Sirolimus


Generic Medicine Info
Indications and Dosage
Oral
Prophylaxis of rejection in kidney graft transplant
Adult: In combination w/ ciclosporin and corticosteroids: Low to moderate risk patient: Loading dose: 6 mg on day 1, given as soon as possible after transplantation. Maintenance: 2 mg once daily, given 4 hr after ciclosporin. Dose adjusted to obtain whole blood trough concentration of 4-12 ng/mL, w/ doses of ciclosporin and corticosteroids gradually reduced. After 2-3 mth, dose adjusted to obtain trough concentration of 12-20 ng/mL, ciclosporin gradually stopped over 4-8 wk. High risk patient: Loading dose: 15 mg. Maintenance: Initially, 5 mg daily. Continue concurrent admin w/ ciclosporin and corticosteroids for 1 yr following transplantation. Dose adjusted based on clinical status.
Child: ≥13 yr <40 kg: Loading dose: 3 mg/m2. Maintenance: Initially, 1 mg/m2, adjusted according to whole blood trough concentration.

Oral
Lymphangioleiomyomatosis
Adult: Initially, 2 mg once daily. Obtain trough concentration in 10-20 days and adjust dose to maintain a target concentration of 5-15 ng/mL.
Hepatic Impairment
Mild to moderate (Child-Pugh category A or B): Reduce maintenance dose by approx 33%. Severe (Child-Pugh category C): Reduce maintenance dose by approx 50%.
Administration
May be taken with or without food. Take consistently either always w/ or always w/o meals. Avoid grapefruit juice.
Contraindications
Lactation.
Special Precautions
May increase susceptibility to opportunistic infections (e.g. BK virus-associated nephropathy, JC-virus associated progressive multifocal leukoencephalopathy (PML), Pneumocystis carinii pneumonia (antimicrobial prophylaxis for 1 yr after transplant is recommended), cytomegalovirus (CMV) infection (3 mth prophylaxis after transplant needed) and possible development of lymphoma and other malignancies. Use in liver and lung transplant patients is not recommended. Hepatic impairment. Childn. Pregnancy.
Adverse Reactions
Peripheral oedema, lymphocele, hypokalaemia, hypophosphataemia, hyperlipidaemia, hypercholesterolaemia, hypertriglyceridaemia, hyperglycaemia, HTN, tachycardia, venous thromboembolism, GI disturbance, UTI, stomatitis, arthralgia, epistaxis, acne, rash, bone necrosis, pyrexia, nausea, headache, pain, increased creatinine and blood lactate dehydrogenase (LDH); anaemia, thrombocytopenia, neutropenia, leucopenia, thrombocytopenic purpura, haemolytic-uraemic syndrome; angioedema, dermatitis, vasculitis; ovarian cyst and menstrual disorders (e.g. amenorrhoea, menorrhagia), azoospermia, infertility; fluid accumulation (e.g. lymphoedema, pleural effusions, and pericardial effusions); abnormal wound healing after transplantation; nephrotoxicity (e.g. proteinuria, focal segmental glomerulosclerosis, nephrotic syndrome); hepatoxicity. Rarely, pulmonary embolism, pulmonary haemorrhage, pancreatitis, and alveolar proteinosis.
Potentially Fatal: Interstitial lung disease. Rarely, hepatic necrosis.
Patient Counseling Information
Avoid excessive exposure to UV light.
MonitoringParameters
Monitor whole blood trough concentration; LFTs, CBC, serum cholesterol and triglycerides, serum creatinine, BP, and urinary protein.
Drug Interactions
Increased concentration w/ inhibitors of P-glycoprotein and CYP3A4 isoezyme (e.g. ciclosporin, verapamil, diltiazem, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin, nicardipine, fluconazole, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, danazol, protease inhibitors). Decreased concentration w/ inducers of P-glycoprotein and CYP3A4 isoezyme (e.g. rifampin, rifabutin, rifapentine, carabamazepine, phenobarbital, phenytoin). May diminish the effect of live vaccines (e.g. MMR, oral polio, BCG, yellow fever, varicella, TY21a typhoid).
Food Interaction
Increased concentration w/ grapefruit juice. Decreased concentration w/ St. John’s wort. High-fat meals decrease peak blood concentration but increase AUC.
Action
Description: Sirolimus is a potent macrolide which suppresses the antigenic and cytokine-mediated T-cell activation and proliferation. It forms a complex w/ the immunophilin, FK binding protein-12 (FKBP-12), which inhibits the activation of the regulatory kinase, mammalian target of rapamycin (mTOR), halting the progression from G1 to the S phase of the cell cycle. It also inhibits antibody production.
Pharmacokinetics:
Absorption: Rapidly but poorly absorbed from the GI tract. Bioavailability: 27% relative to oral soln (tab) and 14% (oral soln). Time to peak plasma concentration: Approx 2 hr.
Distribution: Volume of distribution: 4-20 L/kg. Plasma protein binding: Approx 92%, mainly to albumin.
Metabolism: Extensively metabolised in the intestinal wall by P-glycoprotein and in the liver by CYP3A4 isoenzyme via O-demethylation and hydroxylation.
Excretion: Mainly via faeces (91%); urine (2%). Elimination half-life: 62 hr.
Chemical Structure

Chemical Structure Image
Sirolimus

Source: National Center for Biotechnology Information. PubChem Database. Sirolimus, CID=5284616, https://pubchem.ncbi.nlm.nih.gov/compound/Sirolimus (accessed on Jan. 23, 2020)

Storage
Tab: Store between 20-25°C. Protect from light. Oral soln: Store between 2-8°C. Protect from light.
MIMS Class
ATC Classification
L04AA10 - sirolimus ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
References
Anon. Sirolimus. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 16/06/2016.

Anon. Sirolimus. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/06/2016.

Buckingham R (ed). Sirolimus. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/06/2016.

Joint Formulary Committee. Sirolimus. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/06/2016.

Sirolimus Solution (Greenstone LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 27/10/2015.

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