Drugs List

Therapeutic Indications

Uses

Mixed dyslipidaemia: adjunct to diet and exercise

Fenofibrate with simvastatin is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk patients with mixed dyslipidaemia to reduce triglycerides and increase HDL-C levels when LDL-C levels are adequately controlled with the corresponding dose of simvastatin monotherapy.

Contraindications

Children under 18 years
Creatine kinase levels over 5 times upper limit of normal
Photoallergic or phototoxic reactions to fibrates
Photosensitivity to ketoprofen
Within 7 days of discontinuing fusidic acid
Breastfeeding
Galactosaemia
Gall bladder disorder
Gallbladder disease
Hereditary fructose intolerance
Myopathy
Pancreatitis
Pregnancy
Renal impairment - eGFR below 60 ml/minute/1.73 m squared
Serum transaminases above 3 times upper limit of normal
Severe hepatic impairment
Unexplained elevated serum transaminases

Precautions and Warnings

Family history of hereditary muscular disorders
Females of childbearing potential
High alcohol intake
Hypoalbuminaemia
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
History of non-traumatic rhabdomyolysis
History of renal impairment
History of venous thromboembolism
Hypothyroidism
Lactose intolerance
Renal impairment - eGFR 60 to 89 ml/minute/1.73 m squared

Advise ability to drive/operate machinery may be affected by side effects
Correct hypothyroidism before treatment
Exclude/correct secondary causes of dyslipidaemia prior to treatment
Contains lactose
Contains soya or soya derivative
Contains sunset yellow (E110) - may cause allergic reaction
Preparation contains sucrose
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
Monitor serum creatinine
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
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Discontinue if hepatitis develops
Discontinue if myopathy is suspected
Advise patient to seek advice at first indications of pregnancy
Discontinue if ALT level exceeds 3 times the upper limit of normal
Discontinue if AST level exceeds 3 times the upper limit of normal
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
Advise patient grapefruit products may increase plasma level
Dietary restrictions should be maintained

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 7days 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, raises blood glucose levels 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.

Pancreatitis has been reported in patients taking fenofibrate. This may be as a result of a direct drug effect, obstruction of the common bile duct or a failure of efficacy in patients with severe hypertriglyceridaemia.

Pregnancy and Lactation

Pregnancy

Fenofibrate with simvastatin is contraindicated in pregnancy.

Fenofibrate
Fenofibrate is contraindicated during pregnancy.

Although there is insufficient data in humans, animal studies have demonstrated embryotoxicity and therefore fenofibrate should not be taken during pregnancy. Schaefer (2007) states inadvertent treatment with fenofibrate does not necessitate termination of pregnancy or requirement for invasive diagnostic procedures. It is unknown if it crosses the placenta.

Simvastatin
Simvastatin is contraindicated during pregnancy.

A mixture of human malformations have been reported with the used 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) concludes 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 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

Fenofibrate with simvastatin is contraindicated in breastfeeding.

Fenofibrate
Fenofibrate is contraindicated during breastfeeding.

There is no data available on the excretion of fenofibrate or its metabolites into breast milk. Lactating mothers should be advised not to breastfeed their child during treatment especially due to the infant's need for cholesterol and the carcinogenicity observed in rats treated with this product. An alternative drug is preferred, especially while nursing a newborn or pre-term infant. The relative low molecular weight (about 319) of the active metabolite suggest that it is excreted into the breast milk (Briggs, 2011). Schaefer (2007) suggests that there is no disadvantage to the mother if treatment is stopped during breastfeeding.

Simvastatin
Simvastatin is contraindicated while breastfeeding.

At the time of writing, there is little published experience concerning the use of statins during breastfeeding. Due to the possible inhibition of cholesterol biosynthesis by statins, there is a theoretical risk posed to the neonate. The products of cholesterol biosynthesis, including cholesterol are essential for neonatal development. Therefore, the use of statins is contraindicated while breastfeeding. The suspension of treatment while breastfeeding is not considered likely to detrimentally affect the long term course of hyperlipidaemia, therefore simvastatin use during breastfeeding is not recommended.

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
Alanine aminotransferase increased
Alopecia
Anaemia
Asthenia
Biliary colic
Blood urea increased
Cholangitis
Cholecystitis
Cholelithiasis
Constipation
Creatine phosphokinase increased
Deep vein thrombosis (DVT)
Depression
Dermatitis
Diabetes mellitus
Diarrhoea
Dizziness
Dyspepsia
Eczema
Erectile dysfunction
Erythema multiforme
Flatulence
Gamma glutamyl transferase (GGT) increased
Gastro-enteritis
Haemoglobin decrease
Headache
Hepatic failure
Hepatitis
Homocysteine level increased
Hypersensitivity reactions
Immune mediated necrotizing myopathy
Impaired memory
Increase in alkaline phosphatase
Increase in serum glucose
Increase in serum transaminases
Increased glycated haemoglobin (HbA1c) levels
Increased platelet count
Insomnia
Interstitial lung disease
Jaundice
Memory loss
Muscle spasm
Myalgia
Myopathy
Myositis
Nausea
Nightmares
Pancreatitis
Paraesthesia
Peripheral neuropathy
Photosensitivity
Pruritus
Pulmonary embolism
Rash
Rhabdomyolysis
Serum creatinine increased
Sexual dysfunction
Sleep disturbances
Stevens-Johnson syndrome
Tendinopathy
Thromboembolism
Toxic epidermal necrolysis
Upper respiratory tract infection
Urticaria
Vomiting
Weakness
White blood cell count decreased

Presentation

Oral formulations of fenofibrate with simvastatin

Drugs List

Therapeutic Indications

Uses

Mixed dyslipidaemia: adjunct to diet and exercise

Fenofibrate with simvastatin is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk patients with mixed dyslipidaemia to reduce triglycerides and increase HDL-C levels when LDL-C levels are adequately controlled with the corresponding dose of simvastatin monotherapy.

Dosage

Response should be monitored by determination of serum lipid values (total cholesterol (TC), LDL-C, triglycerides (TG)).

Adults

Elderly

Additional Dosage Information

Contraindications

Children under 18 years
Creatine kinase levels over 5 times upper limit of normal
Photoallergic or phototoxic reactions to fibrates
Photosensitivity to ketoprofen
Within 7 days of discontinuing fusidic acid
Breastfeeding
Galactosaemia
Gall bladder disorder
Gallbladder disease
Hereditary fructose intolerance
Myopathy
Pancreatitis
Pregnancy
Renal impairment - eGFR below 60 ml/minute/1.73 m squared
Serum transaminases above 3 times upper limit of normal
Severe hepatic impairment
Unexplained elevated serum transaminases

Precautions and Warnings

Family history of hereditary muscular disorders
Females of childbearing potential
High alcohol intake
Hypoalbuminaemia
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
History of non-traumatic rhabdomyolysis
History of renal impairment
History of venous thromboembolism
Hypothyroidism
Lactose intolerance
Renal impairment - eGFR 60 to 89 ml/minute/1.73 m squared

Advise ability to drive/operate machinery may be affected by side effects
Correct hypothyroidism before treatment
Exclude/correct secondary causes of dyslipidaemia prior to treatment
Contains lactose
Contains soya or soya derivative
Contains sunset yellow (E110) - may cause allergic reaction
Preparation contains sucrose
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
Monitor serum creatinine
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
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Discontinue if hepatitis develops
Discontinue if myopathy is suspected
Advise patient to seek advice at first indications of pregnancy
Discontinue if ALT level exceeds 3 times the upper limit of normal
Discontinue if AST level exceeds 3 times the upper limit of normal
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
Advise patient grapefruit products may increase plasma level
Dietary restrictions should be maintained

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 7days 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, raises blood glucose levels 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.

Pancreatitis has been reported in patients taking fenofibrate. This may be as a result of a direct drug effect, obstruction of the common bile duct or a failure of efficacy in patients with severe hypertriglyceridaemia.

Pregnancy and Lactation

Pregnancy

Fenofibrate with simvastatin is contraindicated in pregnancy.

Fenofibrate
Fenofibrate is contraindicated during pregnancy.

Although there is insufficient data in humans, animal studies have demonstrated embryotoxicity and therefore fenofibrate should not be taken during pregnancy. Schaefer (2007) states inadvertent treatment with fenofibrate does not necessitate termination of pregnancy or requirement for invasive diagnostic procedures. It is unknown if it crosses the placenta.

Simvastatin
Simvastatin is contraindicated during pregnancy.

A mixture of human malformations have been reported with the used 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) concludes 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 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

Fenofibrate with simvastatin is contraindicated in breastfeeding.

Fenofibrate
Fenofibrate is contraindicated during breastfeeding.

There is no data available on the excretion of fenofibrate or its metabolites into breast milk. Lactating mothers should be advised not to breastfeed their child during treatment especially due to the infant's need for cholesterol and the carcinogenicity observed in rats treated with this product. An alternative drug is preferred, especially while nursing a newborn or pre-term infant. The relative low molecular weight (about 319) of the active metabolite suggest that it is excreted into the breast milk (Briggs, 2011). Schaefer (2007) suggests that there is no disadvantage to the mother if treatment is stopped during breastfeeding.

Simvastatin
Simvastatin is contraindicated while breastfeeding.

At the time of writing, there is little published experience concerning the use of statins during breastfeeding. Due to the possible inhibition of cholesterol biosynthesis by statins, there is a theoretical risk posed to the neonate. The products of cholesterol biosynthesis, including cholesterol are essential for neonatal development. Therefore, the use of statins is contraindicated while breastfeeding. The suspension of treatment while breastfeeding is not considered likely to detrimentally affect the long term course of hyperlipidaemia, therefore simvastatin use during breastfeeding is not recommended.

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
Alanine aminotransferase increased
Alopecia
Anaemia
Asthenia
Biliary colic
Blood urea increased
Cholangitis
Cholecystitis
Cholelithiasis
Constipation
Creatine phosphokinase increased
Deep vein thrombosis (DVT)
Depression
Dermatitis
Diabetes mellitus
Diarrhoea
Dizziness
Dyspepsia
Eczema
Erectile dysfunction
Erythema multiforme
Flatulence
Gamma glutamyl transferase (GGT) increased
Gastro-enteritis
Haemoglobin decrease
Headache
Hepatic failure
Hepatitis
Homocysteine level increased
Hypersensitivity reactions
Immune mediated necrotizing myopathy
Impaired memory
Increase in alkaline phosphatase
Increase in serum glucose
Increase in serum transaminases
Increased glycated haemoglobin (HbA1c) levels
Increased platelet count
Insomnia
Interstitial lung disease
Jaundice
Memory loss
Muscle spasm
Myalgia
Myopathy
Myositis
Nausea
Nightmares
Pancreatitis
Paraesthesia
Peripheral neuropathy
Photosensitivity
Pruritus
Pulmonary embolism
Rash
Rhabdomyolysis
Serum creatinine increased
Sexual dysfunction
Sleep disturbances
Stevens-Johnson syndrome
Tendinopathy
Thromboembolism
Toxic epidermal necrolysis
Upper respiratory tract infection
Urticaria
Vomiting
Weakness
White blood cell count decreased

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: 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 14 March 2016.

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

Summary of Product Characteristics: Cholib 145mg/20mg film coated tablets. BGP Products Ltd. Revised April 2015.
Summary of Product Characteristics: Cholib 145mg/40mg film coated tablets. BGP Products Ltd. Revised April 2015.

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
Fenofibrate Last revised: 6 December 2013
Last accessed: 14 March 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
Simvastatin Last revised: 7 September 2013
Last accessed: 14 March 2016