Brands, Medical Use, Clinical Data
Drug Category
- Immunosuppressive Agents
- Antifungals
Dosage Forms
Brands / Synonyms
Antibiotic AY 22989; Rapamune; Rapamycin
Indications
For the prophylaxis of organ rejection in patients receiving renal transplants.
Pharmacology
Sirolimus, 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.
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.
Absorption
Not Available
Toxicity
Not Available
Biotrnasformation / Drug Metabolism
Not Available
Contraindications
Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any component
of the drug product.
Drug 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 NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous
administration, the mean Cmax and AUC of sirolimus were increased by 116% and 230%, respectively, relative
to administration of sirolimus alone. However, when given 4 hours after NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus
Cmax 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 NeoralÒ Soft Gelatin
Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus
Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours
after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to
administration of sirolimus alone.
Mean cyclosporineCmax and AUC were not significantly affected when sirolimus was given simultaneously
or when administered 4 hours after NeoralÒ Soft Gelatin Capsules
(cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after
NeoralÒ in renal post-transplant patients over 6 months, cyclosporine
oral-dose clearance was reduced, and lower doses of NeoralÒ 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 NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous
administration, meanCmax and AUC were increased by 512% and 148%, respectively, relative to administration
of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimusCmax 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 SandimmuneÒ 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 SandimmuneÒ Oral Solution (cyclosporine oral solution) administration. However, the %CV was higher
(range 85.9% - 165%) than those from previous studies.
SandimmuneÒ Oral Solution (cyclosporine oral solution) is not
bioequivalent to NeoralÒ Oral Solution (cyclosporine oral solution
MODIFIED), and should not be used interchangeably. Although there is no published data comparing
SandimmuneÒ Oral Solution (cyclosporine oral solution) to
SangCyaÒ Oral Solution (cyclosporine oral solution [MODIFIED]), they
should not be used interchangeably. Likewise, SandimmuneÒ Soft Gelatin
Capsules (cyclosporine capsules) are not bioequivalent to NeoralÒ 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 Cmax,tmax,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
Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr.
ErythromycinCmax and AUC were increased 1.6- and 1.7-fold, respectively, andtmax 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 RapamuneÒ Oral Solution, as reflected by increases in sirolimus Cmax,tmax,and
AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminalt1/2 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 andCmax 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. SirolimusCmax and AUC were increased 2.3- and 2.2-fold,
respectively, without substantial change intmax. The Cmax and AUC of the pharmacologically
active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax 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/OvralÒ ):
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 (BactrimÒ ): 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.
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