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Sirolimus (Rapamycin)

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(Immunosuppressants)

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CAS for Sirolimus: 53123-88-9

Sirolimus(Rapamycin) is an immunosuppressive agent. Sirolimus(Rapamycin) is a macrocyclic lactone produced by Streptomyces hygroscopicus . The chemical name of Sirolimus(Rapamycin) (Rapamycin) (also known as rapamycin) is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H -pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4 H ,6 H ,31 H )-pentone. Its molecular formula is C 51 H 79 NO 13 and its molecular weight is 914.2. The structural formula of Sirolimus(Rapamycin) (Rapamycin) is shown below.

Sirolimus(Rapamycin) (Rapamycin) is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

Rapamune ? is available for administration as an oral solution containing 1 mg/mL Sirolimus(Rapamycin) (Rapamycin) . Rapamune is also available as a white, triangular-shaped tablet containing 1-mg Sirolimus(Rapamycin) (Rapamycin) , and as a yellow to beige triangular-shaped tablet containing 2-mg Sirolimus(Rapamycin) (Rapamycin) .

The inactive ingredients in Rapamune ? Oral Solution are Phosal 50 PG ? (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids , and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution contains 1.5% - 2.5% ethanol.

The inactive ingredients in Rapamune ? Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, and other ingredients. The 2 mg dosage strength also contains iron oxide yellow 10 and iron oxide brown 70.

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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 poor aqueous solubility and high erythrocyte and plasma protein binding of Sirolimus(Rapamycin) , it is anticipated that Sirolimus(Rapamycin) is not dialyzable to any significant extent. In mice and rats, the acute oral lethal dose was greater than 800 mg/kg.

DOSAGE AND ADMINISTRATION

It is recommended that Rapamune Oral Solution and Tablets be used initially in a regimen with cyclosporine and corticosteroids. Cyclosporine withdrawal is recommended 2 to 4 months after transplantation in patients at low to moderate immunologic risk.

The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied and it is therefore not recommended. This includes patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine > 4.5 mg/dL, black patients, re-transplants, multi-organ transplants, patients with high panel of reactive antibodies..

Two-mg of Rapamune oral solution has been demonstrated to be clinically equivalent to 2-mg Rapamune oral tablets and hence, are interchangeable on a mg to mg basis. However, it is not known if higher doses of Rapamune oral solution are clinically equivalent to higher doses of tablets on a mg to mg basis.. Rapamune is to be administered orally once daily.

Rapamune and cyclosporine combination therapy: The initial dose of Rapamune should be administered as soon as possible after transplantation. For de novo transplant recipients, a loading dose of Rapamune of 3 times the maintenance dose should be given. A daily maintenance dose of 2-mg is recommended for use in renal transplant patients, with a loading dose of 6 mg. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg was used in clinical trials of the oral solution and was shown to be safe and effective, no efficacy advantage over the 2-mg dose could be established for renal transplant patients. Patients receiving 2 mg of Rapamune Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of Rapamune Oral Solution per day.

Rapamune following cyclosporine withdrawal: Initially, patients considered for cyclosporine withdrawal should be receiving Rapamune and cyclosporine combination therapy. At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks and the Rapamune ? dose should be adjusted to obtain whole blood trough concentrations within the range of 12 to 24 ng/mL (chromatographic method). Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy, and laboratory parameters. Cyclosporine inhibits the metabolism and transport of Sirolimus(Rapamycin) , and consequently, Sirolimus(Rapamycin) concentrations will decrease when cyclosporine is discontinued unless the Rapamune dose is increased. The Rapamune ? dose will need to be approximately 4-fold higher to account for both the absence of the pharmacokinetic interaction (approximately 2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (approximately 2-fold increase).

Frequent Rapamune ? dose adjustments based on non-steady-state Sirolimus(Rapamycin) concentrations can lead to overdosing or underdosing because Sirolimus(Rapamycin) has a long half-life. Once Rapamune ? maintenance dose is adjusted, patients should be retained on the new maintenance dose at least for 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients dose adjustments can be based on simple proportion: new Rapamune ? 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 considerably increase Sirolimus(Rapamycin) trough concentrations: Rapamune ? loading dose = 3 กม (new maintenance dose - current maintenance dose). The maximum Rapamune ? 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(Rapamycin) trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

To minimize the variability of exposure to Rapamune, this drug should be taken consistently with or without food. Grapefruit juice reduces CYP3A4-mediated drug metabolism and potentially enhances P-gp mediated drug counter-transport from enterocytes of the small intestine. This juice must not be administered with Rapamune or used for dilution.

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