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Muscle Effects: Simvastatin and other inhibitors of HMG-CoA reductase occasionally causes myopathy, which is manifested as muscle pain or weakness associated with grossly elevated creatine phosphokinase (CPK) [>10 times the upper limit of normal (ULN)]. Rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria, has been reported rarely. In the Scandinavian Simvastatin Survival Study, there was 1 case of myopathy among 1399 patients taking 20 mg and no cases among 822 patients taking 40 mg daily for a median duration of 5.4 years. In two 6-months controlled clinical trials, there was 1 case of myopathy among 436 patients taking 40 mg and 5 cases among 669 patients taking 80 mg. The risk of myopathy is increased by concomitant therapy with certain drugs, some of which were excluded by the designs of these studies.
Myopathy Caused by Drug Interactions: The incidence and severity of myopathy are increased by concomitant administration of HMG-CoA reductase inhibitors with drugs that can cause myopathy when given alone eg, gemfibrozil and other fibrates and lipid-lowering doses (1 g/day) of niacin (nicotinic acid). In addition, the risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Simvastatin and other HMG-CoA reductase inhibitors are metabolised by the cytochrome P-450 isoform 3A4 (CYP3A4). Certain drugs that have a significant inhibitory effect at therapeutic doses on this metabolic pathway can substantially raise the plasma levels of HMG-CoA reductase inhibitors and thus increase the risk of myopathy. These include cyclosporin, the azole antifungals eg, itraconazole and ketoconazole, the macrolide antibiotics, erythromycin and clarithromycin, HIV protease inhibitors and antidepressant nefazodone.
Reducing the Risk of Myopathy: General Measures: Patients starting therapy with simvastatin should be advised of the risk of myopathy and told to report promptly unexplained muscle pain, tenderness or weakness. A CPK level >10 times ULN in a patient with unexpected muscle symptoms indicates myopathy. Simvastatin therapy should be discontinued from treatment, muscle symptoms and CPK increases resolved.
Of the patient with rhabdomyolysis, many had complicated medical histories. Some had preexisting renal insufficiency, usually as a consequence of long-standing diabetes. In such patients, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with simvastatin should be stopped a few days before elective major surgery and when any major acute medical or surgical condition supervenes.
Measures to Reduce the Risk of Myopathy Caused by Drug Interactions: Physicians contemplating combined therapy with simvastatin and any of the interacting drugs should weigh the potential benefits and risks, and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness or weakness, particularly during the initial month of therapy and during any periods of upward dosage titration of either drug. Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy.
The combined use of simvastatin with fibrates or niacin should be avoided unless the benefit of further alteration in lipid levels outweigh the increased risk of this drug combination. Combinations of fibrates or niacin with low doses of simvastatin have been used without myopathy in small, short-term clinical trials with careful monitoring. Addition of these drugs must be used with simvastatin; clinical experience suggests that the risk of myopathy is less than that with the fibrates.
In patients taking concomitant cyclosporin, fibrates or niacin, the dose of simvastatin should generally not exceed 10 mg/day (see Dosage & Administration) as the risk of myopathy increases substantially at higher doses. Concomitant use of simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors or nefazodone is not recommended. If no alternative to a short course of treatment with itraconazole, ketoconazole, erythromycin, clarithromycin is available, a brief suspension of simvastatin therapy can be considered, as there are no known adverse consequences to brief interruption of long-term cholesterol-lowering therapy. Concomitant use with other medicines labelled as having the potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
Hypertriglyceridaemia: Although Corstat has a triglyceride-lowering effect, it is not indicated where hypertriglyceridaemia is the abnormality of most concern (ie, hyperlipidaemia types I, IV and V).
Hepatic Effects: Minor asymptomatic transient rises in serum transaminases may occur soon after initiation of therapy with simvastatin which do not require Corstat to be discontinued. There is no evidence that these changes are due to hypersensitivity to Corstat.
In the Scandinavian Simvastatin Survival, the number of patients with ≥1 transaminase elevation to >3 times the upper limit of normal, over the course of the study, was not significantly different between the simvastatin and placebo groups [14 (0.7%) vs 12 (0.6%)], the number of patients with single elevations of SGPT (ALT) to 3 times the upper limit of normal was significantly higher in the transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2221) and 5 in the placebo group (n=2223). Of the 1986 simvastatin-treated patients in 4S with normal liver function tests (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to >3 times the upper limit of normal 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 1105 patients, the 6-month incidence of persistent hepatic transaminase elevations was 0.7% and 1.8% at the 40- and 80-mg dose, respectively.
It is recommended that liver function tests be performed before treatment begins and periodically thereafter (eg, twice a year) for the 1'st year of treatment or until 1 year after the last elevation in dose in all patients. Patients titrated to the 80-mg dose should receive an additional test at 3 months. 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 3 times the upper limit of normal and are persistent, Corstat should be discontinued.
Corstat 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.
Ophthalmic Examination: In the absence of any drug therapy, an increase in the prevalence of lens opacities with time is expected as a result of ageing. Current long-term data from clinical trials do not indicate an adverse effect of simvastatin on the human lens.
Effects on the Ability to Drive or Operate Machinery: Not applicable.
Use in pregnancy: Corstat is contraindicated in pregnancy (see Contraindications).
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidaemia. Moreover, cholesterol and other products of cholesterol biosynthesis pathway are essential components for foetal development during, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase eg, Corstat to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway. Corstat is contraindicated for use in pregnancy and women of child bearing potential unless such patient are highly unlikely to conceive or such patients are adequately protected by nonhormonal methods. An interval of 1 month should elapse between the end of therapy with Corstat and planned conception. If the patient becomes pregnant while taking simvastatin, Corstat should be discontinued immediately and the patient apprised of the potential hazard to the foetus.
The active metabolite of simvastatin was shown to produce foetal malformation in the offspring of pregnant rats. A few reports have been received of congenital anomalies in infants whose mothers were treated during pregnancy with HMG-CoA reductase inhibitors.
In a review of approximately 100 prospectively followed pregnancies in women exposed to Corstat or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies are expected in the general population. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Corstat during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognised.
Use in lactation: It is not yet known whether simvastatin or its metabolites are excreted in human milk. Corstat should be avoided during lactation.
Use in children: Safety and effectiveness in children have not been established. Corstat is not recommended for paediatric use at this time.
