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| __NOTOC__
| | #REDIRECT [[Simvastatin#Warnings]] |
| {{Simvastatin}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Warnings and Precautions==
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| ===Myopathy/Rhabdomyolysis===
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| 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.
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| The risk of [[myopathy]], including [[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% and 0.08% at 20 and 40 mg/day, respectively. The incidence of [[myopathy]] with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
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| In a clinical trial in which 12,064 patients with a history of [[myocardial infarction]] were treated with ZOCOR (mean follow-up 6.7 years), the incidence of [[myopathy]] (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of [[rhabdomyolysis]] (defined as [[myopathy]] with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of [[myopathy]], including [[rhabdomyolysis]], was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
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| The risk of [[myopathy]], including [[rhabdomyolysis]], is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of ZOCOR should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. If, however, a patient who is currently tolerating the 80-mg dose of ZOCOR needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of [[myopathy]], including [[rhabdomyolysis]], and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2).]
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| There have been 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.
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| All patients starting therapy with ZOCOR, or whose dose of ZOCOR is being increased, should be advised of the risk of [[myopathy]], including [[rhabdomyolysis]], and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ZOCOR. ZOCOR therapy should be discontinued immediately if [[myopathy]] is diagnosed or suspected. 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 ZOCOR or whose dose is being increased, but there is no assurance that such monitoring will prevent [[myopathy]].
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| 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. ZOCOR therapy should be discontinued if markedly elevated CPK levels occur or [[myopathy]] is diagnosed or suspected. ZOCOR 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]].
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| ====Drug Interactions====
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| The risk of [[myopathy]] and [[rhabdomyolysis]] is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of [[myopathy]]. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or grapefruit juice [see Clinical Pharmacology (12.3)]. Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See Contraindications (4) andDrug Interactions (7.1).]
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| The combined use of simvastatin with [[gemfibrozil]], [[cyclosporine]], or [[danazol]] is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].
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| Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause [[myopathy]] when given alone and the risk is increased when they are co-administered [see Drug Interactions (7.2)].
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| Cases of [[myopathy]], including [[rhabdomyolysis]], have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7)].
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| The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates, ≥1 g/day of [[niacin]], or, for patients with HoFH, [[lomitapide]]), [[amiodarone]], [[dronedarone]], [[verapamil]], [[diltiazem]], [[amlodipine]], or [[ranolazine]] [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3)] [also see Dosage and Administration, Patients with Homozygous Familial Hypercholesterolemia (2.4)].
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| Cases of [[myopathy]], including [[rhabdomyolysis]], have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day [[niacin]]) of [[niacin]]-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of [[myopathy]] is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a [[niacin]]-containing product. Caution should be used when treating Chinese patients with simvastatin in 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. It is unknown if the risk for [[myopathy]] with coadministration of simvastatin with lipid-modifying doses of [[niacin]]-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4)].
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| Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3, 2.4), Drug Interactions (7), Clinical Pharmacology (12.3)].
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| {|
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| |[[File:simvastatin01.jpg|thumb|800px]]
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| ===Liver Dysfunction===
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| 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]].
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| In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)], 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%]). 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 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 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. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
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| In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.
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| 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 ZOCOR, promptly interrupt therapy. If an alternate etiology is not found do not restart ZOCOR. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate [[myopathy]] [see Warnings and Precautions (5.1)].
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| 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.
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| 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.
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| ====Endocrine Function====
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| Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including ZOCOR.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = ZOCOR (SIMVASTATIN) TABLET, FILM COATED [MERCK SHARP & DOHME CORP.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fdbfe194-b845-42c5-bb87-a48118bc72e7 | publisher = | date = | accessdate = 18 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| {{Statins}}
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| {{Merck&Co}}
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| [[Category:Alcohols]] | | [[Category:Alcohols]] |