ZOCOR Simvastatin 20mg Tablet 30's

Patients at High Risk of Coronary Heart Disease (CHD) or with Existing CHD: In patients at high risk of CHD (with or without hyperlipidemia), i.e., patients with diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or with existing CHD, SIMVASTATIN (ZOCOR) is indicated to: Reduce the risk of total mortality by reducing CHD deaths; Reduce the risk of major vascular events (a composite of non-fatal myocardial infarction, CHD death, stroke, or revascularization procedures); Reduce the risk of major coronary events (a composite of non-fatal myocardial infarction or CHD deaths); Reduce the risk of stroke; Reduce the need for coronary revascularization procedures (including coronary artery bypass grafting and percutaneous transluminal coronary angioplasty); Reduce the need for peripheral and other non-coronary revascularization procedures; Reduce the risk of hospitalization for angina pectoris.
In patients with diabetes, SIMVASTATIN (ZOCOR) reduces the risk of developing peripheral macrovascular complications (a composite of peripheral revascularization procedures, lower limb amputations, or leg ulcers).
In hypercholesterolemic patients with coronary heart disease, SIMVASTATIN (ZOCOR) slows the progression of coronary atherosclerosis, including reducing the development of new lesions and new total occlusions.
Patients with Hyperlipidemia: SIMVASTATIN (ZOCOR) is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, TG, and apolipoprotein B (apo B), and to increase HDL-C in patients with primary hypercholesterolemia including heterozygous familial hypercholesterolemia (Fredrickson type IIa), or combined (mixed) hyperlipidemia (Fredrickson type IIb), when response to diet and other nonpharmacological measures is inadequate. SIMVASTATIN (ZOCOR), therefore, lowers LDL-C/HDL-C and total-C/HDL-C ratios.
SIMVASTATIN (ZOCOR) is indicated for the treatment of patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia).
SIMVASTATIN (ZOCOR) is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).
SIMVASTATIN (ZOCOR) is also indicated as an adjunct to diet and other non-dietary measures for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) to reduce elevated total-C, LDL-C and apo B.
Pediatric Patients with Heterozygous Familial Hypercholesterolemia: SIMVASTATIN (ZOCOR) is indicated as an adjunct to diet to reduce total-C, LDL-C, TG, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heterozygous familial hypercholesterolemia (HeFH).

 

The dosage range for SIMVASTATIN (ZOCOR) is 5-80 mg/day, given as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients at high risk for cardiovascular complications who have not achieved treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see Myopathy/Rhabdomyolysis under Precautions).
Patients at High Risk of Coronary Heart Disease (CHD) or with Existing CHD: The usual starting dose of SIMVASTATIN (ZOCOR) is 40 mg/day given as a single dose in the evening in patients at high risk of CHD (with or without hyperlipidemia), i.e., patients with diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or with existing CHD. Drug therapy can be initiated simultaneously with diet and exercise.
Patients with Hyperlipidemia (who are not in the previously mentioned risk categories): The patient should be placed on a standard cholesterol-lowering diet before receiving SIMVASTATIN (ZOCOR) and should continue on this diet during treatment with SIMVASTATIN (ZOCOR).
The usual starting dose is 20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg/day given as a single dose in the evening. Patients with mild to moderate hypercholesterolemia can be treated with a starting dose of 10 mg of SIMVASTATIN (ZOCOR). Adjustments of dosage, if required, should be made as specified previously.
Patients with Homozygous Familial Hypercholesterolemia: Based on the results of a controlled clinical study, the recommended dosage for patients with homozygous familial hypercholesterolemia is SIMVASTATIN (ZOCOR) 40 mg/day in the evening. The 80-mg dose is only recommended when the benefits are expected to outweigh the potential risks (see Contraindications and Myopathy/Rhabdomyolysis under Precautions). SIMVASTATIN (ZOCOR) should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
In patients taking lomitapide concomitantly with SIMVASTATIN (ZOCOR), the dose of SIMVASTATIN (ZOCOR) should not exceed 40 mg/day (see Myopathy/Rhabdomyolysis under Precautions and Interactions).
Concomitant Therapy: SIMVASTATIN (ZOCOR) is effective alone or in combination with bile acid sequestrants.
In patients taking SIMVASTATIN (ZOCOR) concomitantly with fibrates, other than gemfibrozil (see Contraindications) or fenofibrate, the dose of SIMVASTATIN (ZOCOR) should not exceed 10 mg/day. In patients taking amiodarone, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with SIMVASTATIN (ZOCOR), the dose of SIMVASTATIN (ZOCOR) should not exceed 20 mg/day. In patients taking amlodipine concomitantly with SIMVASTATIN (ZOCOR), the dose of SIMVASTATIN (ZOCOR) should not exceed 40 mg/day. (See Myopathy/Rhabdomyolysis under Precautions and Interactions.)
Dosage in Renal Insufficiency: Because SIMVASTATIN (ZOCOR) does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency.
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see Pharmacology: Pharmacokinetics under Actions).
Dosage in Pediatric Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia: The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy.
Mode of Administration: SIMVASTATIN (ZOCOR) is available for oral administration as tablets.

 

Overdosage

May be taken with or without food.

Hypersensitivity to any component of this preparation.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and nursing (see Precautions and Use in Pregnancy & Lactation).
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and drugs containing cobicistat) (see Myopathy/Rhabdomyolysis under Precautions and Interactions).
Concomitant administration of gemfibrozil, cyclosporine, or danazol (see Myopathy/Rhabdomyolysis under Precautions and Interactions).

Myopathy/Rhabdomyolysis: Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X 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 HMG-CoA reductase inhibitory activity in plasma (i.e., elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (see Interactions). Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with SIMVASTATIN (ZOCOR), 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which patients with a history of myocardial infarction were treated with SIMVASTATIN (ZOCOR) 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.
The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 80-mg dose of SIMVASTATIN (ZOCOR) should only be used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking simvastatin 80 mg for whom an interacting agent is needed, a lower dose of simvastatin or an alternative statin-based regimen with less potential for drug-drug interactions should be used (see as follows; Dosage & Administration and Contraindications).
All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved (see Adverse Reactions). Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased. Periodic CK determinations are recommended for patients titrating to the 80-mg dose. 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. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing simvastatin to Asian patients and the lowest dose necessary should be employed.
Drug Interactions: The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin with the following drugs: Contraindicated Drug: Potent inhibitors of CYP3A4: Concomitant use with medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, or drugs containing cobicistat) is contraindicated. If short-term treatment with potent CYP3A4 inhibitors is unavoidable, therapy with simvastatin should be suspended during the course of treatment. (See Contraindications, Interactions and Pharmacology: Pharmacokinetics under Actions.)
Gemfibrozil, cyclosporine or danazol: Concomitant use of these drugs with simvastatin is contraindicated. (See Contraindications and Other drug interactions under Interactions).
Other Drugs: Fusidic acid: Patients on fusidic acid treated concomitantly with simvastatin may have an increased risk of myopathy/rhabdomyolysis (see Other drug interactions under Interactions and Pharmacology: Pharmacokinetics under Actions). Co-administration with fusidic acid is not recommended. In patients where the use of systemic fusidic acid is considered essential, simvastatin should be discontinued throughout the duration of fusidic acid treatment. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of simvastatin and fusidic acid should only be considered on a case-by-case basis under close medical supervision.
Other fibrates: The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with fibrates other than gemfibrozil (see Contraindications) or fenofibrate. When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone. Addition of fibrates to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. Combinations of fibrates with simvastatin have been used without myopathy in small short-term clinical studies with careful monitoring. (See Interactions.)
Amiodarone: In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone. (See Other drug interactions under Interactions.)
Calcium channel blockers: Verapamil or diltiazem: In a clinical trial, patients on diltiazem treated concomitantly with simvastatin 80 mg had an increased risk of myopathy. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil or diltiazem. (See Other drug interactions under Interactions.)
Amlodipine: In a clinical trial, patients on amlodipine treated concomitantly with simvastatin 80 mg had a slightly increased risk of myopathy (see Other drug interactions under Interactions). The dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine.
Lomitapide: The dose of simvastatin should not exceed 40 mg daily in patients with HoFH receiving concomitant medication with lomitapide (see Other drug interactions under Interactions).
Moderate inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy. When coadministering simvastatin with a moderate inhibitor of CYP3A4, a dose adjustment of simvastatin may be necessary.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore, a dose adjustment of simvastatin may be necessary. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir. (See Other drug interactions under Interactions.)
Niacin (≥1 g/day): Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid-modifying doses (≥1 g/day) of niacin. 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, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin. Therefore, the benefit of the combined use of simvastatin with niacin should be carefully weighed against the potential risks of the combination. In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with extended-release niacin/laropiprant 2 g/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in non-Chinese patients, co-administration of simvastatin with lipid-modifying doses (≥1 g/day) of niacin is not recommended in Asian patients. (See Other drug interactions under Interactions.)
Daptomycin: Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA reductase inhibitors coadministered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to suspending SIMVASTATIN (ZOCOR) temporarily in patients taking daptomycin (see Interactions).
Hepatic Effects: In clinical studies, persistent increases (to more than 3X ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When the drug 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. Some of these patients had abnormal liver function tests (LFTs) prior to therapy with simvastatin and/or consumed substantial quantities of alcohol.
In 4S, the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs 12 [0.6%]). The frequency of single elevations of SGPT (ALT) to 3X ULN was significantly higher in the simvastatin group in the first year of the study (20 vs 8, p=0.023), but not thereafter. Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1986 simvastatin patients in 4S with normal LFTs at baseline, only 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1,105 patients, the 6-month incidence of persistent hepatic transaminase elevations considered drug related was 0.7% and 1.8% at the 40- and 80-mg dose, respectively.
In HPS, in which 20,536 patients were randomized to receive SIMVASTATIN (ZOCOR) 40 mg/day or placebo, the incidences of elevated transaminases (>3X ULN confirmed by repeat test) were 0.21% (n=21) for patients treated with SIMVASTATIN (ZOCOR) and 0.09% (n=9) for patients treated with placebo.
It is recommended that LFTs be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show
evidence of progression, particularly if they rise to 3X ULN and are persistent, the drug should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see Myopathy/Rhabdomyolysis as previously mentioned). 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 (ZOCOR), promptly interrupt therapy. If an alternate etiology is not found, do not restart SIMVASTATIN (ZOCOR).
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 interruption of treatment was not required.
Ophthalmic Evaluations: In the absence of any drug therapy, an increase in the prevalence of lens opacities with time is expected as a result of aging. Current long-term data from clinical studies do not indicate an adverse effect of simvastatin on the human lens.
Use in Children: 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 one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See Dosage & Administration and Adverse Reactions) Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy (see Contraindications, Precautions and Use in Pregnancy & Lactation). Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.
Use in the Elderly: For patients over the age of 65 years who received simvastatin in controlled clinical studies, efficacy, as assessed by reduction in total-C and LDL-C, appeared similar to that seen in the population as a whole, and there was no apparent increase in the overall frequency of clinical or laboratory adverse findings. However, in a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy compared to patients <65 years of age.

 

Use In Pregnancy & Lactation

SIMVASTATIN (ZOCOR) is generally well-tolerated; for the most part side effects have been mild and transient in nature. Less than 2% of patients were discontinued from controlled clinical studies due to side effects attributable to SIMVASTATIN (ZOCOR).
In the pre-marketing controlled clinical studies, adverse effects occurring with a frequency of 1% or more and considered by the investigator as possibly, probably or definitely drug related were: abdominal pain, constipation and flatulence. Other side effects occurring in 0.5-0.9% of patients were asthenia and headache.
Myopathy has been reported rarely. See Myopathy/Rhabdomyolysis under Precautions.
In HPS involving 20,536 patients treated with 40 mg/day of SIMVASTATIN (ZOCOR) (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with SIMVASTATIN (ZOCOR) and patients treated with placebo over the mean 5 years of the study. In this mega-trial, only serious adverse effects and discontinuations due to any adverse effects were recorded. Discontinuation rates due to side effects were comparable (4.8% in patients treated with SIMVASTATIN (ZOCOR) compared with 5.1% in patients treated with placebo). The incidence of myopathy was <0.1% in patients treated with SIMVASTATIN (ZOCOR). Elevated transaminases (>3X ULN confirmed by repeat test) occurred in 0.21% (n=21) of patients treated with SIMVASTATIN (ZOCOR) compared with 0.09% (n=9) of patients treated with placebo.
In 4S involving 4,444 patients treated with 20-40 mg/day of SIMVASTATIN (ZOCOR) (n=2,221) or placebo (n=2,223), the safety and tolerability profiles were comparable between treatment groups over the median 5.4 years of the study.
The following additional side effects were reported either in uncontrolled clinical studies or in marketed use: nausea, diarrhea, rash, dyspepsia, pruritus, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, insomnia, depression, vomiting, anemia, erectile dysfunction, and interstitial lung disease. Rarely rhabdomyolysis and hepatitis/jaundice, and very rarely fatal and non-fatal hepatic failure have occurred.
There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see Myopathy/Rhabdomyolysis under Precautions).
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea, and malaise.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Laboratory Test Findings: Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. Liver function test abnormalities generally have been mild and transient. Increases in serum CK levels, derived from skeletal muscle, have been reported (see Precautions).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including SIMVASTATIN (ZOCOR).
Pediatric Patients (Ages 10-17 years): In a study involving pediatric patients 10-17 years of age with heterozygous familial hypercholesterolemia (n=175), the safety and tolerability profile of the group treated with SIMVASTATIN (ZOCOR) was generally similar to that of the group treated with placebo (see Use in Children under Precautions).

 

Multiple mechanisms may contribute to potential interactions with HMG-Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
Contraindicated drugs: Concomitant use of the following drugs is contraindicated: Potent Inhibitors 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. Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Concomitant use of drugs labeled as having a potent inhibitory effect on CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) is contraindicated. See Contraindications, Myopathy/Rhabdomyolysis under Precautions and Pharmacology: Pharmacokinetics under Actions.
Gemfibrozil, Cyclosporine or Danazol: See Contraindications, Myopathy/Rhabdomyolysis under Precautions and Pharmacology: Pharmacokinetics under Actions.
Other drug interactions: Other Fibrates: The risk of myopathy is increased by gemfibrozil (see Contraindications) and other fibrates (except fenofibrate); these lipid-lowering drugs can cause myopathy when given alone. When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. See Contraindications and Myopathy/Rhabdomyolysis under Precautions.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid (see Myopathy/Rhabdomyolysis under Precautions and Pharmacology: Pharmacokinetics under Actions).
Amiodarone: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone, with simvastatin (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Calcium Channel Blockers: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Lomitapide: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of lomitapide (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Moderate Inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy (see Myopathy/Rhabdomyolysis under Precautions).
Inhibitors of the Transport Protein OATP1B1: Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see Contraindications and Myopathy/Rhabdomyolysis under Precautions).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Simvastatin is a substrate of the efflux transporter BCRP. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy. When coadministering simvastatin with an inhibitor of BCRP, a dose adjustment of simvastatin may be necessary (see Dosage & Administration; Myopathy/Rhabdomyolysis under Precautions and Pharmacology: Pharmacokinetics under Actions).
Niacin (nicotinic acid) (≥1 g/day): Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day) of niacin (see Myopathy/Rhabdomyolysis under Precautions).
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by coadministration of HMG-CoA reductase inhibitors and daptomycin (see Myopathy/Rhabdomyolysis under Precautions).
Other interactions: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250-ml glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, because larger quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during simvastatin therapy (see Myopathy/Rhabdomyolysis under Precautions).
Coumarin Derivatives: 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. In patients taking coumarin anticoagulants, 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.

Storage

Action

Dyslipidaemic Agents