Formulary
Sirolimus: Indications, Dosing, Side Effects and Interactions
Sirolimus is a non-calcineurin inhibiting immunosuppressant.
MedNext Academy | 5 min read
Sirolimus: Indications, Dosing, Side Effects and Interactions
Sirolimus is a non-calcineurin inhibiting immunosuppressant.
Drug action
Sirolimus is a non-calcineurin inhibiting immunosuppressant.
Indications and dose
**Prophylaxis of organ rejection in kidney allograft recipients**
- **Adult** (By Mouth): Initially 6 mg for 1 dose, to be given after surgery once wound has healed, then 2 mg once daily ; to be given in combination with ciclosporin and corticosteroid for 2-3 months (sirolimus doses should be given 4 hours after ciclosporin), ciclosporin should then be withdrawn over 4-8 weeks (if not possible, sirolimus should be discontinued and an alternate immunosuppressive regimen used), dose to be adjusted according to whole blood-sirolimus trough concentration.
**Facial angiofibroma associated with tuberous sclerosis complex**
- **Adult** (To The Skin): Apply a thin layer of gel twice daily to the affected areas, in the morning and at bedtime. A dose of sirolimus 0.25 mg (equivalent to 125 mg of gel or approximately 0.5 cm gel strand) should be administered per 50 cm 2 lesion, and applied twice daily; maximum total daily dose sirolimus 1.6 mg (equivalent to 800 mg of gel or approximately 2.5 cm gel strand), discontinue treatment if no response after 12 weeks.
**As a component of immunosuppressive therapy for renal transplantation in children and adolescents only if intolerance necessitates the withdrawal of a calcineurin inhibitor for sirolimus**
- **Child** (By mouth): (consult local protocol).
**Facial angiofibroma associated with tuberous sclerosis complex for sirolimus**
- **Child 6-11 years** (To the skin): Apply a thin layer of gel twice daily to the affected areas, in the morning and at bedtime. A dose of sirolimus 0.25 mg (equivalent to 125 mg of gel or approximately 0.5 cm gel strand) should be administered per 50 cm2 lesion, and applied twice daily; maximum total daily dose sirolimus 1.2 mg (equivalent to 600 mg of gel or approximately 2 cm gel strand), discontinue treatment if no response after 12 weeks.
- **Child 12-17 years** (To the skin): Apply a thin layer of gel twice daily to the affected areas, in the morning and at bedtime. A dose of sirolimus 0.25 mg (equivalent to 125 mg of gel or approximately 0.5 cm gel strand) should be administered per 50 cm2 lesion, and applied twice daily; maximum total daily dose sirolimus 1.6 mg (equivalent to 800 mg of gel or approximately 2.5 cm gel strand), discontinue treatment if no response after 12 weeks.
Cautions
General cautions: Hyperlipidaemia; increased susceptibility to lymphoma and other malignancies, particularly of the skin (limit exposure to UV light) Specific cautions: With oral use Increased susceptibility to infection (especially urinary-tract infection) With topical use Immunosuppression
Side effects
General side-effects: Common or very common Increased risk of infection; skin reactions; stomatitis Specific side-effects: Common or very common With oral use Abdominal pain; anaemia; arthralgia; ascites; constipation; diabetes mellitus; diarrhoea; dyslipidaemia; electrolyte imbalance; embolism and thrombosis; fever; haemolytic uraemic syndrome; haemorrhage; headache; healing impaired; hyperglycaemia; hypertension; interstitial lung disease; leucopenia; lymphatic vessel disorders; menstrual cycle irregularities; nausea; neoplasms; neutropenia; oedema; osteonecrosis; ovarian cyst; pain; pancreatitis; pericardial effusion; pleural effusion; proteinuria; sepsis; tachycardia; thrombocytopenia With topical use Asteatosis; conjunctivitis; eye erythema; eye irritation; nasal discomfort; photosensitivity; skin haemorrhage Uncommon With oral use Clostridioides difficile colitis; focal segmental glomerulosclerosis; hepatic failure; nephrotic syndrome; pancytopenia; post transplant lymphoproliferative disorder Frequency not known With oral use Posterior reversible encephalopathy syndrome (PRES)
Interactions
**Severe interactions:**
- Ketoconazole (CYP3A4 inhibitor) Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from this medicine oral solution as...
- Diltiazem (CYP3A4 inhibitor) The simultaneous oral administration of 10 mg of this medicine oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus.
- Verapamil (CYP3A4 inhibitor) Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both medicinal products.
- Erythromycin (CYP3A4 inhibitor) Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both medicinal products.
- Ciclosporin (CYP3A4 substrate) The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA).
- Oral contraceptives No clinically significant pharmacokinetic interaction was observed between this medicine oral solution and 0.3 mg norgestrel/0.03 mg ethinyl estradiol.
- No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone,...
**Other interactions (36):**
- Sirolimus is extensively metabolised 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 (see section 4.4).
Pregnancy
Avoid unless essential (toxicity in animal studies). M
Breast feeding
With oral use: Discontinue breast-feeding (no information available). M Specialist sources also note a lack of data and that safer alternatives are preferable, especially with regards to premature infants, or in the neonatal period. However, the large molecular weight and high plasma-protein binding mean excretion into milk is unlikely, and poor oral bioavailability would suggest limited absorption by an infant, and so it may be compatible in some circumstances. With topical use: Specialist sources suggest limited systemic absorption so unlikely to affect nursing infant.
Hepatic impairment
With oral use: Caution (risk of increased exposure) M . With topical use: Avoid in severe impairment (no information available, though in general blood concentrations are low following topical administration). M Dose adjustments With oral use: Maintenance dose reduction of approx. 50% in severe impairment-monitor whole blood-sirolimus trough concentration every 5-7 days until 3 consecutive measurements have shown stable blood-sirolimus concentration. M
Medicinal forms
Tablet,Solution,Gel
Clinical governance
**Author:** MedNext Clinical Team. **Clinical reviewer:** Dr Shameer Deen, MBBS, MS, MRCS. **Sources:** BNF, Indian Pharmacopoeia, CIMS India. **Correction:** Report errors at support@mednext.academy.
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