Sirolimus

Registered South African indications:

• Prophylaxis of organ rejection in renal transplant

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• De novo liver or lung transplantation
• Concomitant use with grapefruit juice

Cautions 

• Renal impairment
• Hepatic impairment
• Elderly
• Porphyria
• Renal transplant patients at high immunological risk
• Renal transplant patients with delayed graft function
• High total immunosuppressive burden
• Liver and lung transplant patients
• Alcoholism
• Epilepsy
• Liver disease
• Exposure to sunlight and ultraviolet light in patients with increased risk for skin cancer
• Body mass index > 30kg/m² 
• Hyperlipidaemia
• Black patients
• Fructose intolerance
• Sucrase-isomaltase insufficiency
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Patients with sporadic lymphangioleiomyomatosis (S-LAM)

Forms avail. in SA and covered in this monograph: tab

Prophylaxis against organ rejection in renal transplant patients (additional agents required)

• Oral (tab): Loading dose: 6mg, immediately; Maintenance: 2mg, dly

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To be administered as soon as possible after transplantation, followed by the maintenance dose until results of therapeutic monitoring are available

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It is recommended that sirolimus be used initially in a regimen with ciclosporin and a tapering regimen of corticosteroids

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Maintenance regimen as single-agent

• Consult specialist for dosages and regimens

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Optimal therapy requires close therapeutic plasma concentration monitoring in all patients. The accepted sirolimus therapeutic range value may vary depending on the therapeutic drug monitoring service provider and the clinical condition

Decisions related to sirolimus dose adjustment, co-administration of corticosteroids, or discontinuation of other immunosuppressants must be confirmed by an expert transplantation specialist

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See additional prescribing points 

Not established for use in children below 18 years

Pregnancy 

• Contraindicated

Breastfeeding 

• Contraindicated

Fertility

• Impairments of sperm parameters have been observed among some patients treated with sirolimus
• These effects have been reversible upon discontinuation with sirolimus in most cases
• In reproduction toxicity studies in male rats, decreased fertility was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study
• Reductions in testicular weights and/or histological lesions (e.g. tubal atrophy and tubular giant cells) were observed in rats and in a monkey study

Renal Impairment 

• Caution; no dose adjustment recommended 

Hepatic Impairment 

• Mild to moderate: Caution; no dose adjustment recommended
  Blood trough levels should be closely monitored
• Severe: Caution; dose adjustment recommended
  Maintenance dose to be reduced by approximately 50%
  Therapeutic drug monitoring should be performed every 5-7 days until 3 consecutive trough levels have shown stable concentrations after dose adjustment or after loading dose

Elderly 

• Caution; no dose adjustment recommended 

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Immunosuppressive therapy increases infection risk and may trigger acute cases of porphyria

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Posterior reversible encephalopathy syndrome

Cardiovascular Disorders

• Tachycardia
• Pericardial effusion
• Hypertension
• Deep vein thrombosis (DVT)

Respiratory Disorders 

• Pulmonary embolism
• Pneumonitis
• Pleural effusion
• Epistaxis
• Pulmonary haemorrhage
• Alveolar proteinosis

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Constipation
• Nausea
• Pancreatitis
• Stomatitis
• Ascites

Hepatobiliary Disorders

• Hepatic failure
• Abnormal hepatic function tests

Genitourinary Disorders

• Proteinuria
• Nephrotic syndrome
• Focal segmental glomerulosclerosis  
• Menstrual disorder
• Amenorrhoea
• Menorrhagia
• Ovarian cyst

Endocrine and Metabolic Disorders

• Hypokalaemia
• Hypophosphataemia
• Hyperlipidaemia
• Hyperglycaemia
• Hypertriglyceridaemia
• Diabetes mellitus
• Increased blood creatinine

Musculoskeletal Disorders

• Arthralgia
• Osteonecrosis

Skin and Subcutaneous Tissue Disorders

• Rash
• Acne
• Exfoliative dermatitis
• Hypersensitivity vasculitis
• Non-melanoma skin cancer
• Neuroendocrine carcinoma of the skin

Immune, Blood and Lymphatic System Disorders

• Pneumonia
• Fungal infection
• Viral infection
• Bacterial infection
• Herpes simplex infection
• Urinary tract infection
• Sepsis
• Pyelonephritis
• Cytomegalovirus infection
• Pneumocystis carinii infection
• Herpes zoster caused by varicella zoster virus
• Clostridium difficile colitis
• Mycobacterial infection, including tuberculosis
• Epstein-Barr virus infection
• Pyrexia
• Lymphoma
• Malignant melanoma
• Post-transplant lymphoproliferative disorder
• Thrombocytopaenia
• Anaemia
• Leucopenia
• Haemolytic uraemic syndrome
• Neutropaenia
• Pancytopaenia
• Thrombotic thrombocytopaenic purpura
• Hypersensitivity reactions
  - Anaphylactic/anaphylactoid reactions
  - Angioedema
  - Exfoliative dermatitis
  - Hypersensitivity vasculitis
• Lymphoedema
• Lymphocele

Others

• Oedema
• Increased blood lactate dehydrogenase
• Impaired healing

• CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Clotrimazole
• Fluconazole
• Telithromycin
• Clarithromycin
• Troleandomycin
• Erythromycin
• Diltiazem
• Ritonavir
• Indinavir
• Boceprevir
• Telaprevir
• Nicardipine
• Bromocriptine
• Cimetidine
• Danazol
• CYP3A4 inducers
• Rifampicin
• Rifabutin
• St John's Wort
• Carbamazepine
• Phenobarbital
• Phenytoin
• HMG-CoA reductase inhibitors
• Fibrates
• Angiotensin converting enzyme (ACE) inhibitors
• P-gp inhibitors
• Calcineurin inhibitors
• Verapamil
• Ciclosporin
• Oral contraceptives
• Cisapride  
• Metoclopramide
• Live vaccines
• Grapefruit juice

• Sirolimus concentration
• Renal function
• Hepatic function
• Lipid profile
• Full blood count
• Urine protein excretion

Use of additional agents

• To minimise variability, sirolimus should be taken at the same time in relation to ciclosporin, 4 hours after the ciclosporin dose, either with or without food
• In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be attempted, the combination of ciclosporin and sirolimus should not be maintained for more than 3 months post-transplantation

Dose adjustments

• If further dose adjustment(s) are required during maintenance therapy (after discontinuation of ciclosporin), in most patients these adjustments can be based on simple proportion:
  - Dose adjustments for sirolimus: New dose = current dose x (target concentration/current concentration)
  - A loading dose should be given based on the following calculation: Loading dose = 3 x (new maintenance dose -current maintenance dose)

Therapeutic monitoring

• Blood sirolimus levels should be closely monitored in patients with:
  - Hepatic impairment
  - Coadministration of CYP3A4 inducers and inhibitors (and after their discontinuation)
  - Markedly reduced ciclosporin dosing or if discontinued
• Therapeutic monitoring should not be the only basis for adjusting sirolimus therapy as careful attention should be made to clinical signs and symptoms, tissue biopsies and laboratory parameters

Sirolimus inhibits T-cell activation and proliferation that occurs in response to antigenic and cytokine (Interleukin 2, 4 and 15) stimulation by blocking calcium dependent and calcium independent intracellular signal transduction. It also inhibits antibody production. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition of mTOR results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression.

Tablet 1mg

• Rapamune (Pfizer) originator