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Sirolimus

Pronunciation

(sir OH li mus)

Index Terms

  • Rapamycin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral:

Rapamune: 1 mg/mL (60 mL) [contains alcohol, usp]

Tablet, Oral:

Rapamune: 0.5 mg, 1 mg, 2 mg

Generic: 0.5 mg, 1 mg, 2 mg

Brand Names: U.S.

  • Rapamune

Pharmacologic Category

  • Immunosuppressant Agent
  • mTOR Kinase Inhibitor

Pharmacology

Sirolimus inhibits T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation and inhibits antibody production. Its mechanism differs from other immunosuppressants. Sirolimus binds to FKBP-12, an intracellular protein, to form an immunosuppressive complex which inhibits the regulatory kinase, mTOR (mechanistic target of rapamycin). This inhibition suppresses cytokine mediated T-cell proliferation, halting progression from the G1 to the S phase of the cell cycle. It inhibits acute rejection of allografts and prolongs graft survival.

In lymphangioleiomyomatosis, the mTOR signaling pathway is activated through the loss of the tuberous sclerosis complex (TSC) gene function (resulting in cellular proliferation and release of lymphangiogenic growth factors). By inhibiting the mTOR pathway, sirolimus prevents the proliferation of lymphangioleiomyomatosis cells.

Absorption

Rapid

Distribution

12 L/kg (range: 4 to 20 L/kg)

Metabolism

Extensive; in intestinal wall via P-glycoprotein and hepatic via CYP3A4 to 7 major metabolites

Excretion

Feces (91% via P-glycoprotein-mediated efflux into gut lumen); urine (2%)

Time to Peak

Oral solution: 1 to 3 hours; Tablet: 1 to 6 hours

Half-Life Elimination

Mean: 62 hours (range; 46 to 78 hours); extended in hepatic impairment (Child-Pugh class A or B) to 113 hours

Protein Binding

~92%, primarily to albumin

Special Populations: Renal Function Impairment

Minimal (2.2%) renal excretion of the drug and its metabolites.

Special Populations: 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.

Special Populations: Gender

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

Use: Labeled Indications

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

Renal transplantation: 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 safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients. The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established.

Use: Unlabeled

Prophylaxis of organ rejection and allograft vasculopathy in heart transplant recipients; prevention acute graft-versus-host disease (GVHD) in allogeneic stem cell transplantation; treatment of refractory acute or chronic GVHD; treatment of chordoma, renal angiomyolipoma, or lymphangioleiomyomatosis

Contraindications

Hypersensitivity to sirolimus or any component of the formulation

Dosage

Low-to-moderate immunologic risk renal transplant patients: Adolescents ≥13 years and Adults: Dosing by body weight: Oral:

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

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

High immunologic risk renal transplant patients: Adults: Oral: Loading dose: 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 to maintain trough concentrations within desired range based on risk and concomitant therapy. Maximum daily dose: 40 mg. Dosage should be adjusted at intervals of 7 to 14 days 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). 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 dose in 1 day: 40 mg; if required dose is >40 mg (due to loading dose), divide loading dose over 2 days. 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: Cyclosporine withdrawal is not recommended in high immunological risk 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 (measured by chromatographic methodology).

Lymphangioleiomyomatosis: Adults: Oral: Initial: 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.

Graft-versus-host disease (GVHD): Adults: Oral:

GVHD prophylaxis (off-label use): 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)

Treatment of refractory acute GVHD (off-label use): 4 to 5 mg/m2 for 14 days (no loading dose) (Benito 2001)

Treatment of chronic GVHD (off-label use): 6 mg loading dose, followed by 2 mg daily (target trough level: 7 to 12 ng/mL) for 6 to 9 months (Couriel 2005)

Heart transplantation (off-label use): Adults: Oral: 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]) or may have sirolimus added to a calcineurin inhibitor to prevent or minimize further transplant related vasculopathy or renal toxicity due to calcineurin inhibitor use.

Conversion from a calcineurin inhibitor (CNI) (ie, cyclosporine, tacrolimus): 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).

Conversion from antiproliferative drug (ie, azathioprine or mycophenolate) while maintaining calcineurin inhibitor: 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).

Renal angiomyolipoma (off-label use): Adults: Oral: Initial: 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 in renal impairment: 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.

Dosage adjustment in hepatic impairment:

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%.

Administration

Initial dose should be administered as soon as possible after transplant. Sirolimus should be taken 4 hours after oral cyclosporine (Neoral or Gengraf). Should be administered consistently (either with or without food).

Solution: Mix (by stirring vigorously) with at least 2 ounces 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 4 ounces of water or orange juice, stirred vigorously, and the patient should drink the contents at once.

Tablet: Do not crush, split, or chew.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

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

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

Drug Interactions

ACE Inhibitors: Sirolimus may enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of Sirolimus. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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

Boceprevir: May increase the serum concentration of Sirolimus. Management: Significant sirolimus dose reductions may be required if used with boceprevir. Concurrent use should be performed with great caution and close monitoring of both sirolimus concentrations and clinical response. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Clotrimazole (Topical): May increase the serum concentration of Sirolimus. Monitor therapy

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

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Crizotinib: May increase the serum concentration of Sirolimus. Avoid combination

CycloSPORINE (Systemic): Sirolimus 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. 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. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Efavirenz: May decrease the serum concentration of Sirolimus. Management: Closely monitor sirolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of sirolimus may be required. Consider therapy modification

Enzalutamide: May decrease the serum concentration of Sirolimus. Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluconazole: May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Consider therapy modification

Fosaprepitant: May increase the serum concentration of Sirolimus. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus concentrations if fosphenytoin/phenytoin is initiated/dose increased. Monitor for increased sirolimus concentrations with phenytoin discontinuation/dose decrease. Sirolimus dose adjustments may be necessary. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Itraconazole: May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Consider therapy modification

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Sirolimus. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Micafungin: May increase the serum concentration of Sirolimus. Monitor therapy

Mifepristone: May increase the serum concentration of Sirolimus. Management: Avoid sirolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nelfinavir: May increase the serum concentration of Sirolimus. Management: Carefully monitor the need for sirolimus dosage reductions when coadministered with nelfinavir. Sirolimus dosage reduction will probably be needed. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Sirolimus. Management: Monitor for increased sirolimus effects/toxicities and sirolimus serum concentrations after initiation of ombitasvir/paritaprevir/ritonavir/dasabuvir. Consider empiric sirolimus dose reductions. Canadian labeling recommends avoiding this combination. Consider therapy modification

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: May decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus serum concentrations if phenytoin is initiated/dose increased. Monitor for increased sirolimus concentrations with phenytoin discontinuation/dose decrease. Sirolimus dose adjustments may be necessary. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Posaconazole: May increase the serum concentration of Sirolimus. Avoid combination

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifampin: May increase the metabolism of Sirolimus. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): May enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus may decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Avoid combination

Telaprevir: May increase the serum concentration of Sirolimus. Management: Significant sirolimus dose reductions are likely to be required if used with telaprevir. Concurrent use should be performed with great caution and close monitoring of both sirolimus concentrations and clinical response. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Voriconazole: May increase the serum concentration of Sirolimus. Avoid combination

Adverse Reactions

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% (Limited to important or life-threatening): Ascites, azoospermia, cardiac tamponade, cytomegalovirus, dehiscence (fascial), Epstein-Barr infection, exfoliative dermatitis, focal segmental glomerulosclerosis, hepatic necrosis, hepatotoxicity, hyperglycemia, hypersensitivity angiitis, hypersensitivity reaction, hypophosphatemia, incisional hernia, interstitial pulmonary disease (dose related; includes pneumonitis, pulmonary fibrosis, and bronchiolitis obliterans organizing pneumonia with no identified infectious etiology), lymphedema, 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

ALERT: U.S. 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 health care provider 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 recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis; most cases of hepatic artery thrombosis occurred within 30 days post-transplantation, and most led to graft loss or death. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, use in these patients 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, use in these patients is not recommended.

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; concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors) may increase risk.

• Infections: [US Boxed Warning]: 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: [US Boxed Warning]: 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.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; a reduction in the maintenance dose is recommended.

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.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• 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: [US Boxed Warning]: 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: [US Boxed Warning]: 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).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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: [US Boxed Warning]: 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.

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.

Pregnancy Risk Factor

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Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Effective contraception must be initiated before therapy with sirolimus and continued for 12 weeks after discontinuation.

The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 1-877-955-6877.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia, constipation, diarrhea, or arthralgia. Have patient report immediately to prescriber signs of infection, signs of renal impairment, signs of hypokalemia, edema of extremities, extremity discoloration, painful extremities, angina, hemoptysis, severe dizziness, syncope, tachycardia, night sweats, significant headache, skin growths, mole changes, intolerable asthenia, wound healing impairment, ecchymosis, hemorrhaging, menstrual irregularities, signs of pulmonary disorder, signs of progressive multifocal leukoencephalopathy, or signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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