Drugs List

Therapeutic Indications

Uses

Combined hyperlipidaemia: lipid lowering therapy adjunct to diet
Homozygous familial hypercholesterolaemia: Adjunct to diet
Primary hypercholesterolaemia: lipid lowering therapy adjunct to diet
Risk reduction of cardiovascular events

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), either previously treated with a statin or not.

Hypercholesterolaemia
Indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate:

Patients not appropriately controlled with a statin alone.
Patients already treated with a statin and ezetimibe.

Homozygous Familial Hypercholesterolaemia (HoFH)
Indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g. low-density lipoprotein (LDL) apheresis).

Contraindications

Children under 10 years
Creatine kinase levels over 5 times upper limit of normal
Within 7 days of discontinuing fusidic acid
Breastfeeding
Galactosaemia
Moderate hepatic impairment
Myopathy
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute
Serum transaminases above 3 times upper limit of normal

Precautions and Warnings

Asian ancestry
Family history of hereditary muscular disorders
Females of childbearing potential
High alcohol intake
Major surgery
Patients over 65 years
Severe trauma
Glucose-galactose malabsorption syndrome
Hereditary muscular disorder
History of hepatic impairment
History of muscular toxicity secondary to fibrates
History of muscular toxicity secondary to HMG-CoA reductase inhibitors
Hypothyroidism
Lactose intolerance
Renal impairment - creatinine clearance 30-60ml/minute

Advise ability to drive/operate machinery may be affected by side effects
Correct hypothyroidism before treatment
Exclude secondary causes of hypercholesterolaemia before treatment
Contains lactose
Administer 2 hours before or > 4 hours after any bile acid sequestrant
Exclude pregnancy prior to initiation of treatment
Measure creatine kinase levels prior to treatment if risk of rhabdomyolysis
Perform liver function tests before commencing therapy
Monitor blood glucose in high risk patients
Monitor creatine kinase levels in patients at risk of rhabdomyolysis
Monitor creatine kinase levels in patients reporting myalgia
Repeat liver function tests within 3 months and at 12 months
Advise patient to report any symptoms of interstitial lung disease
Advise patients to report muscle pain/tenderness/weakness
Discontinue if myopathy is suspected
Reduce dose or discontinue therapy if liver injury or jaundice occurs
Advise patient to seek advice at first indications of pregnancy
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if AST level exceed 3 times the upper limit of normal & persist
Discontinue if creatine kinase levels >5 times upper limit of normal
Discontinue if evidence of interstitial lung disease
Discontinue if muscular symptoms are severe
Discontinue prior to surgery
Dietary restrictions should be maintained
Grapefruit products increase the plasma level of the statin

Statin therapy has been associated with the development of myalgia, myopathy and rhabdomyolysis, which can rarely be fatal. Myopathy is dose related.
Routine monitoring of creatinine kinase is not necessary in asymptomatic patients.
Do not measure creatine kinase levels following strenuous exercise or in the presence of other factors affecting CK levels. If CK is greater than 5 times the upper limit of normal (ULN) levels prior to treatment, re-measure 5 to 7 days later.
If symptoms of myopathy resolve and levels of creatinine kinase reduce, treatment can be reinitiated at the lowest dose and with close monitoring.

Some evidence suggests that statins as a class raise blood glucose and in some patients, at a high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (raised fasting glucose, raised body mass index at baseline, history of hypertension and raised triglycerides) should be monitored both clinically and biochemically according to national guidelines.

Simvastatin therapy should be temporarily suspended if a short course of itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable.

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (greater than or equal to 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

Coadministration of simvastatin with lipid-modifying doses (greater than or equal to 1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients.

There have been very rare reports of an immune mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

Pregnancy and Lactation

Pregnancy

Ezetimibe and simvastatin is contraindicated during pregnancy.

Simvastatin is contraindicated in pregnancy. It is unknown if simvastatin crosses the placenta. A mixture of human malformations have been reported with the use of statins in the first trimester, these include; VATER-association, neural tube defects, holoprosencephaly, other CNS malformations and limb abnormalities (Schaefer, 2007). None of these malformations have occurred in significant enough quantities to enable causality to be concluded. However, the theoretical risks of reducing cholesterol availability during embryo development should be considered, since simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. The suspension of treatment throughout pregnancy is not considered likely to have a detrimental effect on the long term course of hyperlipidaemia. For these reasons simvastatin should not be used during pregnancy. Schaefer (2007) suggest that inadvertent treatment with a statin during pregnancy, does not require a termination of pregnancy, however, treatment should be stopped immediately and a detailed ultrasound examination should be considered.

Animal studies of ezetimibe during pregnancy showed no evidence of impaired fertility or embryolethal effects in rats and rabbits at doses up to about 10 times the human exposure at 10 mg/day with ezetimibe. 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. The high plasma protein binding should limit the transfer though. Schaefer (2007) states that generally, discontinuing treatment of hypercholesterolaemia during pregnancy is not thought to put the mother at risk.

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 14-17 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 and simvastatin is contraindicated during breastfeeding.

Simvastatin is contraindicated while breastfeeding. It is unknown if simvastatin is excreted into human breast milk. At the time of writing, there is no published experience concerning the use of statins during breastfeeding. The suspension of treatment while breastfeeding is not considered likely to detrimentally affect the long term course of hyperlipidaemia (Hale, 2010). The products of cholesterol biosynthesis, including cholesterol are essential for neonatal development. Therefore, the use of statins is contraindicated while breastfeeding.

Ezetimibe has been observed in the milk of lactating rats with a milk: plasma ratio of 0.5. It is not known whether the drug is excreted into human milk though but due to its prolonged half life and molecular weight it is expected to be. The effects on the nursing infant are unknown. Schaefer (2007) states that lipid reducers should not be used during breastfeeding because their safety is not established.

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 INR
Accelerated erythrocyte sedimentation
Alopecia
Altered liver function tests
Anaemia
Anaphylaxis
Angioedema
Arthralgia
Arthritis
Asthenia
Chest pain
Cholecystitis
Cholelithiasis
Constipation
Cough
Creatine kinase increased
Creatine phosphokinase increased
Decreased appetite
Depression
Dermatomyositis
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Eosinophilia
Erectile dysfunction
Erythema multiforme
Fatigue
Flatulence
Flushing
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-intestinal disturbances
Gastroesophageal reflux disease
Headache
Hepatic failure
Hepatitis
Hot flushes
Hypersensitivity reactions
Hypertension
Immune mediated necrotizing myopathy
Impaired memory
Increase in serum ALT/AST
Increased uric acid level
Insomnia
Interstitial lung disease
Jaundice
Lupus erythematosus-like syndrome
Malaise
Muscle spasm
Muscle weakness
Myalgia
Myopathy
Myositis
Nausea
Pain
Pancreatitis
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Polymyalgia rheumatica
Precipitation of diabetes
Proteinuria
Pruritus
Pyrexia
Rash
Renal failure
Rhabdomyolysis
Serum bilirubin increased
Sexual dysfunction
Sleep disturbances
Tendinopathy
Tendon rupture
Thrombocytopenia
Urticaria
Vasculitis
Vomiting
Weight loss

Presentation

Oral formulations of ezetimibe and simvastatin.

Drugs List

Therapeutic Indications

Uses

Combined hyperlipidaemia: lipid lowering therapy adjunct to diet
Homozygous familial hypercholesterolaemia: Adjunct to diet
Primary hypercholesterolaemia: lipid lowering therapy adjunct to diet
Risk reduction of cardiovascular events

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), either previously treated with a statin or not.

Hypercholesterolaemia
Indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate:

Patients not appropriately controlled with a statin alone.
Patients already treated with a statin and ezetimibe.

Homozygous Familial Hypercholesterolaemia (HoFH)
Indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g. low-density lipoprotein (LDL) apheresis).

Dosage

Adults

Elderly

Children

Additional Dosage Information

Contraindications

Children under 10 years
Creatine kinase levels over 5 times upper limit of normal
Within 7 days of discontinuing fusidic acid
Breastfeeding
Galactosaemia
Moderate hepatic impairment
Myopathy
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute
Serum transaminases above 3 times upper limit of normal

Precautions and Warnings

Asian ancestry
Family history of hereditary muscular disorders
Females of childbearing potential
High alcohol intake
Major surgery
Patients over 65 years
Severe trauma
Glucose-galactose malabsorption syndrome
Hereditary muscular disorder
History of hepatic impairment
History of muscular toxicity secondary to fibrates
History of muscular toxicity secondary to HMG-CoA reductase inhibitors
Hypothyroidism
Lactose intolerance
Renal impairment - creatinine clearance 30-60ml/minute

Advise ability to drive/operate machinery may be affected by side effects
Correct hypothyroidism before treatment
Exclude secondary causes of hypercholesterolaemia before treatment
Contains lactose
Administer 2 hours before or > 4 hours after any bile acid sequestrant
Exclude pregnancy prior to initiation of treatment
Measure creatine kinase levels prior to treatment if risk of rhabdomyolysis
Perform liver function tests before commencing therapy
Monitor blood glucose in high risk patients
Monitor creatine kinase levels in patients at risk of rhabdomyolysis
Monitor creatine kinase levels in patients reporting myalgia
Repeat liver function tests within 3 months and at 12 months
Advise patient to report any symptoms of interstitial lung disease
Advise patients to report muscle pain/tenderness/weakness
Discontinue if myopathy is suspected
Reduce dose or discontinue therapy if liver injury or jaundice occurs
Advise patient to seek advice at first indications of pregnancy
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if AST level exceed 3 times the upper limit of normal & persist
Discontinue if creatine kinase levels >5 times upper limit of normal
Discontinue if evidence of interstitial lung disease
Discontinue if muscular symptoms are severe
Discontinue prior to surgery
Dietary restrictions should be maintained
Grapefruit products increase the plasma level of the statin

Statin therapy has been associated with the development of myalgia, myopathy and rhabdomyolysis, which can rarely be fatal. Myopathy is dose related.
Routine monitoring of creatinine kinase is not necessary in asymptomatic patients.
Do not measure creatine kinase levels following strenuous exercise or in the presence of other factors affecting CK levels. If CK is greater than 5 times the upper limit of normal (ULN) levels prior to treatment, re-measure 5 to 7 days later.
If symptoms of myopathy resolve and levels of creatinine kinase reduce, treatment can be reinitiated at the lowest dose and with close monitoring.

Some evidence suggests that statins as a class raise blood glucose and in some patients, at a high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (raised fasting glucose, raised body mass index at baseline, history of hypertension and raised triglycerides) should be monitored both clinically and biochemically according to national guidelines.

Simvastatin therapy should be temporarily suspended if a short course of itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable.

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (greater than or equal to 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

Coadministration of simvastatin with lipid-modifying doses (greater than or equal to 1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients.

There have been very rare reports of an immune mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

Pregnancy and Lactation

Pregnancy

Ezetimibe and simvastatin is contraindicated during pregnancy.

Simvastatin is contraindicated in pregnancy. It is unknown if simvastatin crosses the placenta. A mixture of human malformations have been reported with the use of statins in the first trimester, these include; VATER-association, neural tube defects, holoprosencephaly, other CNS malformations and limb abnormalities (Schaefer, 2007). None of these malformations have occurred in significant enough quantities to enable causality to be concluded. However, the theoretical risks of reducing cholesterol availability during embryo development should be considered, since simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. The suspension of treatment throughout pregnancy is not considered likely to have a detrimental effect on the long term course of hyperlipidaemia. For these reasons simvastatin should not be used during pregnancy. Schaefer (2007) suggest that inadvertent treatment with a statin during pregnancy, does not require a termination of pregnancy, however, treatment should be stopped immediately and a detailed ultrasound examination should be considered.

Animal studies of ezetimibe during pregnancy showed no evidence of impaired fertility or embryolethal effects in rats and rabbits at doses up to about 10 times the human exposure at 10 mg/day with ezetimibe. 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. The high plasma protein binding should limit the transfer though. Schaefer (2007) states that generally, discontinuing treatment of hypercholesterolaemia during pregnancy is not thought to put the mother at risk.

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 14-17 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 and simvastatin is contraindicated during breastfeeding.

Simvastatin is contraindicated while breastfeeding. It is unknown if simvastatin is excreted into human breast milk. At the time of writing, there is no published experience concerning the use of statins during breastfeeding. The suspension of treatment while breastfeeding is not considered likely to detrimentally affect the long term course of hyperlipidaemia (Hale, 2010). The products of cholesterol biosynthesis, including cholesterol are essential for neonatal development. Therefore, the use of statins is contraindicated while breastfeeding.

Ezetimibe has been observed in the milk of lactating rats with a milk: plasma ratio of 0.5. It is not known whether the drug is excreted into human milk though but due to its prolonged half life and molecular weight it is expected to be. The effects on the nursing infant are unknown. Schaefer (2007) states that lipid reducers should not be used during breastfeeding because their safety is not established.

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 INR
Accelerated erythrocyte sedimentation
Alopecia
Altered liver function tests
Anaemia
Anaphylaxis
Angioedema
Arthralgia
Arthritis
Asthenia
Chest pain
Cholecystitis
Cholelithiasis
Constipation
Cough
Creatine kinase increased
Creatine phosphokinase increased
Decreased appetite
Depression
Dermatomyositis
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Eosinophilia
Erectile dysfunction
Erythema multiforme
Fatigue
Flatulence
Flushing
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-intestinal disturbances
Gastroesophageal reflux disease
Headache
Hepatic failure
Hepatitis
Hot flushes
Hypersensitivity reactions
Hypertension
Immune mediated necrotizing myopathy
Impaired memory
Increase in serum ALT/AST
Increased uric acid level
Insomnia
Interstitial lung disease
Jaundice
Lupus erythematosus-like syndrome
Malaise
Muscle spasm
Muscle weakness
Myalgia
Myopathy
Myositis
Nausea
Pain
Pancreatitis
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Polymyalgia rheumatica
Precipitation of diabetes
Proteinuria
Pruritus
Pyrexia
Rash
Renal failure
Rhabdomyolysis
Serum bilirubin increased
Sexual dysfunction
Sleep disturbances
Tendinopathy
Tendon rupture
Thrombocytopenia
Urticaria
Vasculitis
Vomiting
Weight loss

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: July 2013

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. 66th ed. London: BMJ Group and Pharmaceutical Press; 2013. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com [Accessed on [February 12, 2014]].

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

Summary of Product Characteristics: Inegy Tablets. Merck Sharp & Dohme Ltd. Revised February 2016.

Drug Safety Update. MHRA Volume 1 issue 7 February 2008.
Available at https://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con2033918.pdf
Last accessed: July 8, 2013.

Drug Safety Update. MHRA Volume 3, issue 10 May 2010.
Available at https://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con081866.pdf
Last accessed: July 8, 2013.

Drug Safety Update. MHRA Volume 5, issue 6 January 2012.
Available at https://www.mhra.gov.uk/home/groups/dsu/documents/publication/con140708.pdf
Last accessed: July 8, 2013.

FDA Drug safety Communication: Important safety label changes to cholesterol lowering statin drugs.
Available at https://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
Last accessed: July 8, 2013.

NAPOS, The Drug Database for Acute Porphyria.
Available at: https://www.drugs-porphyria.org/
Simvastatin last revised June 7, 2013.
Last accessed: July 8, 2013.

National Institute for Health and Clinical Excellence, NICE 71, Identification and management of familial hypercholesterolaemia, issued August 2008.
Available at: https://www.nice.org.uk/nicemedia/pdf/CG071NICEGuideline.pdf
Last accessed: July 8, 2013.