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Sirolimus (conventional): Drug information

Sirolimus (conventional): Drug information
(For additional information see "Sirolimus (conventional): Patient drug information" and see "Sirolimus (conventional): Pediatric 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 posttransplantation, 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
Pharmacologic Category
  • Immunosuppressant Agent;
  • mTOR Kinase Inhibitor
Dosing: Adult

Note: Refer to the Sirolimus (Protein Bound) monograph for dosing and information related to the IV sirolimus protein-bound formulation.

Lymphangioleiomyomatosis: Initial: Oral: 2 mg once daily. Obtain trough concentration in 10 to 20 days; adjust dose to maintain a target concentration of 5 to 15 ng/mL.

Dosage adjustment for lymphangioleiomyomatosis: 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 transplant, rejection prophylaxis:

Low-to-moderate immunologic risk:

<40 kg: Loading dose: Oral: 3 mg/m2 on day 1, followed by maintenance dosing of 1 mg/m2 once daily

≥40 kg: Loading dose: Oral: 6 mg on day 1; maintenance: 2 mg once daily

High immunologic risk: Loading dose: Oral: Up to 15 mg on day 1; maintenance: 5 mg/day; obtain trough concentration between days 5 to 7 and adjust accordingly. Continue concurrent cyclosporine/sirolimus/corticosteroid therapy for 1 year following transplantation. Further adjustment of the regimen must be based on clinical status.

Dosage adjustment for renal transplantation: Sirolimus dosages should be adjusted in small increments to maintain 24-hour trough concentrations within desired range based on risk and concomitant therapy. Dosage should be adjusted at intervals of 7 to 14 days to account for the long half-life of sirolimus. Maximum loading dose: 40 mg/day (although typical loading doses are not generally this high). Whole blood 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: According to the manufacturer, cyclosporine withdrawal is not recommended in high immunological risk renal transplant patients. Following 2 to 4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate immunologic risk patients. Cyclosporine should be discontinued over 4 to 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. Dose-adjusted trough target concentrations are typically 16 to 24 ng/mL for the first year post-transplant and 12 to 20 ng/mL thereafter (per the manufacturer; measured by chromatographic methodology). Target trough concentrations of ~5 to 15 ng/mL are often used in clinical practice (Kahan 2000; Stenton 2005); refer to specific institutional protocol for target sirolimus trough concentrations.

Graft-versus-host disease (off-label use):

Graft-versus-host disease, prevention: Oral: 12 mg loading dose on day -3, followed by 4 mg daily (target trough level: 3 to 12 ng/mL); taper off after 6 to 9 months (Armand 2008; Cutler 2007). Additional trials may be necessary to further define the role of sirolimus in this condition.

Treatment of refractory acute graft-versus-host disease: Oral: 4 to 5 mg/m2 for 14 days (no loading dose) (Benito 2001). Additional trials may be necessary to further define the role of sirolimus in this condition.

Treatment of chronic graft-versus-host disease: Oral: 6 mg loading dose, followed by 2 mg daily (target trough level: 7 to 12 ng/mL) for 6 to 9 months (Couriel 2005). Additional trials may be necessary to further define the role of sirolimus in this condition.

Heart transplantation, prophylaxis of organ rejection and allograft vasculopathy (off-label use): Note: The use of sirolimus in the immediate post-cardiac transplant period (ie, de novo heart transplant) as a primary immunosuppressant has fallen out of favor due to adverse effects (eg, impaired wound healing and infection); however, patients may be converted to sirolimus from a calcineurin inhibitor (after at least 6 months from time of transplant [Costanzo 2010]).

Conversion from a calcineurin inhibitor (CNI) (ie, cyclosporine, tacrolimus): 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 level of 8 to 14 ng/mL, withdraw CNI, repeat biopsy 2 weeks after CNI withdrawal (Topilsky 2012). Alternatively, maintain CNI concentrations and initiate sirolimus 1 mg once daily for 1 week; adjust sirolimus to target trough levels of 10 to 15 ng/mL over 2 weeks, then reduce CNI to target 50% of therapeutic concentrations and after 2 weeks evaluate for rejection. If no rejection, continue same regimen for an additional month, then reduce CNI to 25% of therapeutic concentrations with repeat biopsy 2 weeks later; if no rejection, may discontinue CNI after 2 weeks and continue to maintain sirolimus trough levels of 10 to 15 ng/mL (usual doses required to maintain target levels: 1 to 8 mg daily) (Kushwaha 2005). Refer to specific institutional protocol for target sirolimus trough concentrations; trough will vary based on time from transplant, assay method, and concurrent or transitioning therapies.

Conversion from antiproliferative immunosuppressive drug (ie, azathioprine or mycophenolate) while maintaining calcineurin inhibitor: Oral: Upon discontinuation of antiproliferative, administer sirolimus 6 mg loading dose followed by 2 mg once daily titrated to a target trough level of 4 to 15 ng/mL (Mancini 2003) or 4 to 12 ng/mL per ISHLT recommendations (Costanzo 2010).

Lung transplantation, rejection prophylaxis (off-label use): Initial loading dose: Oral: 5 mg once, followed by a maintenance dose of 3 mg once daily; titrate to a target trough level of 5 to 13 ng/mL (Snell 2002). Do not initiate sirolimus until after the bronchial anastomosis has completely healed (approximately 90 days) due to potential fatal airway dehiscence with earlier initiation (King-Biggs 2003). Additional trials may be necessary to further define the role of sirolimus in this condition.

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 (Davies 2011).

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%.

Dosing: Pediatric

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

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: 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 (Denfield 2010)

BSA/weight-directed dosing:

Loading dose: 3 mg/m2 on day 1 (Balfour 2006; Denfield 2010)

Maintenance dose: Evaluate serum trough concentrations and adjust dose to overall target range: 4-12 ng/mL (ISHLT [Costanzo 2010]). Some trials report using lower target ranges of 4-10 ng/mL (Chinnock 2011; Lobach 2005; Matthews 2010). 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) (Lobach 2005). 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) (Matthews 2010). In adolescents <40 kg, an initial maintenance dose of 1 mg/m2/day in 1-2 divided doses has been suggested (Denfield 2010).

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 (Denfield 2010; ISHLT [Costanzo 2010]); some suggest higher initial targets when sirolimus therapy initiated and then decrease to 4-8 ng/mL (Balfour 2005; Chinnock 2011; Lobach 2005).

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 (Hymes 2008; Hymes 2011). 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 (Hymes 2008).

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 (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) (Hammill 2011).

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 (Child-Pugh classes A and B): Reduce maintenance dose by ~33%

Severe hepatic impairment (Child-Pugh class C): Reduce maintenance dose by ~50%

Dosing: Older Adult

Refer to adult dosing.

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 max)]

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

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

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.

Administration: Adult

Oral: Administer consistently (either with or without food). Renal 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.

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.

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.

Use: Labeled Indications

Lymphangioleiomyomatosis: Treatment of lymphangioleiomyomatosis. Therapeutic drug monitoring is recommended for all patients receiving sirolimus.

Renal transplantation (rejection prophylaxis): Prophylaxis of organ rejection in patients receiving renal 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 renal transplant patients are defined (per the manufacturer's labeling) as Black transplant recipients and/or repeat renal 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 (renal 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 renal transplant patients younger than 18 years who are considered at high immunologic risk. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the care of renal 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).

Use: Off-Label: Adult

Chordoma (advanced); Graft-versus-host disease prevention; Acute graft-versus-host disease treatment; Chronic graft-versus-host disease treatment; Heart transplant (prophylaxis of organ rejection and allograft vasculopathy); Lung transplantation (rejection prophylaxis); Renal angiomyolipoma

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.

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 patients 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 patients.

• 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.

• 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 renal transplant patients 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.

• Renal 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 renal function and cause graft loss; consider decreasing immunosuppressive burden if evidence of deteriorating renal function. Use with caution in patients concurrently taking medications which may alter renal function.

• 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 renal 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:

• Liver transplants: Sirolimus is not recommended for use in liver transplantation; 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 in lung transplantation. Bronchial anastomotic dehiscence cases have been reported in lung transplant patients when sirolimus was used as part of an immunosuppressive regimen; most of these reactions were fatal.

• Renal transplant: In renal transplant patients, de novo use without cyclosporine has been associated with higher rates of acute rejection. Sirolimus may delay recovery of renal function in patients with delayed allograft function.

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:

• Appropriate use: In renal transplant patients, sirolimus should be used in combination with cyclosporine (and corticosteroids) initially. Cyclosporine may be withdrawn in low-to-moderate immunologic risk patients after 2 to 4 months, in conjunction with an increase in sirolimus dosage. In high immunologic risk patients, use in combination with cyclosporine and corticosteroids is recommended for the first year. Adjustment of immunosuppressive therapy beyond 12 months should be considered based on clinical judgment.

• Experienced physician: Should only be used by physicians experienced in immunosuppressive therapy and management of transplant patients. 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).

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

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

Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk 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

Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Cannabidiol: May increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

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

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 vaccine at least 28 days after the primary vaccine dose. Patients should also receive 2 booster doses of mRNA vaccine - one 2 months after the 2nd (additional) dose and another 4 months after the first booster dose. 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, and a booster dose 3 months after the 3rd dose in the primary series, to patients taking immunosuppressive medications. Patients 12 years of age and older should also receive a 2nd booster 4 months after the first booster. 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

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

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

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

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

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

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 (High risk 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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk 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

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 (High risk with Inhibitors). Risk C: Monitor therapy

Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. 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

Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Pacritinib: May increase the serum concentration of CYP3A4 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

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

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 post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

Rifabutin: May decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

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

Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of 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 Rubella- or Varicella-Containing Live Vaccines. 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

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

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

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

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

Vaccines (Inactivated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated). 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): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). 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 renal 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 renal 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.

Breastfeeding Considerations

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.

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 to 4 days after loading doses and 7 to 14 days after dosage adjustments for renal transplant patients; 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.

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. Refer to specific protocol for target sirolimus concentration goals.

Serum trough concentration goals for renal 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 (MMF) without steroids: 6 to 8 ng/mL

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

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

Serum trough concentrations for heart transplantation (off-label use):

With calcineurin inhibitor (eg, cyclosporine): 4 to 12 ng/mL (Costanzo 2010)

Without calcineurin inhibitor: 10 to 15 ng/mL (Raichlin 2007a; Raichlin 2007b)

Following conversion from cyclosporine or tacrolimus to sirolimus: Initial (maintained until completion of conversion [~2 weeks]): 8 to 14 ng/mL (Topilsky 2012) or 9 to 15 ng/mL (Zuckermann 2012); Maintenance: 10 to 15 ng/mL (Kushwaha 2005) or 7 to 15 ng/mL (Zuckermann 2012)

Serum trough concentrations for lymphangioleiomyomatosis: 5 to 15 ng/mL

Serum trough concentrations for GVHD prophylaxis in allogeneic stem cell transplant (off-label use): 3 to 12 ng/mL (Armand 2008; Cutler 2007)

Serum trough concentrations for advanced chordoma (off-label use): 15 to 20 ng/mL (Stacchiotti 2009)

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)

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

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

Renal function impairment: 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.

Gender: Clearance is 12% lower and the half-life is prolonged in men compared with women (~72 hours versus ~61 hours, respectively).

Pricing: US

Solution (Rapamune Oral)

1 mg/mL (per mL): $37.77

Solution (Sirolimus Oral)

1 mg/mL (per mL): $31.58 - $35.00

Tablets (Rapamune Oral)

0.5 mg (per each): $19.83

1 mg (per each): $39.66

2 mg (per each): $79.32

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.

Brand Names: International
  • Rapalimus (JP);
  • Rapamune (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, FI, FR, GB, GR, HK, HR, HU, IE, IL, IN, IS, IT, JO, KR, KW, LB, LT, LU, MT, MX, MY, NL, NO, NZ, PE, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, VE, VN);
  • Siromune (LB);
  • Sirotan (CL)


For country abbreviations used in Lexicomp (show table)
  1. <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.
  2. Agarwal KA, Pavlakis M. Sexuality, contraception, and pregnancy in kidney transplantation. Kidney Med. 2021;3(5):837-847. doi:10.1016/j.xkme.2021.05.009 [PubMed 34693263]
  3. Ahmadi M, Abdolmohamadi-Vahid S, Ghaebi M, et al. Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: a double-blind, phase II randomized clinical trial. Int Immunopharmacol. 2019;74:105730. doi:10.1016/j.intimp.2019.105730 [PubMed 31299610]
  4. Antin J, Kim H, Cutler C, et al, "Sirolimus, Tacrolimus, and Low-Dose Methotrexate for Graft-Versus-Host Disease Prophylaxis in Mismatched Related Donor or Unrelated Donor Transplantation," Blood, 2003, 102(5):1601-5. [PubMed 12730113]
  5. Armand P, Gannamaneni S, Kim HT, et al, “Improved Survival in Lymphoma Patients Receiving Sirolimus for Graft-Versus-Host Disease Prophylaxis After Allogeneic Hematopoietic Stem-Cell Transplantation With Reduced-Intensity Conditioning,” J Clin Oncol, 2008, 26(35):5767-74. [PubMed 19001324]
  6. Balfour IC, Srun SW, Wood EG, et al, "Early Renal Benefit of Rapamycin Combined With Reduced Calcineurin Inhibitor Dose in Pediatric Heart Transplantation Patients," J Heart Lung Transplant, 2006, 25(5):518-22. [PubMed 16678029]
  7. Barnes BT, Procaccini D, Crino J, et al. Maternal sirolimus therapy for fetal cardiac rhabdomyomas. N Engl J Med. 2018;378(19):1844-1845. doi:10.1056/NEJMc1800352 [PubMed 29742370]
  8. Benito AI, Furlong T, Martin PJ, et al, “Sirolimus (Rapamycin) for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease,” Transplantation, 2001, 72(12):1924-9. [PubMed 11773890]
  9. Bissler JJ, McCormack FX, Young LR, et al, “Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis,” N Engl J Med, 2008, 358(2):140-51. [PubMed 18184959]
  10. Boulay H, Mazaud-Guittot S, Supervielle J, et al. Maternal, foetal and child consequences of immunosuppressive drugs during pregnancy in women with organ transplant: a review. Clin Kidney J. 2021;14(8):1871-1878. doi:10.1093/ckj/sfab049 [PubMed 34345409]
  11. Cabiddu G, Spotti D, Gernone G, et al; Kidney and Pregnancy Study Group of the Italian Society of Nephrology. A best-practice position statement on pregnancy after kidney transplantation: focusing on the unsolved questions. The Kidney and Pregnancy Study Group of the Italian Society of Nephrology. J Nephrol. 2018;31(5):665-681. doi:10.1007/s40620-018-0499-x [PubMed 29949013]
  12. Chinnock TJ, Shankel T, Deming D, et.al. Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients. Pediatric Transplantation. 2011;15:746-749. [PubMed 21883751]
  13. Costanzo MR, Dipchand A, Starling R, et al, “The International Society of Heart and Lung Transplantation Guidelines for the Care of Heart Transplant Recipients,” J Heart Lung Transplant, 2010, 29(8):914-56. [PubMed 20643330]
  14. Couriel DR, Saliba R, Escalon MP, et al, “Sirolimus in Combination With Tacrolimus and Corticosteroids for the Treatment of Resistant Chronic Graft-Versus-Host Disease,” Br J Haematol, 2005, 130(3):409-17. [PubMed 16042691]
  15. Cutler C, Kim H, Hochberg E, et al, "Sirolimus and Tacrolimus Without Methotrexate as Graft-Versus-Host Disease Prophylaxis After Matched Related Donor Peripheral Blood Stem Cell Transplantation,” Biol Blood Marrow Transplant, 2004, 10(5):328-36. [PubMed 15111932]
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