Drugs List

Therapeutic Indications

Uses

Homozygous familial hypercholesterolaemia (adjunct to statin therapy)
Homozygous sitosterolaemia (phytosterolaemia)
Primary hypercholesterolaemia (hyperlipidaemia type IIa): Adjunct to diet
Risk reduction of cardiovascular events

Primary hypercholesterolaemia
As an adjunct to diet and in combination with an HMG-CoA reductase inhibitor (statin), in primary (heterozygous familial and non-familial) hypercholesterolaemia who are not appropriately controlled with a statin alone.
Ezetimibe may be used as monotherapy, as an adjunctive therapy to diet, for patients in whom a statin is considered inappropriate or is not tolerated.

Prevention of cardiovascular events
Indicated to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when adding to ongoing statin therapy or initiated concomitantly with a statin.

Homozygous Familial Hypercholesterolaemia (HoFH)
As an adjunct to diet and in combination with a statin in patients with HoFH. Patients may also receive other treatments (e.g. LDL apheresis).

Homozygous sitosterolaemia (phytosterolaemia)
As an adjunct to diet in patients with homozygous familial sitosterolaemia.

Contraindications

Children under 10 years
Breastfeeding
Galactosaemia
Hepatic impairment - Child-Pugh score greater than 7

Precautions and Warnings

Glucose-galactose malabsorption syndrome
Lactose intolerance
Pregnancy

Contains lactose
Administer 2 hours before or > 4 hours after any bile acid sequestrant
Advise patients to report muscle pain/tenderness/weakness
Discontinue if myopathy is suspected
Discontinue if CPK rises to > or equal to 10 x upper limit of normal
Dietary restrictions should be maintained

When co-administered with a statin liver function tests should be performed at the start of therapy and thereafter according to the manufacturer's recommendations for the statin. In clinical trials, consecutive elevations of transaminases (equal to or greater than 3 x the upper limit of normal) have been observed.

Pregnancy and Lactation

Pregnancy

Use ezetimibe with caution in pregnancy.

Ezetimibe administered alone should only be used during pregnancy when clearly necessary. Ezetimibe co-administered with a statin is contraindicated during pregnancy.

No evidence of impaired fertility or embryolethal effects were observed in rats at doses up to about 10 times the human exposure at 10mg/day. At the highest dose increased incidences of skeletal abnormalities were observed. These included an extra pair of thoracic ribs, unossified cervical vertebral centra and shortened ribs. No evidence of carcinogenicity in mice and rats was observed when high doses were administered over a 2 year period. There was also no evidence of genotoxic, mutagenic or clastogenic effects with various other assays (Briggs, 2011).

Ezetimibe crosses the placenta in rats and rabbits. It is not known if the drug crosses the human placenta, but due to its molecular weight and prolonged elimination half life it is thought to, however high plasma protein binding should limit the transfer (Briggs, 2011).

Although the animal data suggest a low risk, lack of human pregnancy data prevents a full assessment of this risk and therefore, this drug should not be administered to pregnant women unless clearly necessary. Discontinuation of treatment during pregnancy of hypercholesterolaemia is not thought to put the mother at risk. Briggs (2011) concludes that if treatment is necessary, ezetimibe is thought to be a better choice than HMG-CoA reductase inhibitors and fenofibrate (which are contraindicated). Schaefer (2007) surmises that inadvertent use of ezetimibe does not require either an interruption of pregnancy or invasive diagnostic procedures, but treatment should be reviewed.

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

Ezetimibe is contraindicated in breastfeeding.

There is no relevant published information on the use of ezetimibe during breastfeeding, however there is a concern that it may disrupt infant lipid metabolism. Use of an alternative drug is preferred, particularly when nursing a newborn or preterm infant.

Ezetimibe has been observed in the milk of lactating rats. It is not known whether the drug is excreted into human milk but due to its prolonged half life and molecular weight it would be expected. However, high levels of plasma protein binding should limit the amount secreted. The effects on the infant are unknown, however, if ezetimibe is taken whilst breastfeeding the nursing infant should be closely observed for adverse effects seen in adults (e.g. headache, diarrhoea, pharyngitis, sinusitis and arthralgia) (Briggs, 2011).

Schaefer (2007) states that lipid reducers should not be used during breastfeeding because their safety is not established. Stopping the treatment whilst breastfeeding would seem to have no real disadvantage to the mother. Taking ezetimibe, however, does not require any limitation of breastfeeding, although the continuation of treatment should be critically reviewed.

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
Abnormal liver function tests
Anaphylaxis
Angioedema
Arthralgia
Asthenia
Back pain
Chest pain
Cholecystitis
Cholelithiasis
Constipation
Cough
Creatine phosphokinase increased
Decreased appetite
Depression
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Erythema multiforme
Fatigue
Flatulence
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-intestinal disturbances
Gastroesophageal reflux disease
Headache
Hepatitis
Hot flushes
Hypersensitivity reactions
Hypertension
Increase in serum transaminases
Muscle spasm
Myalgia
Myopathy
Nausea
Neck pain
Painful extremities
Pancreatitis
Paraesthesia
Peripheral oedema
Pruritus
Rash
Rhabdomyolysis
Thrombocytopenia
Urticaria

Presentation

Oral formulations of ezetimibe

Drugs List

Therapeutic Indications

Uses

Homozygous familial hypercholesterolaemia (adjunct to statin therapy)
Homozygous sitosterolaemia (phytosterolaemia)
Primary hypercholesterolaemia (hyperlipidaemia type IIa): Adjunct to diet
Risk reduction of cardiovascular events

Primary hypercholesterolaemia
As an adjunct to diet and in combination with an HMG-CoA reductase inhibitor (statin), in primary (heterozygous familial and non-familial) hypercholesterolaemia who are not appropriately controlled with a statin alone.
Ezetimibe may be used as monotherapy, as an adjunctive therapy to diet, for patients in whom a statin is considered inappropriate or is not tolerated.

Prevention of cardiovascular events
Indicated to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when adding to ongoing statin therapy or initiated concomitantly with a statin.

Homozygous Familial Hypercholesterolaemia (HoFH)
As an adjunct to diet and in combination with a statin in patients with HoFH. Patients may also receive other treatments (e.g. LDL apheresis).

Homozygous sitosterolaemia (phytosterolaemia)
As an adjunct to diet in patients with homozygous familial sitosterolaemia.

Dosage

Adults

Elderly

Children

Patients with Hepatic Impairment

Contraindications

Children under 10 years
Breastfeeding
Galactosaemia
Hepatic impairment - Child-Pugh score greater than 7

Precautions and Warnings

Glucose-galactose malabsorption syndrome
Lactose intolerance
Pregnancy

Contains lactose
Administer 2 hours before or > 4 hours after any bile acid sequestrant
Advise patients to report muscle pain/tenderness/weakness
Discontinue if myopathy is suspected
Discontinue if CPK rises to > or equal to 10 x upper limit of normal
Dietary restrictions should be maintained

When co-administered with a statin liver function tests should be performed at the start of therapy and thereafter according to the manufacturer's recommendations for the statin. In clinical trials, consecutive elevations of transaminases (equal to or greater than 3 x the upper limit of normal) have been observed.

Pregnancy and Lactation

Pregnancy

Use ezetimibe with caution in pregnancy.

Ezetimibe administered alone should only be used during pregnancy when clearly necessary. Ezetimibe co-administered with a statin is contraindicated during pregnancy.

No evidence of impaired fertility or embryolethal effects were observed in rats at doses up to about 10 times the human exposure at 10mg/day. At the highest dose increased incidences of skeletal abnormalities were observed. These included an extra pair of thoracic ribs, unossified cervical vertebral centra and shortened ribs. No evidence of carcinogenicity in mice and rats was observed when high doses were administered over a 2 year period. There was also no evidence of genotoxic, mutagenic or clastogenic effects with various other assays (Briggs, 2011).

Ezetimibe crosses the placenta in rats and rabbits. It is not known if the drug crosses the human placenta, but due to its molecular weight and prolonged elimination half life it is thought to, however high plasma protein binding should limit the transfer (Briggs, 2011).

Although the animal data suggest a low risk, lack of human pregnancy data prevents a full assessment of this risk and therefore, this drug should not be administered to pregnant women unless clearly necessary. Discontinuation of treatment during pregnancy of hypercholesterolaemia is not thought to put the mother at risk. Briggs (2011) concludes that if treatment is necessary, ezetimibe is thought to be a better choice than HMG-CoA reductase inhibitors and fenofibrate (which are contraindicated). Schaefer (2007) surmises that inadvertent use of ezetimibe does not require either an interruption of pregnancy or invasive diagnostic procedures, but treatment should be reviewed.

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

Ezetimibe is contraindicated in breastfeeding.

There is no relevant published information on the use of ezetimibe during breastfeeding, however there is a concern that it may disrupt infant lipid metabolism. Use of an alternative drug is preferred, particularly when nursing a newborn or preterm infant.

Ezetimibe has been observed in the milk of lactating rats. It is not known whether the drug is excreted into human milk but due to its prolonged half life and molecular weight it would be expected. However, high levels of plasma protein binding should limit the amount secreted. The effects on the infant are unknown, however, if ezetimibe is taken whilst breastfeeding the nursing infant should be closely observed for adverse effects seen in adults (e.g. headache, diarrhoea, pharyngitis, sinusitis and arthralgia) (Briggs, 2011).

Schaefer (2007) states that lipid reducers should not be used during breastfeeding because their safety is not established. Stopping the treatment whilst breastfeeding would seem to have no real disadvantage to the mother. Taking ezetimibe, however, does not require any limitation of breastfeeding, although the continuation of treatment should be critically reviewed.

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
Abnormal liver function tests
Anaphylaxis
Angioedema
Arthralgia
Asthenia
Back pain
Chest pain
Cholecystitis
Cholelithiasis
Constipation
Cough
Creatine phosphokinase increased
Decreased appetite
Depression
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Erythema multiforme
Fatigue
Flatulence
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-intestinal disturbances
Gastroesophageal reflux disease
Headache
Hepatitis
Hot flushes
Hypersensitivity reactions
Hypertension
Increase in serum transaminases
Muscle spasm
Myalgia
Myopathy
Nausea
Neck pain
Painful extremities
Pancreatitis
Paraesthesia
Peripheral oedema
Pruritus
Rash
Rhabdomyolysis
Thrombocytopenia
Urticaria

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 ( https://www.toxbase.org/ ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: March 2016

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 9 March 2016.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications Accessed on 9 March 2016.

Summary of Product Characteristics: Ezetrol 10mg Tablets. MSD Ltd. Revised February 2016.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Ezetimibe Last revised: 7 September 2013
Last accessed: 9 March 2016