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Sirolimus (conventional): Pediatric drug information

Sirolimus (conventional): Pediatric drug information
(For additional information see "Sirolimus (conventional): Drug information" and see "Sirolimus (conventional): Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Immunosuppression:

Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression.

Experienced physician:

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.

Liver transplantation:

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.

Lung transplantation:

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.

Brand Names: US
  • Rapamune
Brand Names: Canada
  • Rapamune
Therapeutic Category
  • Immunosuppressant Agent;
  • mTOR Kinase Inhibitor
Dosing: Pediatric

Note: Sirolimus tablets and oral solution are not bioequivalent due to differences in absorption; however, clinical equivalence has been demonstrated at the 2 mg dose. 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

Heart transplantation: Limited data available: Children and Adolescents: Oral: Note: Not used first-line; most data describes as alternative immunosuppression in combination with either cyclosporine or tacrolimus in patients for renal-sparing effects, following retransplantation (treatment of rejection) or to prevent or promote regression of transplant coronary artery disease (Ref)

BSA/weight-directed dosing:

Loading dose: 3 mg/m2 on day 1 (Ref)

Maintenance dose: Evaluate serum trough concentrations and adjust dose to overall target range: 4-12 ng/mL (Ref). Some trials report using lower target ranges of 4-10 ng/mL (Ref). In children, a specific maintenance dose has not been reported in the majority of trials. In 16 pediatric patients (age range: 2-18 years), the mean reported dose to reach target serum concentration of 5-10 ng/mL was 7 mg/m2 (or 0.25 mg/kg) (Ref). One trial used an initial median dose of 1 mg once daily (range: 0.3-2 mg once daily) and adjusted to achieve target concentration of 4-8 ng/mL (final dosage range 0.3-4 mg once daily) (Ref). In adolescents <40 kg, an initial maintenance dose of 1 mg/m2/day in 1-2 divided doses has been suggested (Ref).

Alternative fixed dosing: Adolescents with weight ≥40 kg: Loading dose: 6 mg on day 1; then maintenance: 2 mg once daily; evaluate serum trough concentrations and adjust dose to overall target range: 4-12 ng/mL (Ref); some suggest higher initial targets when sirolimus therapy initiated and then decrease to 4-8 ng/mL (Ref).

Renal transplantation, prophylaxis of organ rejection

Renal transplantation, prophylaxis of organ rejection (low to moderate immunologic risk): Oral:

Conversion from tacrolimus in patients with stable graft function: Children and Adolescents: Limited data available: Initial maintenance dose: 3 mg/m2/day divided every 12 hours; adjust dose to achieve target sirolimus serum trough concentration (Ref). In one trial, a loading dose of 5 mg/m2 on day 1 was used, followed by maintenance doses of 3 mg/m2/day divided every 12 hours (Ref).

Manufacturer's recommendations: Adolescents:

Weight <40 kg: Loading dose: 3 mg/m2 on day 1; initial maintenance dose: 1 mg/m2/day divided every 12 hours or once daily; adjust dose to achieve target sirolimus trough blood concentration

Weight ≥40 kg: Loading dose: 6 mg on day 1; maintenance: 2 mg once daily; adjust dose to achieve target sirolimus trough blood concentration.

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 7-14 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 equals current dose multiplied by (target concentration/current concentration). Note: If large dose increase is required, consider loading dose calculated as:

Loading dose equals (new maintenance dose minus current maintenance dose) multiplied by 3

Maximum daily dose: 40 mg/day; if required dose is >40 mg (due to loading dose), divide over 2 days. Serum concentrations 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 2-4 months of combined therapy, withdrawal of cyclosporine may be considered in low to moderate risk patients. Cyclosporine should be discontinued over 4-8 weeks, and a necessary increase in the dosage of sirolimus (up to fourfold) should be anticipated due to removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects.

Vascular anomalies/tumors; refractory

Vascular anomalies/tumors (eg, Kaposiform hemangioendothelioma); refractory: Very limited data available: Infants ≥7 months, Children, and Adolescents ≤14 years: Oral: Oral solution: Initial: 0.8 mg/m2 twice daily (approximately every 12 hours); titrate to a serum trough concentration of 10-15 ng/mL; dosing based on a pilot case series (n=6), the mean response time was 25 days (range: 8-65 days) (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

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.

Dosing: Hepatic Impairment: Pediatric

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%.

Dosing: Adult

(For additional information see "Sirolimus (conventional): Drug information")

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

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

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

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

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

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

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

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

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.

Dosing: Kidney Impairment: Adult

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.

Dosing: Hepatic Impairment: Adult

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%.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence of many adverse effects is dose related. Reported events exclusive to renal transplant recipients unless otherwise noted. Frequency not always defined.

Cardiovascular: Peripheral edema (≥20% to 58%, LAM and renal transplants), hypertension (49%), edema (18% to 20%), chest pain (LAM), deep vein thrombosis, pulmonary embolism, tachycardia

Central nervous system: Headache (≥20% to 34%, LAM and renal transplants), pain (29% to 33%), dizziness (LAM)

Dermatologic: Acne vulgaris (≥20% to 22%, LAM and renal transplants), skin rash (10% to 20%)

Endocrine & metabolic: Hypertriglyceridemia (45% to 57%), hypercholesterolemia (≥20% to 46%, LAM and renal transplants), amenorrhea, diabetes mellitus, hypermenorrhea, hypervolemia, hypokalemia, increased lactate dehydrogenase, menstrual disease, ovarian cyst

Gastrointestinal: Constipation (36% to 38%), abdominal pain (≥20% to 36%, LAM and renal transplants), diarrhea (≥20% to 35%, LAM and renal transplants), nausea (≥20% to 31%, LAM and renal transplants), stomatitis (3% to >20%)

Genitourinary: Urinary tract infection (33%)

Hematologic & oncologic: Anemia (23% to 33%), thrombocytopenia (14% to 30%), lymphoproliferative disorder (≤3%; including lymphoma), skin carcinoma (≤3%; includes basal cell carcinoma, squamous cell carcinoma, melanoma), hemolytic-uremic syndrome, leukopenia, lymphocele, thrombotic thrombocytopenic purpura

Infection: Herpes simplex infection, herpes zoster, sepsis

Neuromuscular & skeletal: Arthralgia (25% to 31%), myalgia (LAM), osteonecrosis

Renal: Increased serum creatinine (39% to 40%), pyelonephritis

Respiratory: Nasopharyngitis (LAM), epistaxis, pneumonia, upper respiratory tract infection (LAM)

Miscellaneous: Wound healing impairment

<3%, postmarketing, and/or case reports: Abnormal hepatic function tests, anaphylactoid reaction, anaphylaxis, angioedema, ascites, azoospermia, cardiac tamponade, cytomegalovirus, dehiscence (fascial), Epstein-Barr infection, exfoliative dermatitis, fluid retention, focal segmental glomerulosclerosis, gingival hyperplasia, hepatic necrosis, hepatotoxicity, hyperglycemia, hypersensitivity angiitis, hypersensitivity reaction, hypophosphatemia, incisional hernia, increased serum ALT, increased serum AST, increased susceptibility to infection (including opportunistic), interstitial pulmonary disease (dose related; includes pneumonitis, pulmonary fibrosis, and bronchiolitis obliterans organizing pneumonia with no identified infectious etiology), joint disorders, lymphedema, Merkel cell carcinoma, mycobacterium infection, nephrotic syndrome, neutropenia, pancreatitis, pancytopenia, pericardial effusion, pleural effusion, pneumonia due to Pneumocystis carinii, progressive multifocal leukoencephalopathy, proteinuria, pseudomembranous colitis, pulmonary alveolitis, pulmonary hemorrhage, renal disease (BK virus-associated), reversible posterior leukoencephalopathy syndrome, tuberculosis, weight loss, wound dehiscence

Contraindications

Hypersensitivity to sirolimus or any component of the formulation

Warnings/Precautions

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.

Warnings: Additional Pediatric Considerations

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).

Dosage Forms: US

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

Generic Equivalent Available: US

Yes

Pricing: US

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.

Dosage Forms: Canada

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

Administration: Pediatric

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 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 of water or orange juice; stir contents vigorously and have patient drink solution at once.

Oral tablets: Do not crush, split, or chew.

Administration: Adult

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.

Hazardous Drugs Handling Considerations

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.

Storage/Stability

Oral solution: Store at 2°C to 8°C (36°F to 46°F). Protect from light. A slight haze may develop in refrigerated solutions, but the quality of the product is not affected. After opening, solution should be used within 1 month. If necessary, may be stored at temperatures up to 25°C (77°F) for ≤15 days after opening. Product may be stored in amber syringe for a maximum of 24 hours (at room temperature or refrigerated). Discard syringe after single use. Solution should be used immediately following dilution.

Tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Medication Guide and/or Vaccine Information Statement (VIS)

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.

Use

Prophylaxis of organ rejection in renal transplant recipients at low-moderate immunologic risk in combination with corticosteroids and cyclosporine (cyclosporine may be withdrawn after 2-4 months in conjunction with an increase in sirolimus dosage) (FDA approved in ages ≥13 years and adults); prophylaxis of organ rejection in renal transplant recipients at high immunologic risk in combination with cyclosporine and corticosteroids for the first year (FDA approved in ages ≥18 years and adults); has also been used for primary immunosuppression in heart and intestinal transplantation (given in conjunction with a calcineurin inhibitor, as a substitute for a calcineurin inhibitor to reduce side effects, or to eliminate steroid use); rescue agent for acute and chronic organ rejection (rescue due to calcineurin toxicity or to treat resistant acute or chronic rejection despite calcineurin inhibitor therapy); prevention of acute graft-versus-host disease (GVHD) in allogeneic stem cell transplantation; treatment of refractory acute or chronic GVHD; treatment of vascular anomalies

Medication Safety Issues
Sound-alike/look-alike issues:

Rapamune may be confused with Rapaflo.

Sirolimus (conventional) may be confused with everolimus, pimecrolimus, silodosin, sirolimus (protein bound), sirolimus (topical), tacrolimus, temsirolimus, temozolomide, tesamorelin.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

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 (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). 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

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. 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

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

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

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

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 decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk X: Avoid combination

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination

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

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

Fluconazole: May increase the serum concentration of Sirolimus (Conventional). Management: Monitor for increased serum concentrations of sirolimus if combined with fluconazole. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

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

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

Nirogacestat: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination

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

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. 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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

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

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 (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification

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

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

Food Interactions

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.

Reproductive Considerations

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).

Pregnancy Considerations

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.

Monitoring Parameters

Monitor LFTs 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 3-4 days after loading doses and 7-14 days after dosage adjustments; 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). Note: Concentrations and ranges are dependent on and will vary with assay methodology (chromatographic or immunoassay); assay methods are not interchangeable.

Reference Range

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.

Children and Adolescents: Note: See institution specific guidelines:

Target serum trough concentration for heart transplantation: 4-12 (ISHLT, Costanzo 2010)

Target serum trough concentration for renal transplantation (based on HPLC methods):

Low to moderate immunologic risk (after cyclosporine withdrawal):

First year after transplant:16-24 ng/mL

After 1 year: 12-20 ng/mL

High immunologic risk (with cyclosporine): 10-15 ng/mL

Target serum trough concentration for vascular anomalies: 10-15 ng/mL (Hammill, 2011)

Adults: Note: Trough concentrations vary based on clinical context and use of additional immunosuppressants. The following represents typical adult ranges.

When combined with tacrolimus and mycophenolate mofetil (MMF) without steroids: 6-8 ng/mL

As a substitute for tacrolimus (starting 4-8 weeks post-transplant), in combination with MMF and steroids: 8-12 ng/mL

Following conversion from tacrolimus to sirolimus >6 months post-transplant due to chronic allograft nephropathy: 4-6 ng/mL

Mechanism of Action

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.

Pharmacokinetics (Adult Data Unless Noted)

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%)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

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).

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Rapamune;
  • (AR) Argentina: Rapamune;
  • (AT) Austria: Rapamune;
  • (AU) Australia: Rapamune;
  • (BE) Belgium: Rapamune;
  • (BR) Brazil: Rapamune;
  • (CH) Switzerland: Rapamune;
  • (CL) Chile: Rapamune;
  • (CN) China: Rapamune | Rui pa ming;
  • (CZ) Czech Republic: Rapamune;
  • (DE) Germany: Rapamune;
  • (EE) Estonia: Rapamune;
  • (ES) Spain: Rapamune;
  • (FI) Finland: Rapamune;
  • (FR) France: Rapamune;
  • (GB) United Kingdom: Rapamune;
  • (GR) Greece: Rapamune;
  • (HK) Hong Kong: Rapamune;
  • (HR) Croatia: Rapamune;
  • (HU) Hungary: Rapamune;
  • (IE) Ireland: Rapamune;
  • (IL) Israel: Rapamune;
  • (IN) India: Emtor | Siromus;
  • (IT) Italy: Rapamune sirolimus;
  • (LT) Lithuania: Rapamune;
  • (LV) Latvia: Rapamune;
  • (MX) Mexico: Cyclentra | P hysplan | Padawat | Rapamune | Renacept;
  • (MY) Malaysia: Rapamune;
  • (NL) Netherlands: Rapamune;
  • (NO) Norway: Rapamune;
  • (NZ) New Zealand: Rapamune;
  • (PH) Philippines: Rapamune;
  • (PK) Pakistan: Siroall | Sirograf;
  • (PL) Poland: Rapamune;
  • (PR) Puerto Rico: Rapamune;
  • (PT) Portugal: Rapamune;
  • (QA) Qatar: Rapamune;
  • (RO) Romania: Rapamune;
  • (RU) Russian Federation: Rapamune;
  • (SA) Saudi Arabia: Rapamune;
  • (SE) Sweden: Rapamune;
  • (SG) Singapore: Rapamune;
  • (SI) Slovenia: Rapamune;
  • (SK) Slovakia: Rapamune;
  • (TH) Thailand: Rapamune;
  • (TR) Turkey: Rapamune;
  • (TW) Taiwan: Rapamune;
  • (ZA) South Africa: Rapamune
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Topic 12761 Version 410.0

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