Simvastatin

Simvastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Simvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular events including myocardial infarction and stroke.

Simvastatin is well absorbed from the gastrointestinal tract. The Bioavailability is approximately <5% (β -hydroxy acid). Time to peak plasma concentration was found to be achieved within 1.3-2.4 hours. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier. Both simvastatin and its β-hydroxy acid metabolite are highly bound (approximately 95%) to human plasma proteins. Simvastatin is metabolized in the liver by the CYP3A4 isoenzyme into β-hydroxy acid and other metabolites and undergoes extensive first-pass effect. Simvastatin is mainly excreted via feces (60%); urine (13%). The Elimination half-life is approximately 1.9 hours (β-hydroxy acid).

Simvastatin shows common side effects like Constipation, stomach pain, Nausea, headache, memory loss or forgetfulness, confusion, and itchy or red skin.

Simvastatin is available in the form of an Oral Tablet and Oral Suspension.

Simvastatin is available in India, the US, Singapore, Russia, Italy, Spain, Canada, Australia, Japan, and China.

Simvastatin belongs to the Antilipemic Agent and acts as an HMG-CoA Reductase Inhibitor.

Simvastatin is a methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects.

The Data on the onset and duration of action of Simvastatin is not clinically established.

The Tmax of Simvastatin is approximately 1.3-2.4 hours.

Simvastatin is available in the form of Oral Tablet.

Simvastatin Tablet is taken orally, usually once daily.

Simvastatin is a cholesterol-lowering medication. It is used in the treatment of Hyperlipidaemia (high levels of blood cholesterol and fats). It is also used to reduce the risk of heart-related complications in people with heart disease, diabetes, or other risk factors. Simvastatin works by reducing the level of bad cholesterol and fats and increasing the level of good cholesterol in the blood.

Simvastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxy acid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

Simvastatin is approved for use in the following clinical indications

Adult indication

• Heterozygous familial hypercholesterolemia
• Homozygous familial hypercholesterolemia
• Prevention of atherosclerotic cardiovascular disease

Although not approved, there have been certain off-label indications. These include

• Transplantation, post kidney

Pediatric indication

• Hyperlipidemia or heterozygous familial hypercholesterolemia (HeFH) and nonfamilial hypercholesterolemia

Adult Dose

• Heterozygous familial hypercholesterolemia

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening.

• Homozygous familial hypercholesterolemia

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening.

• Prevention of atherosclerotic cardiovascular disease
• Primary prevention:

Patients without diabetes, 40 to 75 years of age, and LDL-C 70 to 189 mg/dL

ASCVD 10-year risk 5% to <7.5%:

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥7.5% to <20%:

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening to reduce LDL-C by 30% to 49%; higher-risk patients with multiple risk-enhancing factors may benefit from high-intensity statin therapy (ie, with atorvastatin or rosuvastatin) to reduce LDL-C by ≥50%.

ASCVD 10-year risk ≥20% (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening.

Patients with diabetes

Age 40 to 75 years without additional ASCVD risk factors:

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥20% or multiple ASCVD risk factors (alternative agent)

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening.

Patients with LDL-C ≥190 mg/dL and 20 to 75 years of age (regardless of ASCVD risk estimate or coexisting diabetes mellitus) (alternative agent)

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening.

• Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 20 to 40 mg once daily in the evening.

• Transplantation, post-kidney (off-label)

Oral: Initial: 20 mg once daily; increase dose based on the response, tolerability, and concomitant drugs up to 40 mg once daily.

Pediatric Dose

• Hyperlipidemia or heterozygous familial hypercholesterolemia (HeFH) and nonfamilial hypercholesterolemia

Children ≥4 years and <10 years:

Oral: Initial: 5 mg once daily in the evening increasing to 10 mg once daily after 4 weeks and to 20 mg once daily after another 4 weeks as tolerated; maximum daily dose: 20 mg/day; most experience is with children at least 8 years of age; in trials, the youngest reported patient was 4 years of age.

Children ≥10 years and Adolescents:

Oral: Initial: 10 mg once daily in the evening increasing to 20 mg once daily after 6 weeks and to 40 mg once daily after another 6 weeks as tolerated; maximum daily dose: 40 mg/day.

Simvastatin is available in various strengths as 80 mg; 5 mg; 10 mg; 20 mg; 40 mg; 20 mg/5 mL; 40 mg/5 mL.

Simvastatin is available in the form of Oral Tablets and Oral Suspension.

• Dosage Adjustment in Kidney Patient

Initial: No dosage adjustment is necessary for any degree of kidney dysfunction.

Maximum dose: 40 mg once daily.

• Dosage Adjustment in Hepatic impairment Patient

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

Avoid grapefruit products. Co-administration with grapefruit products may increase the risk for adverse effects such as myalgia.

Simvastatin is contraindicated in patients with

• Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products).
• Concomitant administration of gemfibrozil, cyclosporine, or danazol.
• Hypersensitivity to any component of this medication.
• Active liver disease may include unexplained persistent elevations in hepatic transaminase levels.
• Women who are pregnant or may become pregnant.
• Nursing mothers.

• Diabetes mellitus

Increases in HbA_1c and fasting blood glucose have been reported; however, the benefits of statin therapy far outweigh the risk of dysglycemia.

• 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 elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for myopathy.

Consumption of alcohol is not recommended during treatment with Simvastatin, as it can increase the risk of liver damage.

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 the drug, taking into account the importance of the drug to the mother.

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in the use of the drug in pregnant women clearly outweigh the potential benefits.

Avoid grapefruit products. Co-administration with grapefruit products may increase the risk for adverse effects such as myalgia.

Common Adverse effects

• Atrial fibrillation, edema, Eczema, Abdominal pain, constipation, gastritis, nausea, Cystitis, Increased serum transaminases, Headache, vertigo, Increased creatine phosphokinase in a blood specimen, myalgia, Bronchitis, upper respiratory infection, Swelling.

Rare Adverse effects

• Skin rash, Increased gamma-glutamyl transferase, Diarrhea, dyspepsia, flatulence, Increased serum alkaline phosphatase, Asthenia.

• Strong CYP3A4 Inhibitors, Cyclosporine, Or Danazol

Strong CYP3A4 inhibitors: 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 increase 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, voriconazole, erythromycin, clarithromycin, or telithromycin is unavoidable, therapy with simvastatin must be suspended during treatment.

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of cyclosporine or danazol. Therefore, the concomitant use of these drugs is contraindicated.

• Gemfibrozil

Contraindicated with simvastatin.

• Other Fibrates

Caution should be used when prescribing simvastatin.

• Amiodarone, Dronedarone, Ranolazine, Or Calcium Channel Blockers

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

• Niacin

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin. Coadministration of Simvastatin with lipid-modifying doses (≥1 g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients.

• 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.

• 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 have 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.

• Colchicine

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

• Daptomycin

Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Temporarily suspend Simvastatin in patients taking daptomycin.

The common side effects of Simvastatin include the following

Common

● Constipation, stomach pain, Nausea, headache, memory loss or forgetfulness, confusion, itchy or red skin.

Rare

● Muscle pain, tenderness, or weakness with or without fever or lack of energy, dark red urine, decreased urination, lack of energy, tiredness, or weakness, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, dark colored urine, fever or chills, flushing, blisters, rash, hives, itching, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, difficulty breathing or swallowing, Hoarseness, joint pain, sensitivity to light.

• Pregnancy

Pregnancy Category X

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. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of the use of Simvastatin during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Simvastatin may cause fetal harm when administered to a pregnant woman. If Simvastatin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

• Nursing Mothers

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 the drug, considering the importance of the drug to the mother.

• Pediatric Use

The safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile like that of patients treated with a placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no significant effect on growth or sexual maturation in adolescent boys or girls, or on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin. Simvastatin has not been studied in patients younger than 10 years of age, nor in premenarchal girls.

• Geriatric Use

Of the 2,423 patients who received Simvastatin in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received Simvastatin, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, Simvastatin should be prescribed with caution in the elderly.

A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and Simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.

Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Simvastatin should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age.

• Significant lethality was observed in mice after a single oral dose of 9 g/m². No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m², respectively. No specific diagnostic signs were observed in rodents. At these doses, the only signs seen in dogs were emesis and mucoid stools.
• A few cases of overdosage with Simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

Pharmacodynamic

Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Pharmacokinetics

• Absorption

Simvastatin is well absorbed from the gastrointestinal tract. The Bioavailability is approximately <5% (β -hydroxy acid). Time to peak plasma concentration was found to be achieved within 1.3-2.4 hours.

• Distribution

Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier. Both simvastatin and its β-hydroxy acid metabolite are highly bound (approximately 95%) to human plasma proteins.

• Metabolism

Simvastatin is metabolized in the liver by the CYP3A4 isoenzyme into β-hydroxy acid and other metabolites and undergoes extensive first-pass effect.

• Excretion

Simvastatin is mainly excreted via feces (60%); urine (13%). The Elimination half-life is approximately 1.9 hours (β-hydroxy acid).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019766s085lbl.pdf
• https://reference.medscape.com/drug/zocor-flolipid-simvastatin-342463
• https://medlineplus.gov/druginfo/meds/a692030.html#side-effects
• https://www.mims.com/india/drug/info/simvastatin?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00641
• https://www.drugs.com/dosage/simvastatin.html
• https://www.practo.com/medicine-info/simvastatin-256-api
• https://www.uptodate.com/contents/simvastatin-drug-information#F221266
• https://www.rxlist.com/zocor-drug.htm#clinpharm