Ezetimibe + Simvastatin

Oral
Familial homozygous hypercholesterolaemia

Oral
Primary hypercholesterolaemia

Oral
Cardiovascular risk reduction

Patients taking verapamil, diltiazem, amiodarone, amlodipine, ranolazine, niacin (≥1 g/day), elbasvir, grazoprevir: Max: 10 mg/20 mg daily.

Patients taking ticagrelor, lomitapide: Max: 10 mg/40 mg daily.

Pharmacogenomics:

Simvastatin

Simvastatin, a prodrug, is converted to its active metabolite simvastatin acid (SVA), which is a substrate of the organic anion transporter protein OATP1B1. OATP1B1 mediates the hepatic uptake of statins and other endogenous compounds (e.g. bilirubin) for subsequent elimination. SLCO1B1 gene encodes OATP1B1, certain polymorphism in the SLCO1B1 gene (e.g. 521T>C [rs4149056] polymorphism), can produce a less active form of OATP1B1. The reduced function of this transporter leads to an increased statin systemic exposure which is thought to be the contributor to statin-associated myopathy/statin-associated musculoskeletal symptoms (SAMS). Genetic testing may be helpful in identifying those at significant risk, to reduce simvastatin-induced myopathy and optimise patient adherence.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of January 2022:

Phenotype and Genotype	Implications	Recommendations
SLCO1B1 decreased function Patients carrying 1 normal or increased functional allele and 1 non-functional allele e.g. *1/*5, *1/*15	Increased risk of myopathy; increased SVA exposure in comparison to SLCO1B1 normal function.	An alternative agent is recommended depending on the desired potency; refer to specific country guidelines. If simvastatin treatment is desired, limit dose to <20 mg daily.
SLCO1B1 possible decreased function Patients carrying 1 non-functional allele and 1 unknown/uncertain functional allele e.g. *5/*6, *15/*10, *5/*43	Increased risk of myopathy; increased SVA exposure in comparison to SLCO1B1 normal function.	An alternative agent is recommended depending on the desired potency; refer to specific country guidelines. If simvastatin treatment is desired, limit dose to <20 mg daily.
SLCO1B1 poor function Patients carrying 2 non-functional alleles e.g. *5/*5, *5/*15, *15/*15	Highly increased risk of myopathy; increased SVA exposure in comparison to SLCO1B1 normal and decreased function.	An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of August 2020:

Genotype	Implications	Recommendations
SLCO1B1 521 CC	30-fold to 18% increased risk of myopathy and 48-fold to 12% increased risk of severe myopathy with 80 mg daily doses; 7-fold to 1% increased risk of myopathy and 11-fold to 0.68% increased risk of severe myopathy with 40 mg daily doses.	Choose an alternative agent. Additional risk factors for myopathy should be considered.
SLCO1B1 521 TC	5-fold to 3% increased risk of moderately severe to severe myopathy and 1.3% increased risk of severe myopathy with 80 mg daily doses; 2.6-fold to 0.39% increased risk of moderately severe to severe myopathy and 0.17% increased risk of severe myopathy with 40 mg daily doses.	Choose an alternative agent. Additional risk factors for myopathy should be considered. If simvastatin treatment is desired, avoid doses >40 mg daily.

eGFR <60 mL/min: 10 mg/20 mg once daily in the evening.

May be taken with or without food. Avoid excessive consumption (>1 L/day) of grapefruit juice.

Active liver disease or unexplained persistent elevations of serum transaminases. Concomitant use with strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat), including gemfibrozil, ciclosporin, and danazol; concomitant use and within 7 days of discontinuation of fusidic acid. Pregnancy and lactation.

Patient with a predisposition for myopathy/rhabdomyolysis (e.g. uncontrolled hypothyroidism, personal or familial history of hereditary muscular disorders, history of muscular toxicity with a statin or fibrate, alcohol abuse), diabetes mellitus, or history of liver disease. Patient with SLCO1B1 gene polymorphism. Temporarily discontinue treatment prior to elective major surgery. The 10 mg/80 mg dose is only recommended in patients at high risk of CV complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. Ezetimibe/simvastatin is not recommended for coadministration with niacin (≥1 g) in patients of Asian descent, particularly Chinese patients. Renal and hepatic impairment. Children and elderly.

Significant: Increased HbA_1c and fasting blood sugar; interstitial lung disease (long term therapy). Rarely, immune-mediated necrotising myopathy, new-onset or exacerbation of myasthenia gravis.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, dry mouth, GERD; abdominal distension, pain, or discomfort.
General disorders and administration site conditions: Fatigue, asthenia, peripheral oedema.
Investigations: Increased ALT, AST, and creatine kinase.
Musculoskeletal and connective tissue disorders: Myalgia, muscle spasms, musculoskeletal discomfort or weakness, neck pain, back pain, pain in the extremities, arthralgia.
Nervous system disorders: Headache, dizziness, paraesthesia.
Psychiatric disorders: Insomnia, sleep disorder.
Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infection.
Skin and subcutaneous tissue disorders: Rash, urticaria, pruritus.
Potentially Fatal: Rarely, myopathy, rhabdomyolysis with or without acute renal failure, hepatic failure.

PO: X

Monitor lipid profile (baseline, within 4-12 weeks after initiation or dose adjustment, and as necessary thereafter). Monitor hepatic transaminase levels (baseline); if hepatotoxicity is suspected, monitor AST, ALT, total bilirubin, and alkaline phosphatase. Prothrombin time (in patients taking coumarin anticoagulants) at baseline and during early therapy. Monitor for signs and symptoms of myopathy and rhabdomyolysis. Assess for new onset of diabetes mellitus during treatment. If immune-mediated necrotising myopathy is suspected, consider performing neuromuscular and serologic tests.

Ezetimibe: Decreased absorption with colestyramine (administer at least 2 hours before or 4 hours after colestyramine).
Simvastatin: May increase the risk of myopathy and rhabdomyolysis with fenofibrates, amiodarone, amlodipine, verapamil, diltiazem, ranolazine, ticagrelor, lomitapide, colchicine, niacin (≥1 g/day), dronedarone, and daptomycin. May increase the serum concentration when given with elbasvir and grazoprevir. Increased INR in concomitant use with warfarin or fluindione; perform INR monitoring. Decreased serum concentration with rifampicin.
Potentially Fatal: Simvastatin: Increased risk of myopathy and rhabdomyolysis with fusidic acid, strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat), including gemfibrozil, ciclosporin, and danazol.

Increased serum concentration when given with grapefruit juice. Increased risk of hepatic adverse effects with alcohol.

Description:
Mechanism of Action: Ezetimibe and simvastatin reduce elevated total cholesterol, LDL cholesterol, non-HDL cholesterol, triglycerides, and apolipoprotein B. It also increases HDL cholesterol through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe inhibits cholesterol absorption at the brush border of the small intestine via the sterol transporter Niemann-Pick C1-Like1 (NPC1L1), resulting in decreased cholesterol delivery to the liver, reduced hepatic cholesterol stores, and increased cholesterol clearance from the blood.
Simvastatin is a competitive inhibitor of HMG-CoA reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Onset: Ezetimibe: Within 1 week.
Simvastatin: >3 days.
Pharmacokinetics:
Absorption: Ezetimibe: Rapidly absorbed. Time to peak plasma concentration: 4-12 hours (ezetimibe); 1-2 hours (active metabolite).
Simvastatin: Well absorbed from the gastrointestinal tract. Bioavailability: <5%. Time to peak plasma concentration: 1.3-2.4 hours.
Distribution: Ezetimibe: Plasma protein binding: >90%.
Simvastatin: Plasma protein binding: Approx 95%.
Metabolism: Ezetimibe: Metabolised in the liver and small intestine via glucuronide conjugation to an active glucuronide metabolite. Undergoes enterohepatic recycling.
Simvastatin: Metabolised in the liver by the CYP3A4 isoenzyme. Undergoes extensive first-pass effect.
Excretion: Ezetimibe: Mainly via faeces (78%; 69% as unchanged drug); urine (11%; 9% as glucoronide metabolite). Elimination half-life: 22 hours.
Simvastatin: Mainly via faeces (60%); urine (10-15%). Elimination half-life: 1.9 hours (active metabolite).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 150311, Ezetimibe. https://pubchem.ncbi.nlm.nih.gov/compound/Ezetimibe. Accessed Apr. 26, 2022.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 54454, Simvastatin. https://pubchem.ncbi.nlm.nih.gov/compound/54454. Accessed July 26, 2022.

Store below 30°C.

Dyslipidaemic Agents

C10BA02 - simvastatin and ezetimibe ; Belongs to the class of HMG CoA reductase inhibitors in combination with other lipid modifying agents. Used in the treatment of hyperlipidemia.

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Link E, Parish S, Armitage J et al. SLCO1B1 Variants and Statin-Induced Myopathy - A Genomewide Study. The New England Journal of Medicine. 2008;359(8):789-799. doi: 10.1056/NEJMoa0801936. Accessed 07/12/2021

Annotation of CPIC Guideline for Simvastatin and SLCO1B1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 22/04/2022.

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Inegy 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg Tablets (Merck Sharp & Dohme Ltd). MHRA. https://products.mhra.gov.uk. Accessed 07/12/2021.

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