay method, and concurrent therapies. The following are examples of dosing regimens based on the available literature; refer also to institutional protocols.
Calcineurin inhibitor minimization: Oral: 2 mg once daily in combination with a calcineurin inhibitor (CNI), with or without corticosteroids; reduce the CNI dose by 50% when sirolimus is initiated. Adjust sirolimus dose to maintain target trough concentrations between 4 and 10 ng/mL (Ref).
Calcineurin inhibitor avoidance: Oral: 2 to 4 mg once daily in combination with mycophenolic acid derivatives, with or without corticosteroids; initiate sirolimus within 24 hours after the last dose of the CNI. Adjust dose to maintain sirolimus trough concentrations between 5 and 10 ng/mL (Ref).
Lung transplantation, rejection prophylaxis (off-label use): Note: Do not initiate sirolimus until after the bronchial anastomosis has completely healed (approximately 90 days) due to potential fatal airway dehiscence with earlier initiation (Ref). Dose and target sirolimus trough concentrations must be highly individualized based on time from transplant, assay method, and concurrent therapies. The following is an example of a dosing regimen based on the available literature; refer also to institutional protocols.
Calcineurin inhibitor minimization: Oral: 1 to 2 mg once daily in combination with a calcineurin inhibitor (CNI), with or without corticosteroids; reduce CNI trough target once sirolimus is initiated. Adjust sirolimus dose to maintain target trough concentrations between 6 and 10 ng/mL (Ref).
Lymphangioleiomyomatosis: Initial: Oral: 2 mg once daily. Obtain first trough concentration in 10 to 21 days; adjust dose to maintain a target concentration of 5 to 15 ng/mL (Ref).
Dosage adjustment: Once the maintenance dose is adjusted, further adjustments should be made at 7- to 14-day intervals to account for the long half-life of sirolimus. In general, dose proportionality may be assumed. New sirolimus dose equals current dose multiplied by (target concentration divided by current concentration). Once a stable dose is achieved, trough concentrations should be assessed at least every 3 months.
Renal angiomyolipoma (off-label use): Initial: Oral: 0.5 mg/m2 once daily titrated to a target trough level of 3 to 6 ng/mL (may increase to target trough level of 6 to 10 ng/mL if <10% reduction in lesion diameters at 2 months) for 2 years (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment is necessary. However, adjustment of regimen (including discontinuation of therapy) should be considered when used concurrently with cyclosporine and elevated or increasing serum creatinine is noted.
Loading dose: No dosage adjustment is necessary.
Maintenance dose:
Mild to moderate impairment (Child-Pugh classes A and B): Reduce maintenance dose by ~33%.
Severe impairment (Child-Pugh class C): Reduce maintenance dose by ~50%.
Refer to adult dosing.
(For additional information see "Sirolimus (conventional): Pediatric drug information")
Dosage guidance:
Safety: Dosing presented as both BSA directed (mg/m2) and fixed doses (mg); use caution. Sirolimus tablets and oral solution are not bioequivalent due to differences in absorption; however, clinical equivalence has been demonstrated at the 2 mg dose.
Clinical considerations: Dosage should be individualized and based on monitoring of serum trough concentrations; target range is variable and may depend upon transplantation type, length of time since transplant, renal function, infection, rejection history, drug combinations used, and side effects of individual agents.
Heart transplantation: Limited data available:
Note: Titrate to institution-specific goal trough concentration. Use in combination with cyclosporine or tacrolimus to decrease side effects (eg, renal toxicity or post-transplant lymphoproliferative disease), following retransplantation (treatment of rejection), or to prevent or promote regression of transplant coronary artery disease (Ref). May also be considered as part of a regimen that eliminates the use of cyclosporine or tacrolimus (Ref).
Children and Adolescents:
Loading dose: Oral: 3 mg/m2 once; maximum dose: 6 mg/dose (Ref).
Maintenance dose: Oral: Initial: 1 mg/m2/day; maximum initial dose: 2 mg/dose; doses have been administered once daily or in divided doses twice daily; larger doses may be required to attain goal serum trough concentrations; doses as high as 7 mg/m2/day (or 0.25 mg/kg/day) have been reported (Ref).
Pulmonary vein stenosis; post-surgical or catheter intervention: Very limited data available: Note: Titrate to institution-specific goal serum trough concentration.
Infants ≥4 months: Oral: Initial: 1 mg/m2/dose once daily. A loading dose of 2 mg/m2/dose on day 1 may be recommended in patients on bosentan. Monitor troughs closely (Ref). Higher doses of 0.8 mg/m2/dose every 12 hours have also been described (Ref).
Children: Oral: Initial: 1 mg/m2/dose once daily; maximum initial dose: 2 mg/dose. An optional loading dose of 2 to 3 mg/m2/dose on day 1 can be considered; maximum loading dose: 6 mg/dose; in one trial, therapy was initiated within 24 hours following stent placement and continued for 8 weeks (Ref).
Renal transplantation, prophylaxis of organ rejection (low to moderate immunologic risk): Note: Titrate to institution-specific goal serum trough concentration.
Conversion from tacrolimus in patients with stable graft function at least 3 months post-transplant:
Children and Adolescents: Limited data available: Oral: Loading dose: 5 mg/m2 once; initial maintenance dose: 3 mg/m2/day divided every 12 hours (Ref).
In combination with cyclosporine:
Adolescents:
Weight <40 kg: Oral: Loading dose: 3 mg/m2 on day 1; initial maintenance dose: 1 mg/m2/day once daily.
Weight ≥40 kg: Oral: Loading dose: 6 mg on day 1; maintenance dose: 2 mg once daily.
Dosage adjustment: Sirolimus dosages should be adjusted to maintain trough concentrations within desired range based on risk and concomitant therapy; maximum daily dose: 40 mg/day. Dosage should be adjusted at intervals of 7 to 14 days to account for the long half-life of sirolimus; in children receiving twice-daily dosing, serum concentrations should be checked earlier due to pharmacokinetic differences. In general, dose proportionality may be assumed.
New sirolimus dose = current dose (target concentration ÷ current concentration)
If large dose increase is required, consider loading dose calculated as:
Loading dose = (new maintenance dose – current maintenance dose) × 3
Maximum daily dose: 40 mg/day; if required dose is >40 mg (due to loading dose), divide over 2 days. Serum concentrations should be monitored 3 to 4 days after a loading dose and should not be used as the sole basis for dosage adjustment (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters).
Maintenance therapy after withdrawal of cyclosporine: Following 2 to 4 months of combined therapy, withdrawal of cyclosporine may be considered in low- to moderate-risk patients. Cyclosporine should be discontinued over 4 to 8 weeks, and a necessary increase in the dosage of sirolimus (up to 4-fold) should be anticipated due to removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects.
Vascular anomalies/tumors (eg, Kaposiform hemangioendothelioma, lymphatic malformations); refractory: Limited data available: Note: Titrate to institution-specific goal serum trough concentration.
Infants <6 months: Oral: Oral solution: Initial: 0.4 mg/m2/dose every 12 hours (Ref). Based on use in other indications, consider lower dosing in young infants (Ref).
Infants ≥6 months, Children, and Adolescents: Oral: Initial: 0.8 mg/m2/dose every 12 hours (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary (in loading or maintenance dose); however, adjustment of regimen (including discontinuation of therapy) should be considered when used concurrently with cyclosporine and elevated or increasing serum creatinine is noted.
Loading dose: No dosage adjustment required.
Maintenance dose:
Mild to moderate hepatic impairment: Reduce maintenance dose by ~33%.
Severe hepatic impairment: Reduce maintenance dose by ~50%.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adolescent and adult renal transplant recipients receiving concomitant therapy unless otherwise noted for lymphangioleiomyomatosis (LAM).
>10%:
Cardiovascular: Chest pain (LAM: ≥20%), edema (18% to 20%), hypertension (49%), peripheral edema (LAM: ≥20%; renal transplant: 54% to 58%), tachycardia (3% to 20%), venous thromboembolism (3% to 20%; including deep vein thrombosis, pulmonary embolism)
Dermatologic: Acne vulgaris (LAM: ≥20%; renal transplant: 22%), skin rash (10% to 20%)
Endocrine & metabolic: Diabetes mellitus (3% to 20%), hypercholesterolemia (LAM: ≥20%; renal transplant: 43% to 46%), hypertriglyceridemia (45% to 57%), hypokalemia (3% to 20%), increased lactate dehydrogenase (3% to 20%), menstrual disease (3% to 20%; including amenorrhea, heavy menstrual bleeding)
Gastrointestinal: Abdominal pain (LAM: ≥20%; renal transplant: 36%), constipation (36% to 38%), diarrhea (LAM: ≥20%; renal transplant: 35%), nausea (LAM: ≥20%; renal transplant: 31%), stomatitis (LAM: ≥20%; renal transplant: 3% to 20%)
Genitourinary: Ovarian cyst (3% to 20%), urinary tract infection (33%)
Hematologic & oncologic: Anemia (23% to 33%), hemolytic-uremic syndrome (3% to 20%), leukopenia (3% to 20%), lymphocele (3% to 20%), thrombocytopenia (14% to 30%), thrombotic thrombocytopenic purpura (3% to 20%)
Infection: Herpes simplex infection (3% to 20%), herpes zoster infection (3% to 20%), sepsis (3% to 20%)
Nervous system: Dizziness (LAM: ≥20%), headache (LAM: ≥20%; renal transplant: 34%), pain (29% to 33%)
Neuromuscular & skeletal: Arthralgia (25% to 31%), myalgia (LAM: ≥20%), osteonecrosis (3% to 20%)
Renal: Increased serum creatinine (39% to 40%), pyelonephritis (3% to 20%)
Respiratory: Epistaxis (3% to 20%), nasopharyngitis (LAM: ≥20%), pneumonia (3% to 20%), upper respiratory tract infection (LAM: ≥20%)
Miscellaneous: Wound healing impairment (3% to 20%; including anastomosis disruption [wound, vascular, airway, ureteral, biliary], dehiscence [fascial], incisional hernia, wound dehiscence)
1% to 10%:
Dermatologic: Skin carcinoma (including basal cell carcinoma of skin [≤7%], malignant melanoma [≤1%], squamous cell carcinoma [≤3%])
Gastrointestinal: Pancreatitis (<3%)
Hematologic & oncologic: Lymphoproliferative disorder (≤3%; including malignant lymphoma), malignant neoplasm (1% to 2%)
Infection: Cytomegalovirus disease (<3%), Epstein-Barr infection (<3%), mycobacterium infection (<3%; including tuberculosis)
Frequency not defined:
Endocrine & metabolic: Weight loss (LAM)
Infection: Increased susceptibility to infection (including opportunistic infection)
Postmarketing:
Cardiovascular: Cardiac tamponade (Bertrand 2013), pericardial effusion (Meng 2019)
Dermatologic: Desquamation (palmoplantar) (Liu 2014), exfoliative dermatitis, Merkel cell carcinoma
Endocrine & metabolic: Fluid retention, hyperglycemia, hypophosphatemia
Gastrointestinal: Clostridium difficile colitis
Genitourinary: Azoospermia, proteinuria (Hamdy 2010)
Hematologic & oncologic: Lymphedema (Rashid-Farokhi 2017; Tauveron 2015), neutropenia, pancytopenia, thrombotic microangiopathy (Sartelet 2005)
Hepatic: Abnormal hepatic function tests (including increased serum alanine aminotransferase, increased serum aspartate aminotransferase), ascites, hepatic necrosis, hepatitis (acute) (Jacques 2010), hepatotoxicity
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, angioedema, hypersensitivity angiitis, nonimmune anaphylaxis) (Pasqualotto 2004; Wadei 2004)
Nervous system: Progressive multifocal leukoencephalopathy, reversible posterior leukoencephalopathy syndrome (Gheith 2017)
Renal: Focal segmental glomerulosclerosis, kidney disease (BK virus-associated), nephrotic syndrome
Respiratory: Interstitial lung disease (including cryptogenic organizing pneumonia, pneumonitis, pulmonary fibrosis) (Haydar 2004; Mingos 2005), pleural effusion (Rashid-Farokhi 2017), pulmonary alveolitis, pulmonary hemorrhage, pulmonary toxicity (Saleemi 2020)
Miscellaneous: Drug fever (Aires 2009)
Hypersensitivity to sirolimus or any component of the formulation
Concerns related to adverse effects:
• Anaphylactic/hypersensitivity reactions: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been reported.
• Angioedema: Has been reported; risk is increased in patients with elevated sirolimus levels and/or concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors). Angioedema resolved following discontinuation or dose reduction in some cases.
• Infections: Immunosuppressive agents, including sirolimus, increase the risk of infection. Immune suppression may also increase the risk of opportunistic infections including activation of latent viral infections (including BK virus-associated nephropathy), fatal infections, and sepsis. Prophylactic treatment for Pneumocystis jirovecii pneumonia (PCP) should be administered for 1 year post transplant; prophylaxis for cytomegalovirus (CMV) should be taken for 3 months post transplant in patients at risk for CMV. Progressive multifocal leukoencephalopathy (PML), an opportunistic CNS infection caused by reactivation of the JC virus, has been reported in patients receiving immunosuppressive therapy, including sirolimus. Clinical findings of PML include apathy, ataxia, cognitive deficiency, confusion, and hemiparesis; promptly evaluate any patient presenting with neurological changes; consider decreasing the degree of immunosuppression with consideration to the risk of organ rejection in transplant recipients.
• Interstitial lung disease: Cases of interstitial lung disease (ILD) (eg, pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], pulmonary fibrosis) have been observed (some fatal); may be associated with pulmonary hypertension (including pulmonary arterial hypertension) and risk may be increased with higher trough levels. ILD may resolve with dose reduction or discontinuation of therapy.
• Hyperlipidemia: May increase serum lipids (cholesterol and triglycerides). Use with caution in patients with hyperlipidemia. Monitor cholesterol/lipids; if hyperlipidemia occurs, follow current guidelines for management (diet, exercise, lipid lowering agents). Antihyperlipidemic therapy may not be effective in normalizing levels.
• Kidney effects: May increase serum creatinine and decrease GFR with long-term combination use of sirolimus and cyclosporine. Immunosuppressed patients are at an increased risk of BK viral-associated nephropathy, which may impair kidney function and cause graft loss; consider decreasing immunosuppressive burden if evidence of deteriorating kidney function. Use with caution in patients concurrently taking medications that may alter kidney function.
• Lymphocele/fluid accumulation: Use has been associated with an increased risk of fluid accumulation and lymphocele. Peripheral edema, lymphedema, ascites, and pleural and pericardial effusions (including significant effusions and tamponade) were reported; use with caution in patients in whom fluid accumulation may be poorly tolerated, such as in cardiovascular disease (heart failure or hypertension) and pulmonary disease.
• Malignancy: Immunosuppressive agents, including sirolimus, may be associated with the development of lymphoma and other malignancies, including an increased risk of skin cancer; limit sun and ultraviolet light exposure; use appropriate sun protection.
• Proteinuria: Increased urinary protein excretion has been observed when converting kidney transplant recipients from calcineurin inhibitors to sirolimus during maintenance therapy. A higher level of proteinuria prior to sirolimus conversion correlates with a higher degree of proteinuria after conversion. In some patients, proteinuria may reach nephrotic levels; nephrotic syndrome (new onset) has been reported.
• Wound dehiscence/healing: May be associated with wound dehiscence and impaired healing; use caution in the perioperative period. Patients with a body mass index (BMI) >30 kg/m2 are at increased risk for abnormal wound healing.
Concurrent drug therapy issues:
• Calcineurin inhibitors: Concurrent use with a calcineurin inhibitor (cyclosporine, tacrolimus) may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).
• Cyclosporine: Safety and efficacy of combination therapy with cyclosporine in high immunologic risk patients have not been studied beyond 12 months of treatment. Monitor kidney function closely when combined with cyclosporine; consider dosage adjustment or discontinue in patients with increasing serum creatinine.
• Vaccines: Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective. The use of live vaccines should be avoided.
Special populations:
• Kidney transplant: In kidney transplant recipients, de novo use without cyclosporine has been associated with higher rates of acute rejection. Sirolimus may delay recovery of kidney function in patients with delayed allograft function.
• Liver transplants: Sirolimus is not recommended for use early post transplant; studies indicate an association with an increased risk of hepatic artery thrombosis (HAT), graft failure, and increased mortality (with evidence of infection) in these patients when sirolimus is used in combination with cyclosporine and/or tacrolimus. Most cases of HAT occurred within 30 days of transplant.
• Lung transplants: Sirolimus is not recommended for use early post lung transplantation. Bronchial anastomotic dehiscence cases have been reported in lung transplant recipients when sirolimus was used as part of an immunosuppressive regimen; most of these reactions were fatal.
Dosage form specific issues:
• Product interchangeability: Sirolimus tablets and oral solution are not bioequivalent, due to differences in absorption. Clinical equivalence was seen using 2 mg tablet and 2 mg solution. It is not known if higher doses are also clinically equivalent. Monitor sirolimus levels if changes in dosage forms are made.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).
Other warnings/precautions:
• Experienced physician: Should only be used by physicians experienced in immunosuppressive therapy and management of transplant recipients. Adequate laboratory and supportive medical resources must be readily available.
• Laboratory monitoring: Sirolimus concentrations are dependent on the assay method (eg, chromatographic and immunoassay) used; assay methods are not interchangeable. Variations in methods to determine sirolimus whole blood concentrations, as well as interlaboratory variations, may result in improper dosage adjustments, which may lead to subtherapeutic or toxic levels. Determine the assay method used to assure consistency (or accommodations if changes occur), and for monitoring purposes, be aware of alterations to assay method or reference range and that values from different assays may not be interchangeable.
Animal studies have indicated that sirolimus may inhibit skeletal and muscle growth. There has been at least one human case report of growth failure in a child (Hymes 2011).
Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Rapamune: 1 mg/mL (60 mL) [contains alcohol, usp, polysorbate 80, propylene glycol, soybeans (glycine soja)]
Generic: 1 mg/mL (60 mL)
Tablet, Oral:
Rapamune: 0.5 mg, 1 mg, 2 mg
Generic: 0.5 mg, 1 mg, 2 mg
Yes
Solution (Rapamune Oral)
1 mg/mL (per mL): $39.28
Solution (Sirolimus Oral)
1 mg/mL (per mL): $31.58 - $35.00
Tablets (Rapamune Oral)
0.5 mg (per each): $20.63
1 mg (per each): $41.25
2 mg (per each): $82.50
Tablets (Sirolimus Oral)
0.5 mg (per each): $8.47 - $8.65
1 mg (per each): $16.95 - $17.05
2 mg (per each): $31.50 - $33.90
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Rapamune: 1 mg/mL (60 mL) [contains alcohol, usp, polysorbate 80, propylene glycol, soybean oil]
Tablet, Oral:
Rapamune: 1 mg
Oral: Administer consistently (either with or without food). Kidney transplant: Sirolimus should be taken 4 hours after oral cyclosporine (Neoral or Gengraf).
Solution: Mix (by stirring vigorously) with at least 60 mL of water or orange juice. No other liquids should be used for dilution. Patient should drink diluted solution immediately. The cup should then be refilled with an additional 120 mL of water or orange juice, stirred vigorously, and the patient should drink the contents at once.
Tablet: Do not crush, split, or chew.
Oral: May be taken with or without food, but take medication consistently with respect to meals to minimize absorption variability. Initial dose should be administered as soon as possible after transplant. Sirolimus should be taken 4 hours after oral cyclosporine (Neoral or Gengraf).
Oral solution: Use amber oral syringe to withdraw solution from the bottle. Empty dose from syringe into a glass or plastic cup and mix with at least 2 ounces (60 mL) of water or orange juice. No other liquids should be used for dilution. Patient should stir vigorously and drink the diluted sirolimus solution immediately. Then refill cup with an additional 4 ounces (120 mL) of water or orange juice; stir contents vigorously and have patient drink solution at once.
Oral tablets: Do not crush, split, or chew.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021083s067,021110s085lbl.pdf#page=43, must be dispensed with this medication.
Kidney transplantation (rejection prophylaxis): Prophylaxis of organ rejection in patients receiving kidney transplants (in low-to-moderate immunologic risk patients in combination with cyclosporine and corticosteroids with cyclosporine withdrawn 2 to 4 months after transplant, and in high immunologic risk patients in combination with cyclosporine and corticosteroids for the first year after transplant). Therapeutic drug monitoring is recommended for all patients receiving sirolimus. High immunologic risk kidney transplant recipients are defined (per the manufacturer's labeling) as Black transplant recipients and/or repeat kidney transplant recipients who lost a previous allograft based on an immunologic process and/or patients with high PRA (panel-reactive antibodies; peak PRA level >80%).
Limitations of use (kidney transplantation): Cyclosporine withdrawal has not been studied in patients with Banff grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, patients who are dialysis-dependent, patients with serum creatinine >4.5 mg/dL, Black patients, patients with multiorgan transplants or secondary transplants, or those with high levels of PRA. In patients at high immunologic risk, the safety and efficacy of sirolimus used in combination with cyclosporine and corticosteroids have not been studied beyond 1 year; therefore, after the first 12 months following transplantation, consider any adjustments to the immunosuppressive regimen on the basis of the clinical status of the patient. The safety and efficacy of sirolimus have not been established in patients younger than 13 years or in pediatric kidney transplant recipients younger than 18 years who are considered at high immunologic risk. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the care of kidney transplant recipients recommend not initiating sirolimus until graft function has been established and surgical wounds have healed (KDIGO 2009). Avoid the use of sirolimus in combination with calcineurin inhibitors, particularly in the early posttransplant period due to an increased risk of nephrotoxicity (KDIGO 2009; Webster 2006).
Lymphangioleiomyomatosis: Treatment of lymphangioleiomyomatosis. Therapeutic drug monitoring is recommended for all patients receiving sirolimus.
Chordoma, advanced; Graft-versus-host disease, prevention; Graft-versus-host disease, acute, treatment; Graft-versus-host disease, chronic, treatment; Heart transplant (prophylaxis of organ rejection and allograft vasculopathy); Liver transplantation (rejection prophylaxis); Lung transplantation (rejection prophylaxis); Renal angiomyolipoma
Rapamune may be confused with Rapaflo.
Sirolimus (conventional) may be confused with everolimus, pimecrolimus, silodosin, sirolimus (protein bound), sirolimus (topical), tacrolimus, temsirolimus, temozolomide, tesamorelin.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (immunosuppressant agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care and Long-Term Care Settings).
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Adalimumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Sirolimus Products may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihepaciviral Combination Products: May increase the serum concentration of Sirolimus (Conventional). Risk X: Avoid combination
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bimekizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Bulevirtide: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Cannabidiol: May increase the serum concentration of Sirolimus (Conventional). Management: A dose reduction of sirolimus should be considered when combined with cannabidiol. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Clotrimazole (Oral): May increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Clotrimazole (Topical): May increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
CycloSPORINE (Systemic): Sirolimus (Conventional) may enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE (Systemic) may increase the serum concentration of Sirolimus (Conventional). This is of specific concern with cyclosporine [MODIFIED]. Management: Administer oral doses of sirolimus 4 hours after doses of cyclosporine. Monitor for toxic effects of sirolimus if used with cyclosporine. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Sirolimus (Conventional). Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Risk D: Consider therapy modification
CYP3A4 Inducers (Weak): May decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Sirolimus (Conventional). Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with strong CYP3A4 inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Concomitant use of sirolimus and voriconazole or posaconazole is contraindicated. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Weak): May increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Dinutuximab Beta: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Elacestrant: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Management: If coadministration with these narrow therapeutic index/sensitive P-gp substrates is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of these P-gp substrates. Risk D: Consider therapy modification
Erythromycin (Systemic): May increase the serum concentration of Sirolimus (Conventional). Sirolimus (Conventional) may increase the serum concentration of Erythromycin (Systemic). Management: Monitor for increased serum concentrations of sirolimus if combined with erythromycin. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modification
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification
Futibatinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Gastrointestinal Agents (Prokinetic): May increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Givinostat: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Grapefruit Juice: May increase the serum concentration of Sirolimus (Conventional). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Consider alternatives to this combination when possible. If combined, monitor for decreased effectiveness of these CYP3A4 substrates if combined with ivosidenib. Risk D: Consider therapy modification
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Maribavir: May increase the serum concentration of Sirolimus Products. Risk C: Monitor therapy
Mavacamten: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Micafungin: May increase the serum concentration of Sirolimus Products. Risk C: Monitor therapy
Milk Thistle: May increase the serum concentration of Sirolimus Products. Risk C: Monitor therapy
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Nirmatrelvir and Ritonavir: May increase the serum concentration of Sirolimus (Conventional). Management: Consider avoiding this combination, if possible, through use of alternative anti-COVID-19 therapy. If combined, hold sirolimus during nirmatrelvir/ritonavir treatment and for at least 2 to 3 days after completion. Monitor sirolimus levels closely. Risk D: Consider therapy modification
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olutasidenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid use of olutasidenib with sensitive or narrow therapeutic index CYP3A4 substrates when possible. If concurrent use with olutasidenib is unavoidable, monitor closely for evidence of decreased concentrations of the CYP3A4 substrates. Risk D: Consider therapy modification
Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inducers when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for decreased sirolimus concentrations if combined. Risk D: Consider therapy modification
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Posaconazole: May increase the serum concentration of Sirolimus (Conventional). Risk X: Avoid combination
Pretomanid: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Rifabutin: May decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Sotagliflozin: May decrease the serum concentration of Sirolimus (Conventional). Sotagliflozin may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with sotagliflozin when possible. If combined, monitor for increases or decreases in sirolimus concentrations and increased sirolimus toxicities. Sirolimus dose adjustments may be required. Risk D: Consider therapy modification
Sparsentan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Spironolactone: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Tacrolimus (Systemic): May enhance the adverse/toxic effect of Sirolimus Products. Sirolimus Products may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus Products may decrease the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Taurursodiol: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk X: Avoid combination
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Tovorafenib: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid concurrent use whenever possible; if the combination cannot be avoided, monitor closely for reduced effectiveness of the CYP3A4 substrate. Risk D: Consider therapy modification
Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Trofinetide: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Ustekinumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vedolizumab: May decrease the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Sirolimus (Conventional). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Grapefruit juice may decrease clearance of sirolimus. Ingestion with high-fat meals decreases peak concentrations but increases AUC by 23% to 35%. Management: Avoid grapefruit juice. Take consistently (either with or without food) to minimize variability.
Patients who could become pregnant should use highly effective contraception prior to initiation of sirolimus, during treatment, and for 12 weeks after sirolimus is discontinued.
Sirolimus may impair fertility. Ovarian cysts, amenorrhea, menorrhagia, azoospermia, or oligospermia have been observed following use of oral sirolimus. Sperm banking prior to sirolimus treatment may be considered (KDIGO 2009).
Agents other than sirolimus may be preferred for patients who have had a kidney transplant and are planning to become pregnant (Agarwal 2021; Cabiddu 2018; EBPG 2002; KDIGO 2009; Longhitano 2021; López 2014).
Sirolimus has been evaluated for the treatment of recurrent implantation failure in patients undergoing in vitro fertilization (Ahmadi 2019; Wang 2021).
Sirolimus crosses the placenta (Barnes 2018; Park 2019).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to sirolimus may cause fetal harm.
Outcome data following maternal use of sirolimus in pregnant patients who have had organ transplants is limited (Boulay 2021; Framarino dei Malatesta 2011; Sifontis 2006). Although an increased risk of congenital anomalies has not been observed, due to adverse events observed in animal reproduction studies, agents other than sirolimus may be preferred for use in pregnant patients who have had a kidney transplant (Agarwal 2021; Cabiddu 2018; EBPG 2002; KDIGO 2009; Longhitano 2021; López 2014; Ponticelli 2021).
The use of sirolimus for the treatment of lymphangioleiomyomatosis during pregnancy has been reported (Faehling 2015; Shen 2021); however, available data are insufficient to make recommendations (Gupta 2018; McCormack 2016).
Case reports describe maternal administration of sirolimus for the in-utero treatment of fetal cardiac rhabdomyomas that were possibly associated with tuberous sclerosis complex (Barnes 2018; Dagge 2021; Ebrahimi-Fakhari 2021; Park 2019; Pluym 2020; Vachon-Marceau 2019).
The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.
It is not known if sirolimus is present in breast milk.
According to the manufacturer, the decision to breastfeed during sirolimus therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of sirolimus treatment to the mother.
Baseline fasting lipid panel; urine protein prior to initiation; also consider baseline pulmonary function testing in patients with impaired pulmonary function who are at high risk for pulmonary toxicity. Monitor organ-specific rejection parameters (eg, serum creatinine for kidney transplant recipients) and CBC during treatment. Monitor sirolimus levels in all patients (especially in pediatric patients, patients ≥13 years of age weighing <40 kg, patients with hepatic impairment, or on concurrent potent inhibitors or inducers of CYP3A4 or P-gp, and/or if cyclosporine dosing is markedly reduced or discontinued), and when changing dosage forms of sirolimus. Also monitor serum cholesterol and triglycerides, blood pressure, serum creatinine, and urinary protein. Serum drug concentrations should be determined 3 to 4 days after loading doses and 7 to 14 days after dosage adjustments for kidney transplant recipients; however, these concentrations should not be used as the sole basis for dosage adjustment, especially during withdrawal of cyclosporine (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters). Monitor serum trough concentration 10 to 20 days after initiating therapy for lymphangioleiomyomatosis and 7 to 14 days after dosage adjustments. Once a stable dose is achieved, trough concentrations should be assessed at least every 3 months. Note: Concentrations and ranges are dependent on and will vary with assay methodology (chromatographic or immunoassay); assay methods are not interchangeable.
Oncology uses: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow up. Monitor adherence.
Note: Sirolimus concentrations are dependent on the assay method (eg, chromatographic and immunoassay) used; assay methods are not interchangeable. Determine the assay method used to assure consistency (or accommodations if changes occur) and for monitoring purposes, be aware of alterations to assay method or reference range. Refer to institutional protocols for target sirolimus trough concentration goals.
Serum trough concentrations for advanced chordoma (off-label use): 15 to 20 ng/mL (Stacchiotti 2009).
Serum trough concentrations for graft-versus-host disease prophylaxis in allogeneic stem cell transplant (off-label use): 3 to 12 ng/mL (Armand 2008; Cutler 2007).
Serum trough concentrations for lymphangioleiomyomatosis: 5 to 15 ng/mL.
Serum trough concentrations for renal angiomyolipoma (off-label use): 3 to 6 ng/mL; may increase to 6 to 10 ng/mL if <10% reduction in lesion diameters at 2 months (Davies 2011).
Serum trough concentrations for solid organ transplant (off-label use):
Note: The following indication-specific target trough concentrations are based on the available literature; however, levels must be highly individualized based on time from transplant, assay method, concurrent therapies, and other patient-specific factors (eg, rejection history).
Heart transplantation (off-label use):
With calcineurin inhibitor (eg, cyclosporine): 4 to 15 ng/mL (Mancini 2003) or 4 to 12 ng/mL (ISHLT [Velleca 2022]).
Following conversion from calcineurin inhibitor to sirolimus (calcineurin inhibitor withdrawal):
Immediate calcineurin inhibitor dose reduction approach (maintained until completion of conversion [~2 weeks]): 8 to 14 ng/mL (Topilsky 2012).
Delayed calcineurin inhibitor dose reduction approach: 10 to 15 ng/mL (Kushwaha 2005).
Kidney transplantation:
With calcineurin inhibitor: 3 to 8 ng/mL (Cucchiari 2020).
Without calcineurin inhibitor: 8 to 12 ng/mL (Fleming 2016).
Liver transplantation (off-label use):
With calcineurin inhibitor: 4 to 10 ng/mL (Buchholz 2020).
Without calcineurin inhibitor: 5 to 10 ng/mL (Teperman 2013).
Lung transplantation (off-label use): With calcineurin inhibitor: 6 to 10 ng/mL (Villanueva 2005).
Note: The following trough concentrations for kidney transplantation are based on the manufacturer's labeling, but may not reflect current practice:
Serum trough concentration goals for kidney transplantation (based on HPLC methods):
Concomitant cyclosporine: 4 to 12 ng/mL.
Low to moderate immunologic risk (after cyclosporine withdrawal): 8 to 12 ng/mL.
High immunologic risk (with cyclosporine): 10 to 15 ng/mL.
Note: Trough concentrations vary based on clinical context and use of additional immunosuppressants. The following represents typical ranges.
When combined with tacrolimus and mycophenolate mofetil without steroids: 6 to 8 ng/mL.
As a substitute for tacrolimus (starting 4 to 8 weeks post transplant), in combination with mycophenolate mofetil and steroids: 8 to 12 ng/mL.
Following conversion from tacrolimus to sirolimus >6 months post transplant due to chronic allograft nephropathy: 4 to 6 ng/mL.
Sirolimus inhibits T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation and inhibits antibody production. Its mechanism differs from other immunosuppressants. Sirolimus binds to FKBP-12, an intracellular protein, to form an immunosuppressive complex which inhibits the regulatory kinase, mTOR (mechanistic target of rapamycin). This inhibition suppresses cytokine mediated T-cell proliferation, halting progression from the G1 to the S phase of the cell cycle. It inhibits acute rejection of allografts and prolongs graft survival.
In lymphangioleiomyomatosis, the mTOR signaling pathway is activated through the loss of the tuberous sclerosis complex (TSC) gene function (resulting in cellular proliferation and release of lymphangiogenic growth factors). By inhibiting the mTOR pathway, sirolimus prevents the proliferation of lymphangioleiomyomatosis cells.
Absorption: Rapid
Distribution: 12 L/kg (range: 4 to 20 L/kg)
Protein binding: ~92%, primarily to albumin
Metabolism: Extensive; in intestinal wall via P-glycoprotein and hepatic via CYP3A4 to 7 major metabolites
Bioavailability: Oral solution: 14%; Oral tablet: 27% higher relative to the oral solution; oral solution and tablets are not bioequivalent however, clinical equivalence shown at 2 mg dose
Half-life elimination:
Children: 13.7 ± 6.2 hours
Adults: Mean: 62 hours (range: 46 to 78 hours); extended in hepatic impairment (Child-Pugh class A or B) to 113 hours
Time to peak: Oral solution: 1 to 3 hours; Tablet: 1 to 6 hours
Excretion: Feces (91% due to P-glycoprotein-mediated efflux into gut lumen); urine (2%)
Altered kidney function: Minimal (2.2%) renal excretion of the drug and its metabolites.
Hepatic function impairment: Patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean Cmax. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus half-life and decreases in the mean sirolimus clearance normalized for body weight.
Sex: Clearance is 12% lower and the half-life is prolonged in men compared with women (~72 hours versus ~61 hours, respectively).
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