RAPAMUNE (sirolimus)

RAPAMUNE (sirolimus)

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RAPAMUNE (sirolimus)

Rapamune (sirolimus) is an mTOR inhibitor immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (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-epoxy3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2.

Indications and usage

Prophylaxis of Organ Rejection in Renal Transplantation: Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

  • In patients at low-to moderate-immunologic risk, it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation
  • In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation

Treatment of Patients with Lymphangioleiomyomatosis: Rapamune (sirolimus) is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

Limitations of Use in Renal Transplantation

Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine >4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies

  • In patients at high-immunologic risk, the safety and efficacy of Rapamune used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient
  • In pediatric patients, the safety and efficacy of Rapamune have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high-immunologic risk

Mechanism of Action

Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.

Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

Dosage and administration

Renal Transplant Patients:

  • Administer once daily by mouth, consistently with or without food
  • Administer the initial dose as soon as possible after transplantation and 4 hours after CsA
  • Adjust the Rapamune maintenance dose to achieve sirolimus trough concentrations within the target-range
  • Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment

In renal transplant patients at low-to moderate-immunologic risk:

  • Rapamune and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg
  • Rapamune Following CsA Withdrawal: 2-4 months post-transplantation, withdraw CsA over 4-8 weeks

In renal transplant patients at high-immunologic risk:

  • Rapamune and CsA Combination Therapy (for the first 12 months post-transplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg

Lymphangioleiomyomatosis Patients:

  • Administer once daily by mouth, consistently with or without food
  • Recommended initial Rapamune dose is 2 mg/day
  • Adjust the Rapamune dose to achieve sirolimus trough concentrations between 5-15 ng/mL
  • Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment

Instructions for Dilution and Administration of Rapamune Oral Solution

The amber oral dose syringe should be used to withdraw the prescribed amount of Rapamune Oral Solution from the bottle. Empty the correct amount of Rapamune from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume [minimum of four (4) ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once.

Rapamune Oral Solution contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of Rapamune Oral Solution. It is important that these recommendations be followed closely.

Adverse reations

Prophylaxis of organ rejection in patients receiving renal transplants: Most common adverse reactions (incidence ≥30%) are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.

Lymphangioleiomyomatosis: Most common adverse reactions (incidence ≥20%) are stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

Contraindications

  • Hypersensitivity to Rapamune

Warnings and precautions

Increased Susceptibility to Infection and the Possible Development of Lymphoma: Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.

Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis: The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of Rapamune has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT).

Lung Transplantation – Bronchial Anastomotic Dehiscence: Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen. The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

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Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of Rapamune

Angioedema: Rapamune has been associated with the development of angioedema. The concomitant use of Rapamune with 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 also potentiate angioedema

Fluid Accumulation and Impairment of Wound Healing: There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with Rapamune.

Hyperlipidemia: Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with Rapamune compared with azathioprine or placebo controls in Studies 1 and 2. There were increased incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45- 57%) in patients receiving Rapamune compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune.

Decline in Renal Function: Renal function should be closely monitored during the co-administration of Rapamune with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function.

Latent Viral Infections: 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, including Rapamune.

Embryo-Fetal Toxicity: Based on animal studies and the mechanism of action, Rapamune can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus.

Skin Cancer Events: Patients on immunosuppressive therapy are at increased risk for skin cancer. 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.

Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp: Avoid concomitant use of Rapamune with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin)

Drug interactions

Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p-glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations.

Use with Cyclosporine: Cyclosporine, a substrate and inhibitor of CYP3A4 and P-gp, was demonstrated to increase sirolimus concentrations when co-administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED)

Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp: Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered

Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of Rapamune

Use in specific populations

Pregnancy: Based on animal studies and the mechanism of action, Rapamune can cause fetal harm when administered to a pregnant woman. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses. Advise pregnant women of the potential risk to a fetus.

Lactation: It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rapamune and any potential adverse effects on the breastfed child from Rapamune.

Contraception: Females should not be pregnant or become pregnant while receiving Rapamune. Advise females of reproductive potential that animal studies have been shown Rapamune to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped

Infertility: Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with Rapamune. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of Rapamune. Azoospermia has been reported in males with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases.

Pediatric Use: The safety and efficacy of Rapamune in pediatric patients <13 years have not been established.

Lymphangioleiomyomatosis: The safety and efficacy of Rapamune in pediatric patients <18 years have not been established

Overdosage

Reports of overdose with Rapamune have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section

General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg.

Storage

Rapamune Tablets should be stored at 20°C to 25°C [USP Controlled Room Temperature] (68°F to 77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container as defined in the USP.

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