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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 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 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 ZOCOR should only be used in patients who have been taking this dose for 12 months or more without evidence of muscle toxicity; and should not be started in new patients, including patients already taking lower doses of the drug. 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; 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 Side Effects). 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 Drugs: 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; Actions.)
Gemfibrozil, cyclosporine or danazol: Concomitant use of these drugs with simvastatin is contraindicated. (See Contraindications; 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; 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 10 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 20 mg daily in patients receiving concomitant medication with amlodipine.
Ranolazine: The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with ranolazine.
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 the Transport Protein OATP1B1 (Organic anion-transporting polypeptide [1B1]): 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 Myopathy/Rhabdomyolysis as previously mentioned; Contraindications).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Simvastatin is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. 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 should be considered depending on the prescribed dose. 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 coadministered with lipid-modifying doses (≥1 g/day) of niacin. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with niacin (nicotinic acid) ≥ 1 g/day. 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, and because the incidence of myopathy is higher in Chinese than in non-Chinese patients, coadministration 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 ZOCOR temporarily in patients taking daptomycin (see Other drug interactions under Interactions).
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine. Caution should be exercised when prescribing simvastatin with colchicine.
Avoid grapefruit juice when taking ZOCOR.
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 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 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 ZOCOR, promptly interrupt therapy. If an alternate etiology is not found, do not restart 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 Pregnancy & Lactation: See USE IN PREGNANCY & LACTATION section for further information.
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; Side Effects.) Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy (see Contraindications; 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.
