Sirolimus

Sirolimus is a prescription medication used for the prevention of renal transplant rejection and to treat a rare lung disorder called lymphangioleiomyomatosis (LAM).

• Sirolimus is available under the following different brand names: Rapamune

Adult and pediatric dosage

Tablet

• 0.5mg
• 1mg
• 2mg
• Oral solution
• 1mg/mL

Prophylaxis of Renal Transplant Rejection

Adult dosage

• Initiate with concomitant cyclosporine and corticosteroids
• Oral solutions and tablets interchangeable on an mg per mg basis
• Target whole blood trough concentrations: 16-24 ng/mL for the first year following transplantation; thereafter, 12-20 ng/mL

High immunologic risk

• Less than 40 kg: 3 mg/m² loading dose
• More than or equal to 40 kg: 15 mg orally loading dose
• Maintenance: 5 mg/day orally if more than 40 kg and 1 mg/m²/day if less than 40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
• Concomitant therapy: For the first year, following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; cyclosporine may be initiated at 7 mg/kg/day in divided doses with the dose adjusted to achieve trough concentrations; prednisone should be given at a dose of 5 mg/day

Low-to-moderate immunologic risk

• Less than 40 kg: 3 mg/m² loading dose
• More than or equal to 40 kg: 6 mg orally loading dose
• Maintenance: 2 mg/day orally if more than 40 kg and 1 mg/m²/day if less than 40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
• Dose adjustments: Dose should be adjusted to maintain trough concentrations within the desired range based on clinical state and concomitant therapy; further dose adjustment should not be done sooner than 7-14 days following a dose adjustment
• Concomitant therapy: The following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; may discontinue cyclosporine gradually over 4-8 weeks two to four months after transplant in patients with low immunologic risk, & sirolimus dose increased (serum concentrations of sirolimus may decrease following cyclosporine withdrawal)

Pediatric dosage

• Children below 13 years: Not recommended
• Children above 13 years:

High Immunologic Risk

• Loading dose: less than 40 kg: 3 mg/m² orally
• Loading dose more than or equal to 40 kg: 15 mg orally
• Maintenance: 5 mg/day orally if above 40 kg and 1 mg/m²/day if below 40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
• Concomitant therapy: For the first year, following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; cyclosporine may be initiated at 7 mg/kg/day in divided doses with the dose adjusted to achieve trough concentrations; prednisone should be given at a dose of 5 mg/day

Low-to-moderate Immunologic risk

• Loading dose less than 40 kg: 3 mg/m² orally
• Loading dose more than or equal to 40 kg: 6 mg orally
• Maintenance: 2 mg/day orally if more than or equal to 40 kg and 1 mg/m²/day if less than 40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
• Concomitant therapy: The following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; may discontinue cyclosporine gradually over 4-8 weeks two to four months after transplant in patients with low immunologic risk, & sirolimus dose increased (serum concentrations of sirolimus may decrease following cyclosporine withdrawal)

Lymphangioleiomyomatosis

Adult dosage

• Initial: 2 mg/day orally x10-20 days and then measure whole blood trough level

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of Sirolimus include:

• fever,
• cold symptoms (stuffy nose, sneezing, sore throat),
• mouth sores,
• nausea,
• stomach pain,
• diarrhea,
• headache,
• muscle aches,
• chest pain,
• dizziness, and
• acne.

Serious side effects of Sirolimus include:

• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• brain infection,
• changes in mental state,
• decreased vision,
• weakness on one side of the body,
• problems with speech or walking,
• rash,
• peeling skin,
• wheezing,
• difficulty breathing,
• chest pain or tightness,
• redness, oozing, or slow healing of skin wounds,
• new skin lesion, or a mole that has changed in size or color,
• unusual bleeding or bruising,
• sudden chest pain or discomfort,
• cough,
• tenderness around the transplanted kidney,
• signs of infection--fever, chills, painful mouth sores, skin sores, cold or flu symptoms, pain or burning when urinating, and 
• low red blood cells (anemia)--pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet.

Rare side effects of Sirolimus include:

• none 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first

• Sirolimus has severe interactions with the following drugs:
  • ketoconazole
  • levoketoconazole
  • mifepristone
  • voriconazole
• Sirolimus has serious interactions with at least 168 other drugs.
• Sirolimus has moderate interactions with at least 183 other drugs.
• Sirolimus has minor interactions with the following drugs:
  • alvimopan
  • armodafinil
  • fexofenadine
  • loratadine
  • ruxolitinib
  • ruxolitinib topical

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Hypersensitivity to sirolimus or macrolide antibiotics
• Concomitant live vaccines

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Sirolimus?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Sirolimus?”

Cautions

• Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of this drug
• Not for liver or lung transplant
• Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor
• Progressive multifocal leukoencephalopathy (PML), sometimes fatal, has been reported; commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia
• Based on animal studies and mechanism of action, therapy may cause fetal harm when administered to a pregnant woman; in animal studies, mTOR inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at recommended lowest starting dose; advise pregnant women of the potential risk to a fetus; advise women of childbearing potential to avoid becoming pregnant and to use effective contraception while on therapy and for 12 weeks after ending treatment
• Associated with the development of angioedema; concomitant use of other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema; elevated sirolimus levels (with/without concomitant ACE inhibitors) may potentiate angioedema; in some cases, angioedema has resolved upon discontinuation of therapy dose reduction
• Consult lab regarding the type of assay for drug monitoring; whole blood concentrations are being measured by various chromatographic and immunoassay methodologies; sample concentration values from different assays may not be interchangeable
• Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus; in some cases, was reported with pulmonary hypertension (including pulmonary arterial hypertension as a secondary event; in some cases, the ILD has resolved upon discontinuation or dose reduction; the risk may be increased as trough sirolimus concentration increases
• Safety and efficacy of de novo use of sirolimus without cyclosporine are not established in renal transplant patients; in a multicenter clinical study significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist reported; a benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine
• Fluid accumulation was reported, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving therapy

Impairment of wound healing

• Impaired or delayed wound healing was reported in patients receiving therapy, including lymphocele and wound dehiscence mTOR inhibitors such as sirolimus has been shown in vitro to inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability; lymphocele, a known surgical complication of renal transplantation, reported to occur significantly more often in a dose-related fashion in patients receiving therapy
• Appropriate measures should be considered to minimize complications; patients with body mass index (BMI) above 30 kg/m² may be at increased risk of abnormal wound healing based on data from medical literature
• Increased susceptibility to infection and to develop lymphoma

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

• Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis
• Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use this treatment for prophylaxis of organ rejection in patients receiving renal transplants
• The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient

Hyperlipidemia

• Any patient receiving therapy should be monitored for hyperlipidemia; if detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines
• The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen
• In clinical trials of patients receiving sirolimus plus cyclosporine or after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy; despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels above 240 mg/dL and triglycerides above recommended target levels

Latent viral infection

• Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections; these include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants; this infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss
• Patient monitoring may help detect patients at risk for BK virus-associated nephropathy; reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy

Drug interaction overview

• Coadministration with live virus vaccines is contraindicated (see Black Box Warnings)
• CYP3A4 inhibitors (including grapefruit juice) may increase whole blood levels
• Coadministration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (e.g., rifampin or rifabutin) not recommended
• During therapy with or without cyclosporine, patients with hyperlipidemia administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents
• Concomitant use with a calcineurin inhibitor (e.g., cyclosporine, tacrolimus, sirolimus) may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, thrombotic microangiopathy, pancytopenia, or neutropenia
• Live vaccines should be avoided during treatment; live vaccines may include, but are not limited to, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid; immunosuppressants may affect response to vaccination; during treatment, vaccination may be less effective
• Renal function should be closely monitored during the coadministration with cyclosporine because long-term administration of the combination has been associated with deterioration of renal function; appropriate adjustment of immunosuppressive regimen, including discontinuation of therapy and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels; in patients at low- to moderate-immunologic risk, a continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when benefits outweigh risks of this combination for individual patients; exercise caution when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function; in patients with delayed graft function, therapy may delay recovery of renal function.

Pregnancy and Lactation

• Can cause fetal harm when administered to pregnant women based on animal studies and the mechanism of action

Contraception

• Females should not be pregnant or become pregnant while receiving sirolimus
• Females of reproductive potential are recommended to use highly effective contraception methods during treatment and for 12 weeks after treatment has been stopped

Infertility

• Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment; ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) are reported in females; azoospermia is reported in males and has been reversible upon discontinuation in most cases.

Lactation

• Data are not available regarding the presence of human milk, the effects on breastfed infants, or the effects on milk production
• Sirolimus is excreted in trace amounts in the milk of lactating rats Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from sirolimus, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.