Learn a Drug a Day - Simvastatin

Today's drug is simvastatin.
Its has quite a number of trade names, which it is selling as Covastin, Lipaco, Simtin, Simvacor, Simvor, Vascor, Stavid, Zocor.
What is simvastatin indicated for?
INDICATIONS : 

• It is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: 
• Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. 
• Reduce elevated total-C, LDL-C (low-density-lipoprotein cholesterol), Apo B (Apolipoprotein B), TG (Triglyceride) and increase HDL-C (high-density-lipoprotein cholesterol) in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. (abnormal amount of lipids in the blood.)  
• Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C (very-low-density-lipoprotein cholesterol) in patients with primary dysbetalipoproteinemia. (genetic disorder in which there are high amounts of cholesterol and triglycerides in the blood.)
• Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia.
• Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.

How does simvastatin work?

MECHANISMS OF ACTION : 

• Simvastatin is a prodrug metabolised in the liver to form the active β-hydroxyacid derivative. 
• This inhibits the conversion of HMG-CoA to mevalonic acid by blocking HMG-CoA reductase, an early and rate-limiting step in cholesterol biosynthesis. 
• It reduces total cholesterol, LDL-cholesterol and triglycerides and increases HDL-cholesterol levels.
• Onset of action : 3 days.
• Absorption : Absorbed from the GI tract (oral).
• Distribution : Protein-binding: 95%.
• Metabolism : Extensively hepatic; undergoes metabolism by CYP3A4.
• Excretion : Mainly excreted in the faeces as metabolites. Urine (10-15% inactive form); 1.9 hr (elimination half-life, active metabolite).

How is simvastatin being used?

ROUTE OF ADMINISTRATION : 

• It is taken orally as tablets.
• May be taken with or without food. 
• Avoid excessive consumption (>1 L/day) of grapefruit juice.

Is there any contraindication?

CONTRAINDICATIONS : 

• Acute liver disease or unexplained persistent elevations of serum transaminases. 
• Pregnancy, lactation. 
• Porphyria. (a group of rare disorders passed down through families, caused by a specific abnormality in the heme production process.)
• Patients of Chinese descent should not take 80 mg dose w/ lipid-modifying dose of niacin-containing products (≥1 g/day).

Are there any possible side effects?

SIDE EFFECTS : 

• headache, nausea, 
• flatulence (state of having excessive stomach or intestinal gas), heartburn, abdominal pain, diarrhoea/constipation, dysgeusia (distortion of the sense of taste)
• dose-related myopathy (e.g. myalgia, muscle weakness and dark urine)
• serum transaminases and CPK elevations
• hypersensitivity
• lens opacities, blurring of vision
• dizziness
• sexual dysfunction
• insomnia
• depression 
• upper respiratory symptoms
• Potentially Fatal: Severe rhabdomyolysis (breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream.) with acute renal failure

What precautions are necessary?

PRECAUTIONS : 

(i) General 

• Simvastatin may cause elevation of CK (Creatine kinase) and  transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with simvastatin. 
• Patients should be advised about substances they should not take concomitantly with simvastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness. 
• Patients should also be advised to inform other physicians prescribing a new medication that they are taking simvastatin.

(ii) Myopathy/Rhabdomyolysis

• Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age ( ≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
• In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
• Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. simvastatin therapy should be discontinued if markedly elevated CPK (Creatine phosphokinase) levels occur or myopathy is diagnosed or suspected. Simvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

(iii) Liver Dysfunction

• Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
• It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart simvastatin. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy.
• The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.
• As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.

(iv) Endocrine Function

• Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

DRUG INTERACTIONS : 

(i) Strong CYP3A4 Inhibitors, cyclosporine, or danazol

• Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity. Therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.  
• Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin.
• Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated  
• If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. 
• Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of simvastatin be considered during concomitant use of voriconazole and simvastatin to reduce  the risk of myopathy, including rhabdomyolysis. 
• The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. 

(ii) Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

• Gemfibrozil: Contraindicated with simvastatin.
• Other fibrates: Caution should be used  when prescribing with simvastatin.

(iii) Amiodarone, Ranolazine, or Calcium Channel Blockers

• The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine.

(iv) Niacin 

• Cases of myopathy/rhabdomyolysis  have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding  20 mg/day coadministered with lipid-modifying doses of niacin-containing products.  Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.

(v) Digoxin 

• In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.

(vi) Coumarin Anticoagulants 

• In two clinical studies, one in normal volunteers  and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly  potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. 

(vii) Colchicine 

• Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine. 

Pregnancy and breastfeeding:  

• Simvastatin is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development.
• Women of childbearing potential, who require treatment with simvastatin for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin should be considered. If pregnancy occurs, simvastatin should be immediately discontinued.
• It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.

References : 

1. Simvastatin by MERCK SHARP & DOHME LTD.

2. Simvastatin by Rx List.

3. Simvastatin by MIMS Malaysia.