Drugs List

Therapeutic Indications

Uses

Prophylaxis of acute organ rejection for allogeneic cardiac transplant
Prophylaxis of acute organ rejection for allogeneic hepatic transplant
Prophylaxis of acute organ rejection for allogeneic renal transplant

Prophylaxis of organ rejection in combination with ciclosporin and corticosteroids, in patients with a low to moderate immunological risk receiving an allogeneic renal or cardiac transplant.

Prophylaxis of organ rejection in combination with tacrolimus and corticosteroids, in patients receiving an allogeneic hepatic transplant.

Contraindications

Children under 18 years
Breastfeeding
Galactosaemia
Pregnancy

Precautions and Warnings

Glucose-galactose malabsorption syndrome
Hepatic impairment
Hyperlipidaemia
Lactose intolerance

Administration of live vaccines is not recommended
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Monitor trough levels 4/5days after initiation and dose change until stable
Prophylaxis for pneumocystis jiroveci pneumonia recommended
Treatment to be initiated and supervised by a specialist
Contains lactose
Monitor for proteinuria before and periodically during treatment
Consider immunosuppressant adjustment in the event of PML
Monitor blood glucose
Monitor renal function regularly
Monitor serum lipids
Monitor skin changes
Advise patient to report any new or worsening respiratory symptoms
Advise patient to report any symptoms of interstitial lung disease
Advise patient to report headaches, seizures, confusion, visual disturbance
Consider changes to immunosuppressive regime if creatinine rises
May reduce effectiveness of vaccinations during treatment
Risk of developing opportunistic infections
Treatment may adversely affect wound healing
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Male: May cause infertility
Female: Contraception required during and for 2 months after treatment
Advise patient to avoid exposure to sunlight and UV rays during treatment

Cases of hyperlipidaemia have been reported, patients should be monitored and appropriate treatment given. Treatment should be re-evaluated in patients with severe refractory hyperlipidaemia. Patients receiving a HMG-CoA reductase inhibitor should be monitored for the development of rhabdomyolysis.

A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out through appropriate investigations. Cases of ILD generally resolve after interruption of everolimus with or without glucocorticoid therapy. However, fatal cases have been reported.

There have been reports of worsening proteinuria in patients switching from a calcineurin inhibitor (CNI) to everolimus, reversibility has been observed with interruption of everolimus and reintroduction of CNI.

An increased risk of kidney arterial and venous thrombosis resulting in graft loss has been reported mostly within the first 30 days post-transplantation.

Caution is advised with the use of thymoglobulin induction and everolimus, an increased number of infections include fatal cases were reported in the first 3 months after transplantation.

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) has been reported in some patients treated with this agent. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed.

Pregnancy and Lactation

Pregnancy

Everolimus is contraindicated in pregnancy.

At the time of writing there is limited data on the use of everolimus in human pregnancy. Animal studies have shown reproductive toxicity including embryo and foetotoxicity. Everolimus should not be given unless the potential benefit to the mother outweighs the risk to the foetus.

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

Everolimus is contraindicated in breastfeeding.

At the time of writing it is unknown whether everolimus is excreted in human breast milk. In animal studies everolimus and/or its metabolites were excreted into the milk of lactating rats. A risk to neonates cannot be excluded.

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

Acne
Alterations in hepatic enzymes
Anaemia
Angioedema
Anxiety
Arthralgia
Cough
Diabetes mellitus
Dyspnoea
Epistaxis
Erectile dysfunction
Gastro-intestinal symptoms
Headache
Hepatitis
Hernia
Hyperkalaemia
Hyperlipidaemia
Hypertension
Impaired healing
Infections
Insomnia
Interstitial lung disease
Jaundice
Leukopenia
Lymphocele
Lymphoma
Lymphoproliferative disorders
Male hypogonadism
Malignancies
Myalgia
Oropharyngeal pain
Pancreatitis
Pancytopenia
Pericardial effusion
Peripheral oedema
Pleural effusion
Proteinuria
Pyrexia
Rash
Renal tubular necrosis
Sepsis
Stomatitis
Tachycardia
Thrombocytopenia
Thromboembolism
Thrombosis
Thrombotic microangiopathy
Wound infection

Presentation

Oral formulations containing 250 micrograms, 500 micrograms or 750 micrograms of everolimus

Drugs List

Therapeutic Indications

Uses

Prophylaxis of acute organ rejection for allogeneic cardiac transplant
Prophylaxis of acute organ rejection for allogeneic hepatic transplant
Prophylaxis of acute organ rejection for allogeneic renal transplant

Prophylaxis of organ rejection in combination with ciclosporin and corticosteroids, in patients with a low to moderate immunological risk receiving an allogeneic renal or cardiac transplant.

Prophylaxis of organ rejection in combination with tacrolimus and corticosteroids, in patients receiving an allogeneic hepatic transplant.

Dosage

Whilst the doses stated below are those recommended by the manufacturer, local protocols for the relevant indication should be consulted.

Patients may require dose adjustments based on blood concentrations, tolerability and individual response. Dose adjustments can be made at 4 to 5 day intervals.

Adults

Elderly

Patients with Hepatic Impairment

Therapeutic Drug Monitoring

Whole blood therapeutic drug concentration monitoring is recommended after starting treatment and after any dose adjustments. Monitoring should be carried out every 4 to 5 days until two consecutive trough concentrations show a stable everolimus concentration.

The recommended trough concentration of everolimus is between 3 ng/ml and 8 ng/ml, exposure above 12 ng/ml has not been studied.

Dose adjustments should be based on trough concentrations obtained greater than 4 to 5 days after the previous dose change.

Contraindications

Children under 18 years
Breastfeeding
Galactosaemia
Pregnancy

Precautions and Warnings

Glucose-galactose malabsorption syndrome
Hepatic impairment
Hyperlipidaemia
Lactose intolerance

Administration of live vaccines is not recommended
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Monitor trough levels 4/5days after initiation and dose change until stable
Prophylaxis for pneumocystis jiroveci pneumonia recommended
Treatment to be initiated and supervised by a specialist
Contains lactose
Monitor for proteinuria before and periodically during treatment
Consider immunosuppressant adjustment in the event of PML
Monitor blood glucose
Monitor renal function regularly
Monitor serum lipids
Monitor skin changes
Advise patient to report any new or worsening respiratory symptoms
Advise patient to report any symptoms of interstitial lung disease
Advise patient to report headaches, seizures, confusion, visual disturbance
Consider changes to immunosuppressive regime if creatinine rises
May reduce effectiveness of vaccinations during treatment
Risk of developing opportunistic infections
Treatment may adversely affect wound healing
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Male: May cause infertility
Female: Contraception required during and for 2 months after treatment
Advise patient to avoid exposure to sunlight and UV rays during treatment

Cases of hyperlipidaemia have been reported, patients should be monitored and appropriate treatment given. Treatment should be re-evaluated in patients with severe refractory hyperlipidaemia. Patients receiving a HMG-CoA reductase inhibitor should be monitored for the development of rhabdomyolysis.

A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out through appropriate investigations. Cases of ILD generally resolve after interruption of everolimus with or without glucocorticoid therapy. However, fatal cases have been reported.

There have been reports of worsening proteinuria in patients switching from a calcineurin inhibitor (CNI) to everolimus, reversibility has been observed with interruption of everolimus and reintroduction of CNI.

An increased risk of kidney arterial and venous thrombosis resulting in graft loss has been reported mostly within the first 30 days post-transplantation.

Caution is advised with the use of thymoglobulin induction and everolimus, an increased number of infections include fatal cases were reported in the first 3 months after transplantation.

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) has been reported in some patients treated with this agent. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed.

Pregnancy and Lactation

Pregnancy

Everolimus is contraindicated in pregnancy.

At the time of writing there is limited data on the use of everolimus in human pregnancy. Animal studies have shown reproductive toxicity including embryo and foetotoxicity. Everolimus should not be given unless the potential benefit to the mother outweighs the risk to the foetus.

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

Everolimus is contraindicated in breastfeeding.

At the time of writing it is unknown whether everolimus is excreted in human breast milk. In animal studies everolimus and/or its metabolites were excreted into the milk of lactating rats. A risk to neonates cannot be excluded.

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

Acne
Alterations in hepatic enzymes
Anaemia
Angioedema
Anxiety
Arthralgia
Cough
Diabetes mellitus
Dyspnoea
Epistaxis
Erectile dysfunction
Gastro-intestinal symptoms
Headache
Hepatitis
Hernia
Hyperkalaemia
Hyperlipidaemia
Hypertension
Impaired healing
Infections
Insomnia
Interstitial lung disease
Jaundice
Leukopenia
Lymphocele
Lymphoma
Lymphoproliferative disorders
Male hypogonadism
Malignancies
Myalgia
Oropharyngeal pain
Pancreatitis
Pancytopenia
Pericardial effusion
Peripheral oedema
Pleural effusion
Proteinuria
Pyrexia
Rash
Renal tubular necrosis
Sepsis
Stomatitis
Tachycardia
Thrombocytopenia
Thromboembolism
Thrombosis
Thrombotic microangiopathy
Wound 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: May 2015

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

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.

Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press. Accessed on 11 May 2015.

Martindale: The Complete Drug Reference (online) London: Brayfield A (ed). Pharmaceutical Press. Accessed on 11 May 2015.

Summary of Product Characteristics: Certican tablets. Novartis Pharmaceutical UK. Revised March 2015.