Ezetimibe/ Atorvastatin

Registered South African indications:

• Prevention of cardiovascular events
• Hypercholesterolaemia
• Homozygous familial hypercholesterolaemia (HoFH)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Women of childbearing potential not using appropriate contraceptive measures
• Active liver disease
• Unexplained persistent elevations in serum transaminases exceeding 3 times the upper limit of normal (ULN)
• Coadministration with hepatitis C antivirals glecaprevir/pibrentassvir

Cautions

• Renal impairment
• Hepatic impairment
  - Previous history of liver disease and/or where substantial quantities of alcohol are consumed 
• Elderly (>70 years)
  - Presence of other predisposing factors for rhabdomyolysis 
• Pre-disposing factors for rhabdomyolysis
• Hypothyroidism 
• Personal or familial history of hereditary muscular disorders 
• Previous history of muscular toxicity with a statin or fibrate 
• Situations where an increase in plasma creatine phosphokinase (CPK) levels may occur, such as interactions and special populations including genetic subpopulations
• Significantly elevated CPK levels (> 5 times ULN) at baseline
• Patients without coronary heart disease (CHD) who had:
  - Recent stroke
• - Transient ischaemic attack
• Prior haemorrhagic stroke
• Lacunar infarct
• Prolonged use
• Diabetes mellitus
• High risk of future diabetes
  -Fasting glucose 5,6-6,9 mmol/L
  - BMI >30kg/m²
  - Raised triglycerides
  - Hypertension 
• Hereditary problems of galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

• Prevention of cardiovascular events
  - 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
  - As adjunctive therapy to diet for use in adults with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate, i.e in patients not appropriately controlled with a statin alone or patients already treated with a statin and ezetimibe

Ezetimibe/ Atorvastatin

10/10 (mg)
10/20 (mg)
10/40 (mg)

• Oral (tab): 1 tab, dly; The dose of combined atorvastatin should be determined based on clinical assessment and the latest lipogram results, atorvastatin tolerability, and response to therapy

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The typical dose is 10/10 (mg) once a day

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The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment

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 The patient’s low-density lipoprotein cholesterol (LDL-C) level, coronary heart disease risk status and response to current cholesterol-lowering therapy should be considered when starting therapy or adjusting the dose

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The dose of ezetimibe/ atorvastatin should be individualised based on the known efficacy of the various dose strengths of ezetimibe/ atorvastatin and the response to the current cholesterol-lowering therapy. Adjustment of dose should be made at intervals of 4 weeks or more

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Homozygous familial hypercholesterolaemia (HoFH)
- As adjunctive therapy to diet for use in adults with HoFH

Ezetimibe/ Atorvastatin

10/10 (mg)
10/20 (mg)
10/40 (mg)

• Oral (tab): 1 tab, dly; The dose of combined atorvastatin should be determined based on clinical assessment and the latest lipogram results, atorvastatin tolerability, and response to therapy

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Ezetimibe/ atorvastatin may be used as an adjunct to other lipid-lowering treatments (e.g. low-density lipoprotein [LDL] apheresis) in these patients or if such treatments are unavailable

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See additional prescribing points for co-administration with other medicines

Not established for use in children

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/ atorvastatin is contraindicated during pregnancy
• No clinical data are available on the use of ezetimibe/ atorvastatin during pregnancy. Ezetimibe/ atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with ezetimibe/ atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. The co-administration of ezetimibe and atorvastatin in pregnant rats indicated that there was a test article-related increase in the skeletal variation “reduced ossification of the sternebrae” in the high dose ezetimibe/atorvastatin group. This may be related to the observed decrease in foetal body weights. In pregnant rabbits a low incidence of skeletal deformities (fused sternebrae, fused caudal vertebrae and asymmetrical sternebrae variation) were observed
• Atorvastatin: Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction. Maternal treatment with atorvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis
• Ezetimibe: No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development

• Women of childbearing potential should use appropriate contraceptive measures during treatment

Breastfeeding

• Contraindicated 
• Ezetimibe/ atorvastatin is contraindicated during breastfeeding. Because of the potential for serious adverse reactions, women taking ezetimibe/ atorvastatin should not breastfeed their infants
• Studies on rats have shown that ezetimibe is secreted into breast milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. It is not known if the active components of ezetimibe/ atorvastatin are secreted into human breast milk

Fertility

• No fertility studies were conducted with ezetimibe/ atorvastatin
• Atorvastatin had no effect on male or female fertility in animal studies
• Ezetimibe had no effect on the fertility of male or female rats

Renal Impairment

• Caution; no dose adjustment recommended 

Hepatic Impairment

• Mild: Caution; no dose adjustment recommended 
• Moderate to severe: Not recommended for use 
• Active liver disease: Contraindicated 

Elderly

• Caution; no dose adjustment recommended 

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

Permitted - No warnings

Central Nervous System Disorders

• Depression
• Insomnia
• Sleep disorder
• Nightmares
• Dizziness
• Headache
• Paraesthesia
• Hypoesthesia
• Amnesia
• Peripheral neuropathy
• Fatigue

Cardiovascular Disorders

• Sinus bradycardia
• Hot flush
• Hypertension
• Chest pain

Respiratory Disorders

• Influenza
• Nasopharyngitis
• Dyspnoea
• Cough
• Pharyngolaryngeal pain
• Epistaxis

• Interstitial lung disease

Gastrointestinal Disorders

• Diarrhoea
• Abdominal discomfort
• Abdominal distension
• Abdominal pain
• Abdominal pain lower
• Abdominal pain upper
• Constipation
• Dyspepsia
• Flatulence
• Frequent bowel movements
• Gastritis
• Nausea
• Stomach discomfort
• Pancreatitis
• Gastro-oesophageal reflux disease
• Eructation
• Vomiting
• Dry mouth

Hepatobiliary Disorders

• Hepatitis
• Cholelithiasis
• Cholecystitis
• Cholestasis
• Fatal and non-fatal hepatic failure
• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased alkaline phosphatase
• Increased blood creatine phosphokinase
• Increased gamma-glutamyltransferase
• Increased hepatic enzyme
• Abnormal liver function test

Genitourinary Disorders

• Positive urine white blood cells
• Sexual dysfunction

Endocrine and Metabolic Disorders

• Decreased appetite
• Anorexia
• Hyperglycaemia
• Hypoglycaemia
• Gynaecomastia
• Increased weight
• Diabetes mellitus

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Muscle fatigue
• Muscle spasms
• Muscular weakness
• Pain in extremity
• Myopathy/rhabdomyolysis
• Muscle rupture
• Tendinopathy, sometimes complicated by rupture
• Neck pain
• Joint swelling
• Myositis
• Lupus-like syndrome
• Immune-mediated necrotizing myopathy

Skin and Subcutaneous Tissue Disorders

• Acne
• Rash
• Urticaria
• Alopecia
• Skin rash
• Pruritus
• Erythema multiforme
• Angioneurotic oedema
• Dermatitis bullous
• - Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Thrombocytopaenia
• Hypersensitivity
• Anaphylaxis
• Angioedema
• Oedema
• - Peripheral oedema
• Pyrexia

Sensory Disorders

• Dysgeusia
• Blurred vision
• Visual disturbance
• Tinnitus
• Hearing loss

Others

• Pain

• Glecaprevir
• Pibrentasvir
• CYP3A4 inhibitors
• OATP1B pathway inhibitors
• Cholestyramine
• Ciclosporin
• Fibrates/ fibric acid deriavatives
• Fenofibrate
• Gemfibrozil
• Telithromycin
• Clarithromycin
• Delavirdine
• Stiripentol
• Ketoconazole
• Voriconazole
• Itraconazole
• Posaconazole
• Elbasvir
• Grazoprevir
• HIV protease inhibitors
• Ritonavir
• Lopinavir
• Atazanavir
• Indinavir
• Darunavir
• Erythromycin
• Diltiazem
• Verapamil
• Fluconazole
• Amiodarone
• Verapamil
• Breast cancer resistant protein  (BCRP) inhibitors
• CYP3A4 inducers
• Efavirenz
• Rifampicin
• Colestipol
• Fusidic acid
• Colchicine
• Daptomycin
• Boceprevir
• Warfarin
• Coumarin anticoagulant
• Fluindione
• Digoxin
• Oral contraceptives
• Tipranavir
• Saquinavir
• Fosamprenavir
• Amlodipine
• Telaprevir
• Nacin

Other interactions

• St John's wort
• Grapefruit juice

• Renal impairment
• Hepatic impairment
• Creatine phosphokinase level

Specific cases may require

• International normalised ratio (INR)
• Blood glucose

Co-administration with other medicines 

• Dosing of ezetimibe/ atorvastatin should occur either ≥2hrs before or ≥4hrs after administration of a bile acid sequestrant
• In patients taking hepatitis C antiviral agents elbasvir/grazoprevir concomitantly with ezetimibe/ atorvastatin, the dose of ezetimibe/ atorvastatin should not exceed 10/20mg/day

Creatine phosphokinase measurement 

• Creatine phosphokinase (CPK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CPK increase as this makes value interpretation difficult
• If CPK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results

Checks during treatment 

• Patients must be asked to promptly report muscle pain, cramps or weakness especially if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ezetimibe/ atorvastatin
• If such symptoms occur whilst a patient is receiving treatment with ezetimibe/ atorvastatin, their CPK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped
• If muscular symptoms are severe and cause daily discomfort, even if the CPK levels are elevated to ≤ 5 times ULN, treatment discontinuation should be considered
• If symptoms resolve and CPK levels return to normal, then re-introduction of ezetimibe/ atorvastatin or introduction of another statin-containing product may be considered at the lowest dose and with close monitoring
• Ezetimibe/ atorvastatin must be discontinued if clinically significant elevation of CPK levels (> 10 times ULN) occur or if rhabdomyolysis is diagnosed or suspected
• There have been very rare reports of an immune-mediated necrotising 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

Ezetimibe and atorvastatin are two lipid-lowering compounds with complementary mechanisms of action. The ezetimibe/ atorvastatin combination reduces elevated total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C), and increases high-density lipoprotein cholesterol (HDL-C) through dual inhibition of cholesterol absorption and synthesis.

Ezetimibe 

Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols. Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.

Atorvastatin 

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor). Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL. Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.

COMBINATION PREPARATIONS

Ezetimibe/ Atorvastatin

Tablet 10mg/10mg

• Liptruzet 10/10 (MSD) originator

Tablet 10mg/20mg

• Liptruzet 10/20 (MSD) originator

Tablet 10mg/40mg

• Liptruzet 10/40 (MSD) originator