Rapamune

Pronunciation

Generic Name: Sirolimus
Class: Immunosuppressive Agents
ATC Class: L04AA10
VA Class: IM600
Chemical Name: (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a - hexadecahydro - 9,27 - dihydroxy - 3 - [(1R) - 2 - [(1S,3R,4R) - 4 - hydroxy - 3 - methoxycyclohexyl] - 1 - methylethyl] - 10,21 - dimethoxy - 6,8,12,14,20,26 - hexamethyl - 23,27 - epoxy - 3H - pyrido[2,1 - c][1,4]oxaazacyclohentriacontine - 1,5,11,28,29(4H,6H,31H - pentone
Molecular Formula: C51H79NO13
CAS Number: 53123-88-9

Warning(s)

  • Immunosuppression
  • Immunosuppression may result in increased susceptibility to infection and possible development of lymphoma or other malignancies.1

  • Only clinicians experienced in immunosuppressive therapy and management of renal transplant patients should prescribe sirolimus.1

  • Patients should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources; the clinician responsible for maintenance therapy should have complete information for patient follow-up.1

  • Use Not Recommended in Liver or Lung Transplant Patients
  • Safety and efficacy of sirolimus as immunosuppressive therapy not established in liver or lung transplant patients; such use is not recommended.1 (See Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients under Cautions and see Bronchial Anastomotic Dehiscence in Lung Transplant Patients under Cautions.)

REMS:

FDA approved a REMS for sirolimus to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Potent immunosuppressive agent;1 2 4 7 9 10 macrolide antibiotic.1 2 4 5 6 7 9 10 11

Uses for Rapamune

Renal Allotransplantation

Prevention of renal allograft rejection in patients ≥13 years of age.1 2 The manufacturer recommends therapeutic drug monitoring in all patients receiving the drug.1

Used initially with both cyclosporine and corticosteroids;1 subsequent withdrawal of cyclosporine recommended in patients with low to moderate immunologic risk (see General under Dosage and Administration).1

Safety and efficacy of de novo use of sirolimus without cyclosporine not established.1

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Safety and efficacy of conversion from calcineurin inhibitors (e.g., cyclosporine, tacrolimus) to sirolimus in maintenance renal transplant patients not established.1 (See Proteinuria under Cautions.)

Hepatic Allotransplantation

Has been used for the prevention of rejection of liver allografts; however, manufacturer states that safety and efficacy as immunosuppressive therapy not established in liver transplant patients and that such use is not recommended.1

Associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss, and hepatic artery thrombosis.1 25 36 (See Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients under Cautions and see Specific Drugs and Foods under Interactions.)

Lung Allotransplantation

Has been used for the prevention of rejection of lung allografts; however, manufacturer states that safety and efficacy as immunosuppressive therapy not established in lung transplant patients and that such use is not recommended.1

Cases of bronchial anastomotic dehiscence, mostly fatal, reported in de novo lung transplant patients who received sirolimus in combination with other immunosuppressants.1 (See Bronchial Anastomotic Dehiscence in Lung Transplant Patients under Cautions.)

Rapamune Dosage and Administration

General

  • Distribute medication guide each time sirolimus is dispensed.1

  • Initially, use sirolimus in conjunction with cyclosporine and corticosteroids as soon as possible after renal transplantation.1 In patients with low to moderate immunologic risk, withdraw cyclosporine gradually (over a 4- to 8-week period) at 2–4 months posttransplantation and simultaneously increase sirolimus dosage to achieve recommended sirolimus blood concentrations.1

  • In patients at high immunologic risk (e.g., black ethnicity, repeat transplant following loss of a previous allograft for immunologic reasons, and/or recipient with a high level of panel-reactive antibodies [PRA; peak PRA level >80%]), use sirolimus in conjunction with cyclosporine and corticosteroids for the first 12 months following renal transplantation.1 Safety and efficacy of this combined regimen not studied beyond 12 months following transplantation.1 Base any adjustments to the immunosuppressive regimen after the first 12 months on clinical status of the patient.1

  • Therapeutic Drug Monitoring
  • Monitoring of trough whole blood sirolimus concentrations recommended for all patients, especially those likely to have altered drug metabolism, patients ≥13 years of age who weigh <40 kg, patients with hepatic impairment, when a change in dosage form is made, and during concurrent administration of inhibitors or inducers of CYP3A4.1 2

  • Therapeutic drug monitoring not sole basis for adjusting sirolimus therapy;1 also should carefully monitor clinical signs and symptoms, tissue biopsy findings, and laboratory results.1

  • Recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods.1 497 In clinical practice, however, sirolimus whole blood concentrations currently are being measured by both chromatographic and immunoassay methodologies.1 Measured concentrations of sirolimus in whole blood depend on the type of assay used; concentrations obtained by these different methodologies are not interchangeable.1 496 497

  • Since results are assay and laboratory dependent and the results may change over time, any adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay being used.1 496 497 Communication must be maintained with the laboratory performing the sirolimus assays.1 496 497 Consult specialized references for additional information on sirolimus therapeutic drug monitoring.1

Administration

Oral Administration

Administer orally once daily; give initial dose as soon as possible after transplantation.1 Give consistently with or without food to minimize variability of systemic exposure.1 9

Do not crush, chew, or split tablets; use oral solution in patients unable to take tablets.1

If estimated daily dosage is >40 mg because of the addition of a loading dose, give loading dose in divided doses over 2 days.1 Monitor trough whole blood concentrations at least 3–4 days after loading dose(s).1

Although commercially available tablets and oral solution are not bioequivalent,1 manufacturer states that 2-mg doses given as conventional tablets and as oral solution are therapeutically equivalent and may be interchangeable on a mg-per-mg basis at doses ≤2 mg.1 Not known whether these formulations are therapeutically equivalent at doses >2 mg.1

Administer sirolimus 4 hours after administration of cyclosporine formulations for emulsion (e.g., Neoral oral solution or liquid-filled capsules), since concomitant administration increases rate and extent of sirolimus absorption.1 2

Oral Solution in Bottles

Consult manufacturer’s instructions regarding insertion of adapter assembly into bottle and withdrawal of prescribed dose (using syringe provided by manufacturer).1

Empty contents of syringe into a glass or plastic cup containing ≥60 mL of water or orange juice; stir vigorously for 1 minute and administer immediately.1 Refill container with ≥120 mL of the diluent, stir vigorously, and ingest rinse solution.1 Use only glass or plastic containers.1 Do not administer with grapefruit juice or use grapefruit juice as diluent (see Interactions);1 do not use apple juice or other liquids as diluents.1 Use syringe once and then discard.1

If mouth of bottle must be wiped clean, use dry cloth to avoid introducing water or other liquid into the bottle.1

Consult manufacturer’s instructions if patient must carry a dose for subsequent administration.1

Dosage

When used for the prevention of renal allograft rejection, frequent sirolimus dosage adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing since sirolimus has a long half-life.1 Once maintenance dosage is adjusted, maintain patient on the new dosage for at least 7–14 days before making subsequent dosage adjustment based on drug concentrations.1

Do not give >40 mg of sirolimus within any 1-day period.1 If an estimated daily dose is >40 mg because of the addition of a loading dose, give loading dose over a 2-day period.1 The manufacturer recommends monitoring trough whole blood concentrations of sirolimus at least 3–4 days after administering loading dose(s).1

Pediatric Patients

Renal Allotransplantation
Concomitant Sirolimus and Cyclosporine Therapy in Patients at Low to Moderate Immunologic Risk
Oral

Children ≥13 years of age who weigh ≥40 kg: Loading dose should be equivalent to 3 times the maintenance dosage; e.g., 6 mg as a loading dose in de novo renal transplant recipients and a maintenance dosage of 2 mg daily.1 No efficacy advantage with higher loading and maintenance dosages (loading dose of 15 mg followed by a maintenance dosage of 5 mg daily) in overall patient population.1 14 (See Special Populations under Dosage and Administration.) 2-mg daily maintenance dosage associated with a superior safety profile compared with the 5-mg daily dosage.1

Children ≥13 years of age who weigh <40 kg: Initially, 3 mg/m2 as a loading dose in de novo renal transplant recipients.1 Maintenance dosage of 1 mg/m2 daily.1

Therapeutic drug monitoring recommended in all patients to maintain sirolimus blood concentrations within the recommended range.1 2 9 (See Therapeutic Drug Monitoring under Dosage and Administration.)

Sirolimus Therapy following Cyclosporine Withdrawal in Patients at Low to Moderate Immunologic Risk
Oral

Children ≥13 years of age: As cyclosporine is gradually discontinued over a 4- to 8-week period, increase sirolimus dosage to maintain target trough whole blood concentrations of 16–24 ng/mL for the first year posttransplantation.1 Thereafter, target sirolimus concentrations should be 12–20 ng/mL.1 If subsequent dosage adjustment is required, manufacturer states that new dosage can be estimated based on the following equation:1

New sirolimus dosage = current sirolimus dosage × (target concentration / current concentration)

Loading dose may be necessary if a considerable increase in trough sirolimus concentrations is required.1 Estimate loading dose based on the following equation:1

Sirolimus loading dose = 3 × (new maintenance dosage - current maintenance dosage)

Patients at High Immunologic Risk
Oral

Children ≥13 years of age who weigh ≥40 kg receiving concomitant sirolimus and cyclosporine therapy: Loading dose of ≤15 mg on day 1 posttransplantation.1 On day 2, initial maintenance dosage of 5 mg daily.1 Obtain trough sirolimus concentration between days 5 and 7; adjust maintenance dosage as necessary.1

Initially, cyclosporine dosage of 7 mg/kg daily given in divided doses.1 Subsequently, adjust dosage to achieve target trough blood concentrations.1 Minimum prednisone dosage of 5 mg daily.1

May use antibody induction therapy.1

Adults

Renal Allotransplantation
Concomitant Sirolimus and Cyclosporine Therapy in Patients at Low to Moderate Immunologic Risk
Oral

Adults who weigh ≥40 kg: Loading dose should be equivalent to 3 times the maintenance dosage; e.g., 6 mg as a loading dose in de novo renal transplant recipients and a maintenance dosage of 2 mg daily.1 No efficacy advantage with higher loading and maintenance dosages (loading dose of 15 mg followed by a maintenance dosage of 5 mg daily) in overall patient population.1 14 (See Special Populations under Dosage and Administration.) 2-mg daily maintenance dosage associated with a superior safety profile compared with the 5-mg daily dosage.1

Adults who weigh <40 kg: Initially, 3 mg/m2 as a loading dose in de novo renal transplant recipients.1 Maintenance dosage of 1 mg/m2 daily.1

Therapeutic drug monitoring recommended in all patients to maintain sirolimus blood concentrations within the recommended range.1 2 9 (See Therapeutic Drug Monitoring under Dosage and Administration.)

Sirolimus Therapy following Cyclosporine Withdrawal in Patients at Low to Moderate Immunologic Risk
Oral

As cyclosporine is gradually discontinued over a 4- to 8-week period, increase sirolimus dosage to maintain target trough whole blood concentrations of 16–24 ng/mL for the first year post transplantation.1 Thereafter, target sirolimus concentrations should be 12–20 ng/mL.1 If subsequent dosage adjustment is required, manufacturer states that new dosage can be estimated based on the following equation:1

New sirolimus dosage = current sirolimus dosage × (target concentration / current concentration)

Loading dose may be necessary if a considerable increase in trough sirolimus concentrations is required.1 Estimate loading dose based on the following equation: 1

Sirolimus loading dose = 3 × (new maintenance dosage - current maintenance dosage)

Patients at High Immunologic Risk
Oral

Adults who weigh ≥40 kg receiving concomitant sirolimus and cyclosporine therapy: Loading dose of ≤15 mg on day 1 post transplantation.1 On day 2, initial maintenance dosage of 5 mg daily.1 Obtain trough sirolimus concentration between days 5 and 7; adjust maintenance dosage as necessary.1

Initially, cyclosporine dosage of 7 mg/kg daily given in divided doses.1 Subsequently, adjust dosage to achieve target trough blood concentrations.1 Minimum prednisone dosage of 5 mg daily.1

May use antibody induction therapy.1

Prescribing Limits

Pediatric Patients

Renal Allotransplantation
Oral

Children ≥13 years of age who weigh ≥40 kg: Maximum 40 mg within 1-day period.1

Adults

Renal Allotransplantation
Oral

Maximum 40 mg within 1-day period.1

Special Populations

Hepatic Impairment

Reduce maintenance dosage by approximately one-third in patients with mild or moderate hepatic impairment and by approximately one-half in patients with severe hepatic impairment; loading dose does not require modification.1

Renal Impairment

Dosage adjustment is not necessary.1

Geriatric Patients

Routine dosage adjustment based solely on advanced age does not appear to be necessary.1 However, manufacturer recommends cautious dosage selection, usually starting at lower end of dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant diseases or other drug therapy in this population.1

Cautions for Rapamune

Contraindications

  • Known hypersensitivity to sirolimus or its derivatives or any ingredient in the sirolimus formulation.1

Warnings/Precautions

Warnings

Increased Susceptibility to Infection and Possible Development of Lymphoma

Possible increased susceptibility to infection (including opportunistic infections [e.g., tuberculosis], fatal infections, and sepsis) and possible development of lymphoma or other malignancies, particularly of the skin.1

Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients

Use in combination with other immunosuppressants (e.g., cyclosporine, tacrolimus) associated with increased risk of hepatic artery thrombosis, graft loss, and death in de novo liver transplant recipients.1 25 36 (See Interactions.)

Safety and efficacy of sirolimus as immunosuppressive therapy in liver transplant patients not established; such use is not recommended by manufacturer.1

Bronchial Anastomotic Dehiscence in Lung Transplant Patients

Cases of bronchial anastomotic dehiscence, mostly fatal, reported in de novo lung transplant patients who received sirolimus in combination with other immunosuppressants.1 Safety and efficacy of sirolimus as immunosuppressive therapy in lung transplant patients not established; such use is not recommended by manufacturer.1

Other Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic or anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, reported.1

Angioedema

Associated with angioedema.1 493 494 495 Concurrent use of other drugs causing angioedema (e.g., ACE inhibitors, angiotensin II receptor antagonists, NSAIAs) may increase risk of developing angioedema.1 494

Fluid Accumulation and Abnormal Wound Healing

Impaired or delayed wound healing, including lymphocele and wound dehiscence, reported.1 24 28 Lymphocele, a known surgical complication of renal transplantation, occurred more often in sirolimus-treated patients and appeared to be dose-related.1 2 6 24 28 Abnormal wound healing following transplant surgery, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary), also reported.1 24

Consider appropriate measures to minimize such complications (i.e., patient selection based on BMI, reduced sirolimus dosage, use of closed suction drains, modifications of surgical technique).1 24 28 Patients with a BMI >30 kg/m2 may be at increased risk of abnormal wound healing.1 24 28

Fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically important effusions and tamponade requiring intervention in children and adults), reported.1 29 32

Hyperlipidemia

Increases in serum cholesterol and triglyceride concentrations requiring treatment reported.1 2 3 5 12

Monitor serum lipids; initiate appropriate treatment (diet, exercise, lipid-lowering agents, as indicated) if hyperlipidemia occurs.1

Carefully consider risks/benefits of sirolimus in patients with preexisting hyperlipidemia.1

In clinical trials, concomitant use of sirolimus and HMG-CoA reductase inhibitors and/or fibric acid derivatives generally was well tolerated.1 31 However, manufacturer recommends monitoring patients receiving sirolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative for possible development of rhabdomyolysis and other possible adverse effects (e.g., hepatic toxicity) described in the prescribing information for these antilipemic agents.1 31

Renal Function

Increases in Scr and decreases in GFR reported in patients receiving cyclosporine and sirolimus concurrently compared with those receiving cyclosporine with placebo or azathioprine.1 2

Monitor renal function closely in patients receiving maintenance immunosuppressive regimens that include sirolimus and cyclosporine.1 Consider appropriate adjustments of the immunosuppressive regimen, including discontinuance of sirolimus and/or cyclosporine, in patients with elevated or increasing Scr.1

In patients with low to moderate immunologic risk, consider administering sirolimus in combination with cyclosporine for >4 months posttransplantation only if potential benefits outweigh possible risks.1

Use other nephrotoxic drugs with caution.1 (See Interactions.)

In patients with delayed graft function, sirolimus may delay recovery of renal function.1

Proteinuria

Increased urinary protein excretion commonly observed following conversion from calcineurin inhibitors (e.g., cyclosporine, tacrolimus) to sirolimus in maintenance renal transplant recipients.1 37 Safety and efficacy of such conversion not established.1

Manufacturer recommends periodic quantitative monitoring of urinary protein excretion in sirolimus-treated patients.1 If proteinuria occurs, early treatment may help prevent long-term adverse effects on graft survival.37

Latent Viral Infections

Increased risk of reactivation of latent viral infections in immunosuppressed patients, including those receiving sirolimus.1 484 485 486 487 488 489 490 491 492 (See BK Virus-associated Nephropathy [BKVN] and also Progressive Multifocal Leukoencephalopathy [PML], under Cautions.)

BK Virus-associated Nephropathy (BKVN)

BKVN observed in immunosuppressed patients, including those receiving sirolimus.1 484 485 486 487 488 489 490 491 492 Principally observed in renal transplant patients (usually within the first year posttransplantation); may result in severe allograft dysfunction and/or graft loss.1 484 485 486 487 488 489 490 491 492 Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant.485 486 487 488 489 490 491 492

Monitor patients for signs of BKVN (e.g., deterioration of renal function);1 484 485 486 488 if BKVN develops, institute early treatment and consider initially reducing immunosuppressive therapy.1 484 485 486 487 488 490 491 492 Treatment approaches used anecdotally include antiviral therapy (e.g., cidofovir), leflunomide, IV immunoglobulins, and fluoroquinolone antibiotics; additional experience and well-controlled studies needed to establish optimal treatment.485 486 487 491 492

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic viral infection of the brain caused by the polyomavirus JC (also called the JC virus), reported in patients receiving immunosuppressants, including sirolimus.1 498 499 500 501 502 503 Risk factors include immunosuppressive therapies and impairment of immune function.1 498 499 500 501 502 503 504

Commonly presents with hemiparesis, apathy, confusion, cognitive impairment, and ataxia;1 498 503 consider possible diagnosis of PML in any immunocompromised patient experiencing neurologic manifestations.1 498 499 500 501 502 Consider consulting with a neurologist as clinically indicated.1

Decreasing total immunosuppression may improve outcome, but may also increase risk of graft rejection in transplant recipients;1 498 503 consider the potential risks versus benefits of reduced immunosuppression in such cases.1 498 Although optimal treatment not established, antiviral agents (e.g., cidofovir) have been successfully used in the treatment of PML in several transplant recipients.498 503 Early diagnosis and rapid initiation of treatment appear essential for patient recovery.498 503

Interstitial Lung Disease

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology reported.1 27 Risk may increase as trough sirolimus concentration increases.1 In some cases, interstitial lung disease resolved upon sirolimus discontinuance or dosage reduction.1 27

De Novo Use Without Cyclosporine

Safety and efficacy of de novo use without cyclosporine not established in renal transplant patients.1

Increased Risk of Calcineurin Inhibitor-induced HUS/TTP/TMA

Concomitant use with a calcineurin inhibitor (e.g., cyclosporine, tacrolimus) may increase risk of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).1

Antimicrobial Prophylaxis

Cases of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia reported in sirolimus-treated patients not receiving antimicrobial prophylaxis.1 Manufacturer recommends antimicrobial prophylaxis for P. jiroveci pneumonia for 1 year following transplantation.1

Manufacturer recommends cytomegalovirus (CMV) prophylaxis for 3 months after transplantation, particularly in patients at increased risk for CMV disease.1

Assay for Sirolimus Therapeutic Drug Monitoring

Various chromatographic and immunoassay methodologies used in clinical practice to measure sirolimus whole blood concentrations.1 496 497 Patient sample values from different assays may not be interchangeable.1 496 497 (See Therapeutic Drug Monitoring under Dosage and Administration.)

Skin Cancer

Increased risk for skin cancer with immunosuppressive therapy.1 Limit exposure to sunlight and other UV light; use of protective clothing, sunglasses, and sunscreen with a high protection factor is recommended.1

Interaction with Potent Inhibitors and Inducers of CYP3A4 and/or P-glycoprotein

Concurrent administration of sirolimus with potent inhibitors of CYP3A4 and/or P-glycoprotein (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, telithromycin) or potent inducers of CYP3A4 and/or P-glycoprotein (e.g., rifampin, rifabutin) not recommended.1 (See Specific Drugs and Foods under Interactions.)

Specific Populations

Pregnancy

Category C.1 Women of childbearing potential should use effective contraception before, during, and for 12 weeks after discontinuance of sirolimus therapy.1

The National Transplantation Pregnancy Registry (NTPR) is a pregnancy registry for pregnant women receiving immunosuppressants following any solid organ transplantation; the NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant patients by telephone at 877-955-6877 or via their website: .26

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <13 years of age.1

Safety and efficacy established in pediatric and adolescent renal transplant patients ≥13 years of age judged to be at low to moderate immunologic risk.1 Use of sirolimus in this subpopulation supported by evidence from adequate and well-controlled trials of sirolimus in adults with additional pharmacokinetic data in pediatric renal transplant patients.1

Safety and efficacy data in pediatric and adolescent renal transplant patients <18 years of age judged to be at high immunologic risk (i.e., history of ≥1 acute rejection episodes and/or presence of chronic allograft nephropathy) did not support chronic use of sirolimus in combination with calcineurin inhibitors and corticosteroids because of the higher incidence of lipid abnormalities and deterioration of renal function and the lack of demonstrated therapeutic benefit compared with a calcineurin inhibitor-based regimen.1

Geriatric Use

Studies did not include sufficient numbers of patients >65 years of age to determine whether geriatric patients respond differently than younger patients.1 Differences in responses between geriatric patients and younger patients not identified.1 (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics: Absorption.)

Hepatic Impairment

Prolonged elimination; adjustment of the maintenance dosage and therapeutic drug monitoring are recommended in all patients with hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration and see Elimination: Special Populations under Pharmacokinetics.)

Safety and efficacy of sirolimus as immunosuppressive therapy in liver transplant patients not established; such use is notrecommended.1 (See Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplant Patients under Cautions.)

Common Adverse Effects

Peripheral edema,1 hypercholesterolemia,1 2 6 hypertriglyceridemia,1 2 5 6 12 14 hypertension,1 2 increased Scr,1 constipation,1 abdominal pain,1 diarrhea,1 2 6 headache,1 fever,1 urinary tract infection,1 anemia,1 5 nausea,1 arthralgia,1 2 5 pain,1 acne or acne-like eruption,1 2 493 rash,1 2 thrombocytopenia.1 2 4 5 6 9

Adverse reactions that resulted in sirolimus discontinuance in ≥5% of patients: increased Scr, hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP).1

Interactions for Rapamune

Metabolized by CYP3A4;1 also a substrate for P-glycoprotein.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased blood concentrations of sirolimus).1

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased blood concentrations of sirolimus).1

Nephrotoxic Drugs

Possible increased risk of nephrotoxicity with concurrent use of nephrotoxic drugs (e.g., aminoglycosides, amphotericin B); use with caution.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Acyclovir

Pharmacokinetic interaction unlikely1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Decreased blood sirolimus concentrations1

Use with caution1

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)

Increased bioavailability of sirolimus1 9

Use fluconazole with caution; adjust dosage of sirolimus and/or fluconazole if necessary1

Use of itraconazole, ketoconazole, and voriconazole not recommended; consider alternative antifungal therapy with less interaction potential 1

Antilipemic agents

Concurrent use of HMG-CoA reductase inhibitors and/or fibric acid derivatives appears to be well tolerated1 31

Clinically important pharmacokinetic interaction with atorvastatin unlikely1

Monitor for rhabdomyolysis and other adverse effects (e.g., hepatic toxicity) associated with antilipemic therapy

Bromocriptine

Possible increased blood sirolimus concentrations1

Use with caution1

Calcium-channel blocking agents (diltiazem, nicardipine, nifedipine, verapamil)

Diltiazem: Increased bioavailability of sirolimus1 9

Nicardipine: Increased blood sirolimus concentrations1

Nifedipine: Pharmacokinetic interaction unlikely1

Verapamil: Increased bioavailability of sirolimus and verapamil1 20

Use with caution; adjust dosage of sirolimus and/or calcium-channel blocking agent as necessary1

Sirolimus dosage adjustment not required with concomitant use of nicardipine1

Cimetidine

Increased blood sirolimus concentrations1

Use with caution1

Cisapride

Increased blood sirolimus concentrations1

Use with caution1

Clotrimazole

Increased blood sirolimus concentrations1

Use with caution1

Contraceptives, oral

Pharmacokinetic interaction unlikely1

Co-trimoxazole

Pharmacokinetic interaction unlikely1

Cyclosporine

Increased blood concentrations of sirolimus and cyclosporine1

Possible increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy1

Administer sirolimus 4 hours after Neoral oral solution or capsules1

Danazol

Increased blood sirolimus concentrations1

Use with caution1

Digoxin

Pharmacokinetic interaction unlikely1

Dronedarone

Increased blood sirolimus concentrations;33 34

Manufacturer of dronedarone recommends monitoring sirolimus concentrations; adjust dosage if necessary34

Some clinicians suggest avoiding combined therapy; if cannot be avoided, they recommend reducing sirolimus dosage by 50–75% prior to initiating dronedarone and closely monitoring sirolimus concentrations, particularly during the titration phase33

Glyburide

Hypoglycemic effect of glyburide not affected1

Clinically important pharmacokinetic interaction unlikely1

Grapefruit juice

Increased bioavailability of sirolimus1

Avoid concomitant administration, do not use as diluent1

HIV protease inhibitors

Increased blood sirolimus concentrations1

Use with caution1

Macrolide antibiotics (clarithromycin, erythromycin, troleandomycin)

Increased blood sirolimus concentrations1

Concurrent use of clarithromycin or erythromycin and sirolimus not recommended; consider alternative anti-infective therapy with less interaction potential1

Use troleandomycin with caution; adjust dosage of sirolimus if necessary1

Metoclopramide

Increased blood sirolimus concentrations1 9

Use with caution1

Prednisolone

Pharmacokinetic interaction unlikely1

Rifabutin

Decreased blood sirolimus concentrations1

Avoid concomitant use; consider alternative anti-infective therapy with less interaction potential1

Rifampin

Decreased blood sirolimus concentrations1 9

Avoid concomitant use; consider alternative anti-infective therapy with less interaction potential1

Rifapentine

Possible decreased blood sirolimus concentrations1

Use with caution; adjust dosage of sirolimus and/or rifapentine if necessary1

St. John’s wort

Possible decreased sirolimus concentrations1

Tacrolimus

Possible decreased exposure to tacrolimus35

Increased risk of hepatic artery thrombosis, graft loss, and death in de novo liver transplant recipients1 36

Possible increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy1

Increased risk of wound healing complications, impaired renal function, and insulin-dependent posttransplant diabetes mellitus in heart transplant recipients35

Concomitant use not recommended35

Telithromycin

Increased blood sirolimus concentrations1

Avoid concomitant use; consider alternative anti-infective therapy with less interaction potential1

Vaccines

Possible decreased response to vaccination1

Avoid use of live vaccines1

Rapamune Pharmacokinetics

Absorption

Bioavailability

Rapidly but poorly absorbed from the GI tract.1 2 Following oral administration as solution, peak blood concentrations occur in approximately 1 hour in healthy individuals and in about 2 hours in renal transplant recipients.1 2 Systemic availability of oral solution is about 14%.1

Sirolimus tablets are not bioequivalent to the oral solution; bioavailability of tablet is about 27% higher relative to the solution.1

Food

Administration of sirolimus (as oral solution or tablets) with high-fat meal increases mean total exposure by 23–35% compared with fasting; effect of food on peak blood concentration was inconsistent depending on the dosage form evaluated.1

Special Populations

In renal transplant patients >65 years of age, sirolimus trough concentrations were similar to those observed in adults 18–65 years of age.1

Distribution

Extent

Extensively partitioned into formed blood elements (mean blood-to-plasma ratio of sirolimus is 36 in stable renal allograft recipients).1 2

Distributed into milk in animals; not known whether sirolimus distributes into human milk or crosses the placenta.1

Plasma Protein Binding

Approximately 92% (mainly albumin [97%]; also α1-acid glycoprotein and lipoproteins).1

Elimination

Metabolism

Extensively metabolized in the intestinal wall and liver by CYP3A4; also a substrate for P-glycoprotein; 7 major metabolites.1

Present in human whole blood principally as sirolimus; sirolimus contributes >90% of the immunosuppressive activity.1

Elimination Route

Excreted mainly in feces (91%).1

Half-life

Terminal elimination half-life: About 62 hours in stable renal transplant patients.1 2

Special Populations

In patients with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C), AUC is increased by 43, 94, and 189%, respectively; as severity of hepatic impairment increased, steady increases in mean sirolimus elimination half-lives and decreases in mean sirolimus clearance normalized for body weight observed.1

Stability

Storage

Oral

Tablets

Tight, light-resistant container at 20–25°C.1

Solution

2–8°C for solution in bottles; protect from light.1 Discard bottle 1 month after opening.1 May store solution at room temperature (≤25°C) for up to 15 days.1 May store solution in the amber syringe provided by manufacturer for up to 24 hours at 2–8°C or room temperature (≤25°C).1 Use immediately after dilution.1

If slight haze develops when solution in bottles is refrigerated, allow to stand at room temperature and shake gently until haze disappears.1

Actions

  • Mechanism of action appears to be distinct from that of other immunosuppressants (e.g., tacrolimus, cyclosporine).1 3 4 5 6 9 10 11 Sirolimus inhibits activation of mammalian target of rapamycin (mTOR);3 7 9 unlike tacrolimus and cyclosporine, sirolimus does not block calcineurin pathway.1 2 5 11

  • Inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (e.g., interleukin-2, interleukin-4, interleukin-15) stimulation.1 2 3 4 5 9 Also inhibits interleukin-2-dependent and independent proliferation of B-lymphocytes and the production of antibodies (e.g., immunoglobulins A, M, and G).1 2 7

  • Potent immunosuppressive agent.1 2 4 7 9 10 In animal models, about 27 times as potent as tacrolimus.9

Advice to Patients

  • Importance of providing copy of manufacturer's written patient information (medication guide) each time sirolimus is dispensed, and importance of reading this information prior to taking the drug.1

  • Immunosuppressive therapy increases risk of skin cancer.1 Importance of limiting exposure to sunlight or other UV light by wearing protective clothing and sunglasses and using sunscreens with a high protective factor.1

  • Importance of informing women of childbearing age of potential risks and of need for effective contraception prior to initiation of therapy, during therapy, and for 12 weeks after discontinuance.1 Importance of women informing their clinician if they are breast-feeding or plan to breast-feed.1

  • Importance of avoiding grapefruit juice during sirolimus therapy unless otherwise instructed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements.1

  • Importance of following manufacturer’s instructions for dilution and administration of sirolimus oral solution.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Sirolimus

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

1 mg/mL

Rapamune

Wyeth

Tablets

0.5 mg

Rapamune

Wyeth

1 mg

Rapamune

Wyeth

2 mg

Rapamune

Wyeth

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Rapamune 0.5MG Tablets (WYETH): 30/$189.98 or 90/$534.96

Rapamune 1MG/ML Solution (WYETH): 60/$662.01 or 120/$1,324.02

Rapamune 1MG Tablets (WYETH): 30/$346.99 or 90/$1,019.94

Rapamune 2MG Tablets (WYETH): 100/$2,317.87 or 300/$6,789.67

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Wyeth Laboratories. Rapamune (sirolimus) oral solution and tablets prescribing information. Philadelphia, PA; 2010 Dec.

2. Vasquez EM. Sirolimus: a new agent for prevention of renal allograft rejection. Am J Health-Syst Pharm. 2000; 57:437-51. [IDIS 441422] [PubMed 10711524]

3. Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet. 1999; 353:1083-91. [IDIS 425389] [PubMed 10199367]

4. Watson CJE, Friend PJ, Jamieson NV et al. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation. 1999; 67:505-9. [IDIS 424975] [PubMed 10071017]

5. Groth CG, Bäckman L, Morales JM et al. Sirolimus (rapamycin)-based therapy in human renal transplantation. Transplantation. 1999; 67:1036-42. [IDIS 427774] [PubMed 10221490]

6. Kahan BD, Podbielski J, Napoli KL et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation. 1998; 66:1040-6. [IDIS 416821] [PubMed 9808489]

7. Kahan BD. Sirolimus: a new agent for clinical renal transplantation. Transplant Proc. 1997; 29:48-50. [IDIS 381843] [PubMed 9123092]

9. Gerber DA, Bonham CA, Thomson AW. Immunosuppressive agents: recent developments in molecular action and clinical application. Transplant Proc. 1998; 30: 1573-9. [IDIS 410106] [PubMed 9636637]

10. Kelly PA, Gruber SA, Behbod F et al. Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy. 1997; 17:1148-56. [IDIS 395585] [PubMed 9399599]

11. First MR. An update on new immunosuppressive drugs undergoing preclinical and clinical trials: potential applications in organ transplantation. Am J Kidney Dis. 1997; 29:303-17. [IDIS 381829] [PubMed 9016906]

12. Vasquez MA. New advances in immunosuppression therapy for renal transplantation. Am J Med Sci. 1997; 314:415-35. [IDIS 398611] [PubMed 9413350]

13. Brattstrom C, Wilczek H, Tyden G et al. Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation. 1998; 65:1272-4. [IDIS 407337] [PubMed 9603181]

14. Wyeth, Philadelphia, PA: Personal communication.

15. SangStat Medical Corporation. Dear health care professional letter regarding recall of SangCya. Fremont, CA; July 10, 2000. From FDA website ().

16. Anon. FDA approves new Rapamune labeling likely to improve transplanted kidney functioning. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2003 Apr 11.

17. Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001; 38(Suppl 6):S25-35.

18. Gaber AO, Kahan BD, Van Buren C et al. Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial. Transplantation. 2008; 86:1187-95. [PubMed 19005398]

19. Schena FP, Pascoe MD, Alberu J et al. for the Sirolimus CONVERT Trial study Group. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation. 2009; 87:233-42. [PubMed 19155978]

20. Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet. 2005; 44:769-86. [PubMed 16029064]

21. Danovitch GM (Editor). Immunosuppressive medications and protocols. In Handbook of Kidney Transplantation. 4th Edition. Lippincott Williams and Wilkins; 2005.

22. Rapamune (sirolimus) 1 mg/mL oral solution summary of product characteristics. From the EMEA web site. Accessed 9 Oct 2009.

23. Kahan BD, Napoli KL, Kelly PA et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant. 2000; 14:97-109. [PubMed 10770413]

24. Knight RJ, Villa M, Laskey R et al. Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients. Clin Transplant. 2007 Jul-Aug; 21:460-5.

25. Food and Drug Administration. FDA Alert: Information for healthcare professionals: Sirolimus (marketed as Rapamune). Rockville, MD; 2009 Jun 11. From the FDA website. Accessed 2011 Jan 13.

26. Jefferson Medical College, Thomas Jefferson University. National Transplantation Pregnancy Registry (NTPR). Philadelphia, PA. From the NTPR website. Accessed 2009 Nov 10.

27. Chhajed PN, Dickenmann M, Bubendorf L et al. Patterns of pulmonary complications associated with sirolimus. Respiration. 2006; 73:367-74. [PubMed 16127266]

28. Tiong HY, Flechner SM, Zhou L et al. A systematic approach to minimizing wound problems for de novo sirolimus-treated kidney transplant recipients. Transplantation. 2009; 87:296-302. [PubMed 19155988]

29. Steele GH, Adamkovic AB, Demopoulos LA et al. Pericardial effusion coincident with sirolimus therapy: a review of Wyeth's safety database. Transplantation. 2008; 85:645-7. [PubMed 18347546]

30. Truong U, Moon-Grady AJ, Butani L. Cardiac tamponade in a pediatric renal transplant recipient on sirolimus therapy. Pediatr Transplant. 2005; 9:541-4. [PubMed 16048611]

31. Lisik W, Schoenberg L, Lasky RE et al. Statins benefit outcomes of renal transplant recipients on a sirolimus-cyclosporine regimen. Transplant Proc. 2007; 39:3086-92. [PubMed 18089328]

32. Castro G, Freitas C, Beirâo I et al. Chylous ascites in a renal transplant recipient under sirolimus (rapamycin) treatment. Transplant Proc. 2008; 140:1756-8.

33. Tichy EM, Medwid AJ, Mills EA et al. Significant sirolimus and dronedarone interaction in a kidney transplant recipient. Ann Pharmacother. 2010; 44:1338-41. [PubMed 20484171]

34. Sanofi-Aventis. Multaq (dronedarone hydrochloride) tablets prescribing information. Bridgewater, NJ; 2009 Jul.

35. Astellas Pharma US. Prograf (tacrolimus) capsules and injection prescribing information. Deerfield, IL; 2009 Aug..

36. Kusiak V. Dear health care provider letter regarding increased risk of hepatic artery thrombosis, graft loss, and death associated with use of sirolimus (Rapamune) in combination with other immunosuppressants such as cyclosporine or tacrolimus in de novo liver transplant recipients. Philadelphia, PA: Wyeth Pharmaceuticals; 2002 April 24.

37. Hamdy AF, Bakr MA, Ghoneim MA. Proteinuria among primarily sirolimus treated live-donor renal transplant recipients' long-term experience. Exper Clin Transplantation. 2010; 8:283-91.

484. Food and Drug Administration. FDA alert: Information for healthcare professionals: immunosuppressant drugs: required labeling changes [sirolimus (marketed as Rapamune); cyclosporine (marketed as Sandimmune and generics); cyclosporine modified (marketed as Neoral and generics); mycophenolate mofetil (marketed as Cellcept and generics); mycophenolic acid (marketed as Myfortic)]. Rockville, MD; 2009 Jul 14. From the FDA website.

485. Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis. 2009; 54:131-42. [PubMed 19394729]

486. Bonvoisin C, Weekers L, Xhignesse P et al. Polyomavirus in renal transplantation: a hot problem. Transplantation. 2008; 85:S42-8. [PubMed 18401263]

487. Mannon RB. Polyomavirus nephropathy: what have we learned?. Transplantation. 2004; 77:1313-8. [PubMed 15167583]

488. Ziedina I, Folkmane I, Chapenko S et al. Reactivation of BK virus in the early period after kidney transplantation. Transplant Proc. 2009; 41:766-8. [PubMed 19328975]

489. Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation. 2009; 87:1019-26. [PubMed 19352121]

490. Alméras C, Foulongne V, Garrigue V et al. Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study. Transplantation. 2008; 85:1099-104. [PubMed 18431228]

491. Hirsch HH, Brennan DC, Drachenberg CB et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005; 79:1277-86. [PubMed 15912088]

492. Benavides CA, Pollard VB, Mauiyyedi S et al. BK virus-associated nephropathy in sirolimus-treated renal transplant patients: incidence, course, and clinical outcomes. Transplantation. 2007; 84:83-8. [PubMed 17627242]

493. Mahé E, Morelon E, Lechaton S et al. Cutaneous adverse effects in renal transplant recipients receiving sirolimus-based therapy. Transplantation. 2005; 79:476-82. [PubMed 15729175]

494. Mahé E, Morelon E, Lechaton S et al. Angioedema in renal transplant recipients on sirolimus. Dermatology. 2007; 21:205-9.

495. Wadei H, Gruber SA, El-Amm JM et al. Sirolimus-induced angioedema. Am J Transplant. 2004; 4:1002-5. [PubMed 15147436]

496. Food and Drug Administration. Rapamune(sirolimus). Detailed view: Drug monitoring recommendations. Rockville, MD; 2010 Jan 11. From the FDA web site.

497. Camardo J. Dear health care provider letter regarding an update to the Rapamune prescribing recommendation for therapeutic drug monitoring of sirolimus. Philadelphia, PA; 2009 Dec 12.

498. McCalmont V, Bennett K. Progressive multifocal leukoencephalopathy: a case study. Prog Transplant. 2007; 17:157-60. [PubMed 17624139]

499. Waggoner J, Martinu T, Palmer SM. Progressive multifocal leukoencephalopathy following heightened immunosuppression after lung transplant. J Heart Lung Transplant. 2009; 28:395-8. [PubMed 19332268]

500. Crowder CD, Gyure KA, Drachenberg CB et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant. 2005; 5:1151-8. [PubMed 15816900]

501. Boulton-Jones JR, Fraser-Moodie C, Ryder SD. Long term survival from progressive multifocal leucoencephalopathy after liver transplantation. J Hepatol. 2001; 35:828-9. [PubMed 11738115]

502. Kharfan-Dabaja MA, Ayala E, Greene J et al. Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant. 2007; 39:101-7. [PubMed 17143300]

503. Shitrit D, Lev N, Bar-Gil-Shitrit A et al. Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int. 2005; 17:658-65. [PubMed 15616809]

504. Manfro RC, Vedolin L, Cantarelli M et al. Progressive multifocal leukoencephalopathy in a kidney transplant recipient after conversion to mycophenolic acid therapy. Transpl Infect Dis. 2009; 11:189-90. [PubMed 19210690]

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