Rapamycin

Rapamycin - General Information

A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Rapamycin is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [PubChem]

 

Pharmacology of Rapamycin

Rapamycin, a macrocyclic lactone produced by Streptomyces hygroscopicus, is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids.

 

Rapamycin for patients

Patients should be given complete dosage instructions. Women of childbearing potential should be informed of the potential risks during pregnancy and that they should use effective contraception prior to initiation of Rapamune therapy, during Rapamune therapy and for 12 weeks after Rapamune therapy has been stopped.

Patients should be told that exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer.

PATIENT INSTRUCTIONS FOR RAPAMUNE™ (SIROLIMUS) ORAL SOLUTION Bottles

1. Open the solution bottle. Remove the safety cap by squeezing the tabs on the cap and twisting counterclockwise.
2. On first use, insert the adapter assembly (plastic tube with stopper) tightly into the bottle until it is even with the top of the bottle. Do not remove the adapter assembly from the bottle once inserted.
3. For each use, tightly insert one of the amber syringes with the plunger fully depressed into the opening in the adapter.
4. Withdraw the prescribed amount of Rapamune™ Oral Solution by gently pulling out the plunger of the syringe until the bottom of the black line of the plunger is even with the appropriate mark on the syringe. Always keep the bottle in an upright position. If bubbles form in the syringe, empty the syringe into the bottle and repeat the procedure.
5. You may have been instructed to carry your medication with you. If it is necessary to carry the filled syringe, place a cap securely on the syringe ¾ the cap should snap into place.
6. Then place the capped syringe in the enclosed carrying case. Once in the syringe, the medication may be kept at room temperature or refrigerated and should be used within 24 hours. Extreme temperatures (below 36°F and above 86°F) should be avoided. Remember to keep this medication out of the reach of children.
7. Empty the syringe into a glass or plastic cup containing at least 2 ounces (1/4 cup, 60 mL) of water or orange juice, stir vigorously for one (1) minute and drink immediately. Refill the container with at least 4 ounces (1/2 cup, 120 mL) of water or orange juice, stir vigorously again and drink the rinse solution. Apple juice, grapefruit juice, or other liquids are NOT to be used. Only glass or plastic cups should be used to dilute Rapamune™ Oral Solution. The syringe and cap should be used once and then discarded.
8. Always store the bottles of medication in the refrigerator. When refrigerated, a slight haze may develop in the solution. The presence of a haze does not affect the quality of the product. If this happens, bring the Rapamune™ Oral Solution to room temperature and shake until the haze disappears. If it is necessary to wipe clean the mouth of the bottle before returning the product to the refrigerator, wipe with a dry cloth to avoid introducing water, or any other liquid, into the bottle.

 

Rapamycin Interactions

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

Cyclosporine capsules MODIFIED:

Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp.

Because of the effect of cyclosporine capsules (MODIFIED), it is recommended that sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED).

Studies assessing the effect of concomitant administration of cyclosporine capsules (MODIFIED) with sirolimus oral solution and with sirolimus tablets are summarized below.

Rapamune Oral Solution: In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus either simultaneously or 4 hours after a 300 mg dose of Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean C_max and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C_max and AUC were increased by 37% and 80%, respectively, compared with administration of sirolimus alone.

In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C_max and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean C_max and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone.

Mean cyclosporineC_max and AUC were not significantly affected when sirolimus was given simultaneously or when administered 4 hours after Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral^Ò in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration.

Rapamune Tablets: In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus (Rapamune Tablets) either simultaneously or 4 hours after a 300-mg dose of Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, meanC_max and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimusC_max and AUC were both increased by only 33% compared with administration of sirolimus alone.

Cyclosporine oral solution: In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m²/day was administered simultaneously with Sandimmune^Ò Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (%CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune^Ò Oral Solution (cyclosporine oral solution) administration. However, the %CV was higher (range 85.9% - 165%) than those from previous studies.

Sandimmune^Ò Oral Solution (cyclosporine oral solution) is not bioequivalent to Neoral^Ò Oral Solution (cyclosporine oral solution MODIFIED), and should not be used interchangeably. Although there is no published data comparing Sandimmune^Ò Oral Solution (cyclosporine oral solution) to SangCya^Ò Oral Solution (cyclosporine oral solution [MODIFIED]), they should not be used interchangeably. Likewise, Sandimmune^Ò Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent to Neoral^Ò Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) and should not be used interchangeably.

Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus C_max,t_max,and AUCwere increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.

Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus C_max and AUC were increased 4.4- and 4.2-fold respectively and t_max was increased by 0.4 hr. ErythromycinC_max and AUC were increased 1.6- and 1.7-fold, respectively, andt_max was increased by 0.3 hr.

Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of Rapamune^Ò Oral Solution, as reflected by increases in sirolimus C_max,t_max,and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminalt_1/2 of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.

Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly increased sirolimus oral-dose clearance by 5.5-fold (range = 2.8 to 10), which represents mean decreases in AUC andC_max of about 82% and 71%, respectively. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered.

Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 26 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. SirolimusC_max and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change int_max. The C_max and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and t_max was decreased by 1.2 hr.

Drugs which may be coadministered without dose adjustment

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. A synopsis of the type of study performed for each drug is provided. Sirolimus and these drugs may be coadministered without dose adjustments.

Acyclovir: Acyclovir, 200 mg, was administered once daily for 3 days followed by a single 10-mg dose of sirolimus oral solution on day 3 in 20 adult healthy volunteers.

Atorvastatin: Atorvastatin, 20 mg, was given daily for 10 days to 23 healthy volunteers, followed by a combined regimen of sirolimus oral solution, 2 mg, and atorvastatin, 20 mg, for 5 days.

Digoxin: Digoxin, 0.25 mg, was administered daily for 8 days and a single 10-mg dose of sirolimus oral solution was given on day 8 to 24 healthy volunteers.

Glyburide: A single 5-mg dose of glyburide and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Sirolimus did not affect the hypoglycemic action of glyburide.

Nifedipine: A single 60-mg dose of nifedipine and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers.

Norgestrel/ethinyl estradiol (Lo/Ovral^Ò ): Sirolimus oral solution, 2 mg, was given daily for 7 days to 21 healthy female volunteers on norgestrel/ethinyl estradiol.

Prednisolone: Pharmacokinetic information was obtained from 42 stable renal transplant patients receiving daily doses of prednisone (5-20 mg/day) and either single or multiple doses of sirolimus oral solution (0.5-5 mg/m² q 12h).

Sulfamethoxazole/trimethoprim (Bactrim^Ò ): A single oral dose of sulfamethoxazole (400 mg)/trimethoprim (80 mg) was given to 15 renal transplant patients receiving daily oral doses of sirolimus (8 to 25 mg/m²).

Other drug interactions

Co-administration of sirolimus 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) is not recommended. Sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-gp drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Therefore, absorption and the subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Strong inhibitors of CYP3A4 and P-gp significantly decrease the metabolism of sirolimus and increase sirolimus concentrations, while strong inducers of CYP3A4 and P-gp significantly increase the metabolism of sirolimus and decrease sirolimus concentrations.

In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered.

Sirolimus is a substrate for the multidrug efflux pump, P-gp in the small intestine. Therefore, absorption of sirolimus may be influenced by drugs that affect P-gp.

Aside from those mentioned above, other drugs that increase sirolimus blood concentrations include (but are not limited to):

Calcium channel blockers: nicardipine. Antifungal agents: clotrimazole, fluconazole. Antibiotics: troleandomycin.

Gastrointestinal prokinetic agents: cisapride, metoclopramide.

Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir).

Aside from those mentioned above, other drugs that decrease sirolimus concentrations include (but are not limited to):

Anticonvulsants: carbamazepine, phenobarbital, phenytoin.

Antibiotics: rifapentine.

Care should be exercised when drugs or other substances that are metabolized by CYP3A4 are administered concomitantly with Rapamune. Grapefruit juice reduces CYP3A4-mediated metabolism of Rapamune and must not be used for dilution (see DOSAGE AND ADMINISTRATION).

Herbal Preparations

St. Johnís Wort (hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. Johnís Wort in patients receiving Rapamune could result in reduced sirolimus concentrations.

Vaccination

Immunosuppressants may affect response to vaccination. Therefore, during treatment with Rapamune, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid.

Drug-Laboratory Test Interactions

There are no studies on the interactions of sirolimus in commonly employed clinical laboratory tests.

 

Rapamycin Contraindications

Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any component of the drug product.

 

Additional information about Rapamycin

Rapamycin Indication: For the prophylaxis of organ rejection in patients receiving renal transplants.
Mechanism Of Action: Rapamycin 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. Rapamycin 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.
Drug Interactions: Not Available
Food Interactions: Not Available
Generic Name: Sirolimus
Synonyms: Antibiotic AY 22989
Drug Category: Immunosuppressive Agents; Antifungals
Drug Type: Small Molecule; Approved; Investigational

Other Brand Names containing Sirolimus: Rapamune; Rapamycin;
Absorption: Not Available
Toxicity (Overdose): Not Available
Protein Binding: 92%
Biotransformation: Not Available
Half Life: 57-63 hours
Dosage Forms of Rapamycin: Tablet Oral
Solution Oral
Chemical IUPAC Name: Not Available
Chemical Formula: C51H79NO13
Sirolimus on Wikipedia: https://en.wikipedia.org/wiki/Sirolimus
Organisms Affected: Humans and other mammals