Ezetimibe/ Simvastatin

Registered South African indications:

• Hypercholesterolaemia

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy
• Breastfeeding
• Moderate to severe hepatic impairment
• Unexplained persistent elevations of serum transaminases
• Coadministration with CYP3A4 inhibitors
• Coadministration with gemfibrozil, danazol or cyclosporin
• Coadministration in patients with homozygous familial hypercholesterolaemia with lomitapide (> 40mg simvastatin)

Cautions

• Moderate to severe renal impairment
• Coronary artery disease
• Asian patients
• Patients with SLCO1B1 gene allele
• High doses
• Female gender
• Uncontrolled hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Alcohol abuse
• Major surgery
• Diabetes mellitus
• Children <17 years
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab

Primary hypercholesterolaemia

Ezetimibe/ Simvastatin
10/10 (mg)
10/20 (mg)
10/40 (mg)

• Oral (tab): Initial: 10/10mg 1 tab, dly, at night; Titrate at intervals of 4 weeks

Homozygous familial hypercholesterolaemia
Patients with an coronary artery disease and acute coronary syndrome event history

Ezetimibe/ Simvastatin
10/40 (mg)

• Oral (tab): Initial: 10/40mg 1 tab, dly, at night; Titrate at intervals of 4 weeks

See administration guidelines

Paed. forms avail. in SA and covered in this monograph: tab

Primary hyperlipidaemia

Ezetimibe/ Simvastatin
10/40 (mg)
10/20 (mg)
10/40 (mg)

• Oral (tab): Younger than 10 years: Not established for use
• Oral (tab): Between 10-17 years: 10/10mg 1 tab, dly, at night, Max: 10/40mg 1 tab/24hrs
• Oral (tab): Older than 17 years: See adult dosage

Pregnancy

• Contraindicated
• Atherosclerosis is a chronic process, and ordinarily, discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. Ezetimibe/simvastatin is contraindicated during pregnancy. No clinical data are available on the use of ezetimibe/simvastatin during pregnancy. Animal studies on combination therapy have demonstrated reproduction toxicity
• Simvastatin: The safety of simvastatin in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.
• Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, simvastatin/ezetimibe must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin/ezetimibe must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant
• Ezetimibe: No clinical data are available on the use of ezetimibe during pregnancy

Breastfeeding

• Contraindicated
• Ezetimibe/simvastatin is contraindicated during breastfeeding.  Studies on rats have shown that ezetimibe is excreted into breast milk. It is not known if the active components of simvastatin/ ezetimibe are secreted into human breast milk

Renal Impairment

• CrCl ≥60 ml/min: No dose adjustment recommended
• CrCl <60 ml/min: Caution; no dose adjustment recommended
  Recommended dose: Up to 10/20mg 1 tab, daily, at night; Higher doses should be implemented cautiously

Hepatic Impairment 

• Mild: No dose adjustment recommended
• Moderate to severe: Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Depression
• Headache
• Paresthesia
• Dizziness
• Peripheral neuropathy
• Memory impairment
• Hypertension
• Hot flush
• Chest pain 
• Peripheral oedema

Respiratory Disorders

• Interstitial lung disease 

Gastrointestinal Disorders

• Constipation
• Abdominal pain
• Flatulence
• Dyspepsia
• Diarrhea
• Nausea and vomiting
• Pancreatitis

Hepatobiliary disorders

• Hepatitis
• Jaundice
• Hepatic failure

Endocrine and Metabolic Disorders

• Decreased appetite
• Increase in blood creatine kinase

Musculoskeletal Disorders

• Myopathy 
• Rhabdomyolysis 
• Acute renal failure 
• Myalgia
• Muscle cramps
• Arthralgia
• Muscle spasms
• Neck pain
• Back pain 
• Muscular weakness 
• Pain in extremity 

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Alopecia
• Erythema multiforme
• Urticaria 

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopaenia
• Hypersensitivity reactions

• Amiodarone
• Amlodipine
• Diltiazem
• Verapamil
• Lomitapide 
• CYP3A4 inhibitors
• CYP3A4 inducers
• OATP1B1 inhibitors
• Fibrates
• Elbasvir
• Grazoprevir
• Niacin (nicotinic acid)
• Antacids
• Cholestyramine
• Fusidic acid
• Ciclosporin
• Danazol
• Anticoagulants
• Gemfibrozil
• Grapefruit juice
• Colchicine

None routine. Specific cases may require

• Hepatic function
• Creatine phosphokinase (CK) 
• Blood glucose

Coadministration directions

• Dosing should occur >2 hours before or >4 hours after administration of a bile acid sequestrant
• Patients taking lomitapide should not exceed 40/10mg, dly
• Patients taking amiodarone, verapamil, diltiazem or products containing elbasvir or grazoprevir should not exceed 20/10mg, dly
• Patients taking >1g/day of niacin should not exceed 20/10mg, dly

Ezetimibe
Ezetimibe inhibits the intestinal absorption of cholesterol at the small intestine brush border, leading to a decrease in the delivery of intestinal cholesterol to the liver

Simvastatin
Simvastatin is a selective, competitive inhibitor of HMG CoA reductase, the enzyme which converts HMG CoA to mevalonate, a precursor of sterols. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C (low density lipoprotein cholesterol) receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations 

COMBINATION PREPARATION

Ezetimibe/ Simvastatin

Tablet 10mg/10mg

• Ezesim 10/10 (Forrester Pharma)
• Ezimva 10/10 (Alkem Laboratories)
• Inegy (MSD) originator
• Mezibe Plus 10/10 (Ranbaxy Pharmaceuticals)
• Tryzetor Plus 10/10mg (Pharma Dynamics)

Tablet 10mg/20mg

• Ezesim 10/20 (Forrester Pharma)
• Ezimva 10/20 (Alkem Laboratories)
• Inegy (MSD) originator
• Mezibe Plus 10/20 (Ranbaxy Pharmaceuticals)
• Tryzetor Plus 10/20mg (Pharma Dynamics)

Tablet 10mg/40mg

• Ezesim 10/40 (Forrester Pharma)
• Ezimva 10/40 (Alkem Laboratories)
• Inegy (MSD) originator
• Mezibe Plus 10/40 (Ranbaxy Pharmaceuticals)
• Tryzetor Plus 10/40mg (Pharma Dynamics)