RAPAMUNE

Sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic produced by bacteria Streptomyces hygroscopicus, which was isolated from the soil of the Vai Atari region of Rapa Nui (Easter Island).

It was first isolated and identified as an antifungal agent with potent anticandida activity; however, after its potent antitumor and immunosuppressive activities were later discovered, it was extensively investigated as an immunosuppressive and antitumour agent.

Its primary mechanism of action is the inhibition of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, and survival. mTOR is an important therapeutic target for various diseases, as it was shown to regulate longevity and maintain normal glucose homeostasis.

Targeting mTOR received more attention especially in cancer, as mTOR signalling pathways are constitutively activated in many types of human cancer.

Sirolimus was first approved by the

FDA in for the prophylaxis of organ rejection in patients aged 13 years and older receiving renal transplants.

In November 2000, the drug was recognized by the European Agency as an alternative to calcineurin antagonists for maintenance therapy with corticosteroids.

In May 2015, the FDA approved sirolimus for the treatment of patients with lymphangioleiomyomatosis.

In November 2021, albumin-bound sirolimus for intravenous injection was approved by the FDA for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).

Sirolimus was also investigated in other cancers such as skin cancer, Kaposi's Sarcoma, cutaneous T-cell lymphomas, and tuberous sclerosis.

The topical formulation of sirolimus, marketed as HYFTOR, was approved by the FDA in April 2022: this marks the first topical treatment approved in the US for facial angiofibroma associated with tuberous sclerosis complex.

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recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation.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 ), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation.

It is also used to treat lymphangioleiomyomatosis.

In the

US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).

In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months.

Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued.

Topical sirolimus is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients six years of age and older.

Sirolimus is an immunosuppressant drug with antifungal and antitumour effects.

In animal models, sirolimus prolonged allograft survival following various organ transplants and reversed an acute rejection of heart and kidney allografts in rats.

Upon oral administration of 2 mg/day and 5 mg/day, sirolimus significantly reduced the incidence of organ rejection in low.

• to moderate-immunologic risk renal transplant patients at six months following transplantation compared with either azathioprine or placebo.

In some studies, the immunosuppressive effect of sirolimus lasted up to six months after discontinuation of therapy: this tolerization effect is alloantigen-specific.

Sirolimus potently inhibits antigen-induced proliferation of

T cells, B cells, and antibody production.

In rodent models of autoimmune disease, sirolimus suppressed immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

In adult renal transplant patients with low.

• to moderate-immunologic risk, oral administration of 2 mg sirolimus led to a C max of 14.4 ± 5.3 ng/mL for oral solution and 15.0 ± 4.9 ng/mL for oral tablets.

The t max was 2.1 ± 0.8 hours for oral solution and 3.5 ± 2.4 hours for oral tablets.

In healthy subjects, the t max is one hour.

In a multi-dose study, steady-state was reached six days following repeated twice-daily administration without an initial loading dose, with the average trough concentration of sirolimus increased approximately 2.

• to 3-fold.

It is suspected that a loading dose of three times the maintenance dose will provide near steady-state concentrations within one day in most patients.

The systemic availability of sirolimus is approximately 14%.

In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution.

Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level.

Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable renal transplant patients, are dose-proportional between and 12 mg/m 2.

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 L in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements.

The mean volume of distribution (V ss/F ) of sirolimus is 12 ± 8 L/kg.

Sirolimus undergoes extensive metabolism in the intestinal wall and liver.

Sirolimus is primarily metabolized by

O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive.

Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen.

Hover over products below to view reaction partners Sirolimus 41-O-demethylrapamycin 39-O-Desmethylsirolimus 16-O-Desmethylsirolimus 12-OH-sirolimus 11-OH-sirolimus 25-OH-sirolimus 24-OH-sirolimus 46-OH-sirolimus.

Following oral administration of sirolimus in healthy subjects, about 91% of the radioactivity was recovered from feces and only 2.2% of the radioactivity was detected in urine.

Some of the metabolites of sirolimus are also detectable in feces and urine.

The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.

In adult renal transplant patients with low.

• to moderate-immunologic risk, oral administration of 2 mg sirolimus led to oral clearance of 173 ± 50 mL/h/kg for oral solution and 139 ± 63 mL/h/kg for oral tablets.

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LD of sirolimus is 800 mg/kg in rats and 2500 mg/kg in mouse.

Sirolimus is a narrow therapeutic index drug.

Although there are reports of overdose with sirolimus, there is limited information on overdose in the clinical setting.

Symptoms of overdose are consistent with the adverse effects of sirolimus.

General supportive measures are recommended in the event of an overdose.

Because sirolimus has low aqueous solubility and high erythrocyte and plasma protein binding, it is not expected to be dialyzable to any significant extent.

Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus.

Hypersensitivity to sirolimus.

Sirolimus tablets are to be administered orally once daily, consistently with or without food.

Tablets should not be crushed, chewed or split.

Patients unable to take the tablets should be prescribed the solution and instructed in its use.

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 sirolimus 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: Sirolimus and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg.

Withdrawal: 2 months to 4 months post-transplantation, withdraw CsA over 4 weeks to 8 weeks.

In renal transplant patients at high-immunologic risk: Sirolimus and CsA Combination Therapy (for the first 12 months posttransplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg.

Recommended initial sirolimus dose is 2 mg/day.

Adjust the sirolimus dose to achieve sirolimus trough concentrations between to 15 ng/mL.

Therapeutic drug monitoring is recommended for all patients. 2.1 General Dosing Guidance for Renal Transplant Patients The initial dose of sirolimus tablets should be administered as soon as possible after transplantation.

It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) .

Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life.

Once sirolimus tablets maintenance dose is adjusted, patients should continue on the new maintenance dose for at least to 14 days before further dosage adjustment with concentration monitoring.

In most patients, dose adjustments can be based on simple proportion: new sirolimus tablets dose = current dose x (target concentration/current concentration).

A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 x (new maintenance dose - current maintenance dose).

The maximum sirolimus tablets dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days.

Sirolimus trough concentrations should be monitored at least to 4 days after a loading dose(s).

Two milligrams (2 mg) of Sirolimus Oral Solution have been demonstrated to be clinically equivalent to 2 mg Sirolimus Tablets; hence, at this dose these two formulations are interchangeable.

However, it is not known if higher doses of Sirolimus Oral Solution are clinically equivalent to higher doses of Sirolimus Tablets on a mg-to-mg basis. 2.2 Renal Transplant Patients at Low.

• to Moderate-Immunologic Risk Sirolimus and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids.

A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range.

At to 4 months following transplantation, cyclosporine should be progressively discontinued over to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range.

Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased. 2.3 Renal Transplant Patients at High-Immunologic Risk In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation.

The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months.

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.

For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation.

Beginning on day 2, an initial maintenance dose of 5 mg/day should be given.

A trough level should be obtained between days and 7, and the daily dose of sirolimus should thereafter be adjusted.

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations.

Prednisone should be administered at a minimum of 5 mg/day. Antibody induction therapy may be used. 2.4 Dosing in Patients with Lymphangioleiomyomatosis For patients with lymphangioleiomyomatosis, the initial sirolimus dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in to 20 days, with dosage adjustment to maintain concentrations between to 15 ng/mL.

In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose x (target concentration/current concentration).

Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life.

Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least to 14 days before further dosage adjustment with concentration monitoring.

Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every three months. 2.5 Therapeutic Drug Monitoring Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors.

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy.

Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range.

Following cyclosporine withdrawal in transplant patients at low.

• to moderate-immunologic risk, the target sirolimus trough concentrations should be to 24 ng/mL for the first year following transplantation.

Thereafter, the target sirolimus concentrations should be to 20 ng/mL.

The above recommended 24 hour trough concentration ranges for sirolimus are based on chromatographic methods.

Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies.

Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable.

Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations.

Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.

Therefore, communication should be maintained with the laboratory performing the assay.

A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000. 2.6 Patients with Low Body Weight The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m 2 /day. The loading dose should be 3 mg/m 2. 2.7 Patients with Hepatic Impairment It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment.

It is not necessary to modify the sirolimus loading dose. 2.8 Patients with Renal Impairment Dosage adjustment is not needed in patients with impaired renal function.

Tablets, 0.5 mg are yellow, round, biconvex, coated tablets debossed with "1" in on one side and plain on other side and are supplied as follows: NDC: 70518-4376-00 NDC: 70518-4376-01 PACKAGING: 100 in 1 BOX INNER PACKAGING: 1 in 1 POUCH Since sirolimus is not absorbed through the skin, there are no special precautions.

However, if direct contact occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water.

Do not use Sirolimus

Tablets after the expiration date.

The expiration date refers to the last day of that month.

Store at 20°C to 25°C (68F° 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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Based on animal studies and the mechanism of action, sirolimus 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Sirolimus crossed the placenta and was toxic to the conceptus.

In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day to 15).

Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg).

The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg).

Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg).

NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone.

In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day to 18).

There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e., embryo-fetal abortion or early resorption).

Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg).

In a pre.

• and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20).

An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis).

At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring.

Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

The safety and efficacy of sirolimus in pediatric patients < 13 years have not been established.

The safety and efficacy of sirolimus oral solution and sirolimus tablets have been established for prophylaxis of organ rejection in renal transplantation in children ≥ 13 years judged to be at low.

• to moderate-immunologic risk.

Use of sirolimus oral solution and sirolimus tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of sirolimus oral solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients.

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (< 18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus oral solution or tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival.

The safety and efficacy of sirolimus in pediatric patients <18 years have not been established.

Clinical studies of sirolimus oral solution or tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients.

Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary.

Differences in responses between the elderly and younger patients have not been identified.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy.