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Sirolimus Chemical Structure: Sirolimus in Kenya
Sirolimus Chemical Structure


Prophylaxis of Organ Rejection in Renal Transplantation

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that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation.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 sirolimus tablets be used in combination with cyclosporine and corticosteroids for the first year following transplantation

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 sirolimus used in combination with cyclosporine and corticosteroids have 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 sirolimus have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high- immunologic risk.

The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients.

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established


Sirolimus is 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.

General Dosing Guidance for Renal Transplant Patients

The initial dose of sirolimus should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after the administration of cyclosporine.


Hypersensitivity to the active substance or to any of the excipients.


Sirolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended.

Rifampicin (CYP3A4 inducer)

Co-administration of sirolimus and rifampicin is not recommended .

Ketoconazole (CYP3A4 inhibitor)

Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Sirolimus as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended.

Voriconazole (CYP3A4 inhibitor)

Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended .

Diltiazem (CYP3A4 inhibitor)

If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.

Verapamil (CYP3A4 inhibitor)

Sirolimus levels should be monitored, and appropriate dose reductions of both medicinal products should be considered.

Erythromycin (CYP3A4 inhibitor)

Sirolimus levels should be monitored and appropriate dose reductions of both medicinal products should be considered.

Ciclosporin (CYP3A4 substrate)

It is recommended that Sirolimus be administered 4 hours after ciclosporin (microemulsion).

Oral contraceptives

Although the results of a single-dose interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Sirolimus.

Other possible interactions

Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels. Such inhibitors include certain antifungals (e.g. clotrimazole, fluconazole, itraconazole, voriconazole), certain antibiotics (e.g. troleandomycin, telithromycin, clarithromycin), certain protease inhibitors (e.g. ritonavir, indinavir, boceprevir, telaprevir), nicardipine, bromocriptine, cimetidine, and danazol.

Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g., St. John’s Wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).

Although sirolimus inhibits human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Sirolimus. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.

Grapefruit juice affects CYP3A4-mediated metabolism and should, therefore, be avoided.

Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as cisapride and metoclopramide.

No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulfamethoxazole.


Body as a Whole : Sepsis, lymphocele, herpes zoster infection, herpes simplex infection

Cardiovascular: Venous thromboembolism (pulmonary embolism and deep venous thrombosis), rapid heart rate

Digestive :Stomatitis

Hematologic/Lymphatic: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia

Metabolic: Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes

Musculoskeletal:Bone necrosis

Respiratory :Pneumonia, epistaxis

Skin :Melanoma, squamous cell carcinoma, basal cell carcinoma

Urogenital: Pyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia)

Clinical | Pharmacokinetic data

Pregnancy Category: C
Routes of Administration: Oral
Bioavailability: 14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals
Protein Binding: 92%
Metabolosim: Hepatic
Onset of Action: Not Available
Elimination Half life: 57–63 hours
Excretion: Mostly faecal

Legal Status | Dosage forms & Strengths

Prescription Category:
Prescription only Medicine (POM) , ℞-only
Narcotic Drugs and Psychotropic Substances (Control ) Act Schedule:
This drug is not a controlled substance under Narcotic Drugs and Psychotropic Substances (Control ) Act
Dosage Forms | Strengths:
Tablets | Oral solution

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