Drugs List

Therapeutic Indications

Uses

Renal transplant rejection - prevention
Sporadic lymphangioleiomyomatosis (S-LAM)

Prophylaxis of organ rejection in adult patients at low or moderate immunological risk receiving a renal transplant.

Sporadic lympangioleiomyomatosis (S-LAM) with moderate lung disease or declining lung function.

Contraindications

Children under 18 years
Breastfeeding
Pregnancy

Precautions and Warnings

Body mass index above 30kg per square metre
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Hereditary fructose intolerance
Hyperlipidaemia
Lactose intolerance

Administration of live vaccines is not recommended
Cytomegalovirus prophylaxis recommended for 3 months following transplant
Afro-Caribbean or black patients may show reduced response
Prophylaxis for Pneumocystis carinii required for 12 months post transplant
Treatment to be initiated and supervised by a specialist
May contain polysorbate
Oral solution contains alcohol
Some formulations contain lactose
Some formulations contain sucrose
Some products contain arachis (peanut) oil, soya or soya derivative
500microgram tablets are not bioequivalent with other tablet strengths
Take at the same time in respect to food as absorption may be affected
Consider immunosuppressant adjustment in the event of PML
Monitor for protein in urine
Monitor hepatic function
Monitor renal function during concurrent administration with ciclosporin
Monitor serum lipids
Monitor whole blood levels closely in hepatic impairment
Monitor whole blood levels to adjust dose
Consider changes to immunosuppressive regime if creatinine rises
Consider immunosuppressant adjustment if BK virus nephropathy develops
Delayed graft function: Sirolimus may delay recovery of renal function
Immunosuppressive drugs may increase risk of malignancy
May reduce effectiveness of vaccinations during treatment
Oversuppression of immune system may increase susceptibility to infection
Treatment may adversely affect wound healing
Dose adjustment required when ciclosporin progressively discontinued
Combination treatment with ciclosporin should not exceed 3 months
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
May cause impaired fertility
Female: Contraception required during and for 3 months after treatment
Advise patient on appropriate sun protection methods
Advise patient to avoid exposure to sunlight and UV rays during treatment

Sirolimus is associated with increased serum cholesterol and triglycerides. Patients should be monitored for hyperlipidaemia and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen and continued therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.

There is limited information indicating that black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in black recipients.

Pregnancy and Lactation

Pregnancy

Sirolimus is contraindicated in pregnancy.

At the time of writing there is no adequate data for the use of sirolimus in pregnant women.

Studies in animals have shown reproductive toxicity but not teratogenicity. The potential risk for humans is unknown. Briggs concludes that if sirolimus is used during pregnancy or in the case of inadvertent exposure, close monitoring of the embryo / foetus for developmental toxicity is warranted.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Sirolimus is contraindicated in breastfeeding.

At the time of writing there is not adequate data to support use in breastfeeding. The low molecular weight and long half life suggest excretion into breast milk will occur. The effects of potential exposure on a nursing infant are unknown but consideration should be given to the carcinogenic properties of sirolimus.

Following administration of radio labelled sirolimus, radioactivity is excreted in the milk of lactating rats.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acne
Acute hepatic necrosis (sometimes fatal)
Altered liver function tests
Alveolar proteinosis
Anaemia
Anaphylactic reaction
Anaphylactoid reaction
Anastomotic disruption
Angioedema
Arthralgia
Ascites
Bacterial infection
BK virus associated with nephropathy
Bronchiolitis obliterans
Constipation
Cytomegalovirus infection
Deep vein thrombosis (DVT)
Diabetes
Diarrhoea
Epistaxis
Epstein-Barr virus
Exfoliative dermatitis
Fascial dehiscence
Focal segmental glomerulosclerosis
Fungal infection
Haemolytic uraemic syndrome
Headache
Hepatotoxicity
Herpes simplex
Herpes zoster
Hypercholesterolaemia
Hyperglycaemia
Hypersensitivity reactions
Hypertension
Hypertriglyceridaemia
Hypokalaemia
Hypophosphataemia
Impaired fertility
Impaired healing
Impairments of sperm parameters
Increase in lactate dehydrogenase
Increase in serum ALT/AST
Increased risk of skin cancer
Increased susceptibility to development of lymphoma and other malignancies
Increased susceptibility to infection
Interstitial lung disease
Leucopenia
Lymphocele
Lymphoedema
Lymphoma
Lymphoproliferative disorders
Mycobacterial infection
Nausea
Nephrotic syndrome
Neutropenia
Oedema
Osteonecrosis
Pain
Pancreatitis
Pancytopenia
Pericardial effusion
Peripheral oedema
Pleural effusion
Pneumonia
Pneumonitis
Progressive multifocal leukoencephalopathy (PML)
Proteinuria
Pulmonary embolism
Pulmonary fibrosis
Pulmonary haemorrhage
Pyelonephritis
Pyrexia
Rash
Sepsis
Serum creatinine increased
Stomatitis
Tachycardia
Thrombocytopenia
Thrombotic thrombocytopenic purpura
Tuberculosis
Urinary tract infections
Vasculitis (allergic)
Viral infection

Presentation

Oral formulations of sirolimus.

Drugs List

Therapeutic Indications

Uses

Renal transplant rejection - prevention
Sporadic lymphangioleiomyomatosis (S-LAM)

Prophylaxis of organ rejection in adult patients at low or moderate immunological risk receiving a renal transplant.

Sporadic lympangioleiomyomatosis (S-LAM) with moderate lung disease or declining lung function.

Dosage

Patients should receive the same dose when switching between oral solutions and tablet formulations. Verification that the sirolimus trough concentration levels remains within the recommended target ranges should be carried out 1 to 2 weeks later. When switching between different tablet strengths, verification of trough concentrations is recommended.

Due to manufacturing differences multiples of the 500 microgram tablets are not a suitable substitute for other tablet strengths.

Adults

Patients with Hepatic Impairment

Therapeutic Drug Monitoring

If patients have switched between the tablet and oral solution formulations, it is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations to confirm that the trough concentration is within the recommended target range.

Target whole blood trough concentrations
Prophylaxis of organ rejection
Initial therapy (in combination with ciclosporin): 4 to 12 nanograms per ml.
Maintenance therapy (following discontinuation of ciclosporin therapy): 12 to 20 nanograms/ml.

Adjustments in sirolimus dosage should be based on more than a single trough level obtained more than 5 days after a previous dose change.

Sporadic lymphangioleiomyomatosis (S-LAM)
5 to 15 nanograms/ml.

After adjustment, patients should continue on the new maintenance dose for 7 to 14 days before further adjusting the dose.

Contraindications

Children under 18 years
Breastfeeding
Pregnancy

Precautions and Warnings

Body mass index above 30kg per square metre
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Hereditary fructose intolerance
Hyperlipidaemia
Lactose intolerance

Administration of live vaccines is not recommended
Cytomegalovirus prophylaxis recommended for 3 months following transplant
Afro-Caribbean or black patients may show reduced response
Prophylaxis for Pneumocystis carinii required for 12 months post transplant
Treatment to be initiated and supervised by a specialist
May contain polysorbate
Oral solution contains alcohol
Some formulations contain lactose
Some formulations contain sucrose
Some products contain arachis (peanut) oil, soya or soya derivative
500microgram tablets are not bioequivalent with other tablet strengths
Take at the same time in respect to food as absorption may be affected
Consider immunosuppressant adjustment in the event of PML
Monitor for protein in urine
Monitor hepatic function
Monitor renal function during concurrent administration with ciclosporin
Monitor serum lipids
Monitor whole blood levels closely in hepatic impairment
Monitor whole blood levels to adjust dose
Consider changes to immunosuppressive regime if creatinine rises
Consider immunosuppressant adjustment if BK virus nephropathy develops
Delayed graft function: Sirolimus may delay recovery of renal function
Immunosuppressive drugs may increase risk of malignancy
May reduce effectiveness of vaccinations during treatment
Oversuppression of immune system may increase susceptibility to infection
Treatment may adversely affect wound healing
Dose adjustment required when ciclosporin progressively discontinued
Combination treatment with ciclosporin should not exceed 3 months
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
May cause impaired fertility
Female: Contraception required during and for 3 months after treatment
Advise patient on appropriate sun protection methods
Advise patient to avoid exposure to sunlight and UV rays during treatment

Sirolimus is associated with increased serum cholesterol and triglycerides. Patients should be monitored for hyperlipidaemia and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen and continued therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.

There is limited information indicating that black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in black recipients.

Pregnancy and Lactation

Pregnancy

Sirolimus is contraindicated in pregnancy.

At the time of writing there is no adequate data for the use of sirolimus in pregnant women.

Studies in animals have shown reproductive toxicity but not teratogenicity. The potential risk for humans is unknown. Briggs concludes that if sirolimus is used during pregnancy or in the case of inadvertent exposure, close monitoring of the embryo / foetus for developmental toxicity is warranted.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Sirolimus is contraindicated in breastfeeding.

At the time of writing there is not adequate data to support use in breastfeeding. The low molecular weight and long half life suggest excretion into breast milk will occur. The effects of potential exposure on a nursing infant are unknown but consideration should be given to the carcinogenic properties of sirolimus.

Following administration of radio labelled sirolimus, radioactivity is excreted in the milk of lactating rats.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acne
Acute hepatic necrosis (sometimes fatal)
Altered liver function tests
Alveolar proteinosis
Anaemia
Anaphylactic reaction
Anaphylactoid reaction
Anastomotic disruption
Angioedema
Arthralgia
Ascites
Bacterial infection
BK virus associated with nephropathy
Bronchiolitis obliterans
Constipation
Cytomegalovirus infection
Deep vein thrombosis (DVT)
Diabetes
Diarrhoea
Epistaxis
Epstein-Barr virus
Exfoliative dermatitis
Fascial dehiscence
Focal segmental glomerulosclerosis
Fungal infection
Haemolytic uraemic syndrome
Headache
Hepatotoxicity
Herpes simplex
Herpes zoster
Hypercholesterolaemia
Hyperglycaemia
Hypersensitivity reactions
Hypertension
Hypertriglyceridaemia
Hypokalaemia
Hypophosphataemia
Impaired fertility
Impaired healing
Impairments of sperm parameters
Increase in lactate dehydrogenase
Increase in serum ALT/AST
Increased risk of skin cancer
Increased susceptibility to development of lymphoma and other malignancies
Increased susceptibility to infection
Interstitial lung disease
Leucopenia
Lymphocele
Lymphoedema
Lymphoma
Lymphoproliferative disorders
Mycobacterial infection
Nausea
Nephrotic syndrome
Neutropenia
Oedema
Osteonecrosis
Pain
Pancreatitis
Pancytopenia
Pericardial effusion
Peripheral oedema
Pleural effusion
Pneumonia
Pneumonitis
Progressive multifocal leukoencephalopathy (PML)
Proteinuria
Pulmonary embolism
Pulmonary fibrosis
Pulmonary haemorrhage
Pyelonephritis
Pyrexia
Rash
Sepsis
Serum creatinine increased
Stomatitis
Tachycardia
Thrombocytopenia
Thrombotic thrombocytopenic purpura
Tuberculosis
Urinary tract infections
Vasculitis (allergic)
Viral infection

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: January 2016

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 11 January 2016

Summary of Product Characteristics: Rapamune. Wyeth Pharmaceuticals Ltd. Revised October 2018.