Pharmacological properties
Pharmacodynamics. After oral administration, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to form the corresponding β-hydroxyacid derivative, which has high inhibitory activity against HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase) - an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the initial and most significant stage of xc biosynthesis.
Simvastatin has been shown to reduce normal and elevated LDL-C levels. LDL is formed from VLDL and is catabolized primarily by high-affinity LDL receptors. The mechanism of the LDL-lowering effect of simvastatin may consist of either a reduction in VLDL-C concentrations or stimulation of LDL receptors, resulting in decreased production and increased catabolism of LDL-C. Apolipoprotein B levels are also significantly reduced during simvastatin treatment. In addition, simvastatin markedly increases HDL-C and reduces plasma TG levels. As a result of these changes, the ratio of total cholesterol to HDL-C and LDL-C to HDL-C is reduced.
Pharmacokinetics. Simvastatin is an inactive lactone that is readily hydrolyzed in vivo to β-hydroxyacids, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs primarily in the liver, and the rate of hydrolysis in human plasma is very low.
Pharmacokinetic properties were evaluated in adults. Pharmacokinetic data in children and adolescents are not available.
Absorption. Simvastatin is well absorbed in humans and undergoes extensive first-pass hepatic metabolism. Hepatic clearance is dependent on hepatic blood flow. The liver is the primary site of action for the active form. The systemic availability of β-hydroxyacid following an oral dose of simvastatin has been shown to be 5% of the dose. Cmax of active inhibitors in plasma is achieved approximately 1-2 hours after administration of simvastatin. Concomitant food intake does not affect absorption. Single- and multiple-dose pharmacokinetics of simvastatin have shown that there is no accumulation of the drug following multiple dosing.
Distribution: The binding of simvastatin and its active metabolite to plasma proteins is 95%.
Elimination. Simvastatin is a substrate of CYP 3A4 (see Adverse Effects, Interactions). The major metabolites of simvastatin in human plasma are β-hydroxyacid and 4 additional active metabolites. After oral administration of radioactive simvastatin to humans, 60% of the labeled drug was excreted in the feces and 13% in the urine within 96 hours. The amount recovered in the feces represents the equivalent absorbed drug excreted in the bile, as well as unabsorbed drug. After intravenous injection of the β-hydroxyacid metabolite, its T½ averages 1.9 hours. Only 0.3% of the dose is excreted in the urine in the form of inhibitors.
Simvastatin acid is actively taken up by hepatocytes via the OATP1B1 transporter.
SLCO1B1 polymorphism. Carriers of the c.521TC allele of the SLCO1B1 gene have reduced OATP1B1 protein activity. The mean exposure (AUC) of the main active metabolite, simvastatin acid, is 120% in heterozygous carriers (CT) of the C allele and 221% in homozygous (CC) carriers compared to patients with the most common genotype (TT). The C allele is found in the European population with a frequency of 18%, while the homozygous CC genotype is found with a frequency of 1.5%. Patients with a polymorphism of the SLCO1B1 gene are at risk of increased exposure to simvastatin acid, which may lead to an increased risk of rhabdomyolysis (see Precautions).
Indication
Hypercholesterolemia. Treatment of primary hypercholesterolemia or mixed dyslipidemia as an adjunct to diet when the response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.
Treatment of homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (e.g. low-density lipid apheresis) or when such treatments are inappropriate.
Cardiovascular prevention. Reduction of the risk of mortality in patients with cardiovascular disease and morbidity in patients with overt atherosclerotic cardiovascular disease or diabetes mellitus with normal or elevated cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy.
Application
The dosage range of the drug is 5-80 mg orally once a day in the evening. The dose of the drug should be adjusted, if necessary, at intervals of at least 4 weeks until the maximum daily dose of 80 mg is reached, which should be taken once a day in the evening. The dose of 80 mg is recommended only for patients with severe hypercholesterolemia and a high risk of developing cardiovascular complications, in whom the necessary results are not achieved with the use of lower doses, and when the expected benefits outweigh the potential risks (see special instructions).
Homozygous familial hypercholesterolemia. The recommended starting dose of simvastatin is 40 mg/day taken once in the evening. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
Cardiovascular prevention. The usual dose of simvastatin for patients at high risk of developing coronary heart disease (with or without hyperlipidemia) is 20-40 mg/day taken once in the evening. Drug therapy can be administered concurrently with diet and exercise. Dose titration, if necessary, should be performed as described above.
Concomitant therapy. Simvastatin is effective as monotherapy, as well as in combination with bile acid sequestrants. The drug should be administered no later than 2 hours before or no earlier than 4 hours after taking bile acid sequestrants.
For patients taking simvastatin concomitantly with fibrates, except gemfibrozil (see Adverse Reactions), or with fenofibrate, the dose of simvastatin should not exceed 10 mg/day. For patients taking simvastatin concomitantly with amiodarone, amlodipine, verapamil, or diltiazem, the daily dose of simvastatin should not exceed 20 mg (see Precautions, Interactions).
Dosage in renal impairment. No dosage adjustment is necessary in patients with moderate renal impairment. In patients with severe renal impairment (creatinine clearance 30 ml/min), doses above 10 mg/day should be carefully considered and, if deemed necessary, should be used with caution.
Use in elderly patients. No dose adjustment is necessary.
Use in children (10-17 years of age). For children (boys Tanner stage II and older and girls who have had a menstrual cycle for at least 1 year) aged 10-17 years with heterozygous familial hypercholesterolemia, the recommended usual starting dose is 10 mg once daily in the evening. Before initiating treatment with simvastatin, children should be placed on a standard cholesterol-lowering diet and should continue on simvastatin during treatment.
Recommended doses are 10-40 mg/day; the maximum recommended dose is 40 mg/day. The dose should be selected individually, depending on the goal of therapy and in accordance with the recommendations for treatment in pediatrics (see Features of use). Dose selection should be carried out at intervals of 4 weeks or more.
Experience with the use of simvastatin in prepubertal children is limited.
Children. The safety and efficacy of simvastatin in children aged 10 to 17 years with heterozygous familial hyperlipidemia were evaluated in a controlled clinical trial in boys of Tanner stage II and older and girls who had been menstruating for at least 1 year. The adverse reaction profile in patients treated with simvastatin was generally similar to that in patients treated with placebo. Doses greater than 40 mg have not been studied in this patient population. This study did not report any effects of simvastatin on growth or puberty in children or on menstrual cycle length in girls (see USAGE, Adverse Reactions).
Girls should be counseled about available contraceptive methods during treatment with simvastatin (see Adverse Reactions, Use During Pregnancy or Lactation). In patients under 18 years of age, efficacy and safety have not been studied for treatment periods longer than 48 weeks; long-term effects on physical, intellectual, and sexual development are unknown.
Simvastatin has not been studied in patients under 10 years of age, in prepubertal children, or in premenstrual girls.
Contraindication
Hypersensitivity to simvastatin or any component of this drug; acute liver disease or unexplained persistent elevations of plasma transaminases; concomitant use of potent CYP 3A4 inhibitors (drugs that increase AUC by approximately 5-fold or more) such as itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone (see special instructions and interactions); concomitant use of gemfibrozil, cyclosporine or danazol.
Side effects
The frequency of adverse reactions is indicated as very common (1/10), common (≥1/100, 1/10), uncommon (≥1/1000, 1/100), rare (≥1/10,000, 1/1000), very rare (1/10,000), unknown (cannot be determined based on available data).
From the blood and lymphatic system: rarely - anemia.
From the psyche: very rarely - insomnia; unknown - depression.
From the nervous system: rarely - headache, paresthesia, dizziness, peripheral neuropathy; very rarely - memory impairment.
From the respiratory tract, thoracic organs and mediastinum: unknown - interstitial lung disease (see Features of use).
From the digestive system: rarely - constipation, abdominal pain, flatulence, dyspepsia, diarrhea, nausea, vomiting, pancreatitis.
Hepatobiliary tract: rarely - hepatitis/jaundice; very rarely - fatal and non-fatal liver failure.
Musculoskeletal and connective tissue disorders: rarely - myopathy (including myositis), rhabdomyolysis with or without acute renal failure (see Precautions), muscle pain, muscle spasms; not known - tendinopathy, sometimes complicated by rupture.
Reproductive system and breast disorders: not known - erectile dysfunction.
General disorders and administration-related disorders: rarely - asthenia.
Hypersensitivity syndrome has been reported rarely and includes the following conditions: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnea, and malaise.
Effect on laboratory test results: rarely - increased levels of transaminases in blood plasma (AST, ALT and gamma-glutamyl transpeptidase) (see Features of use, effect on the liver); increased levels of LF; increased levels of creatine kinase (see Features of use).
Increases in HbA1c and fasting plasma glucose have been reported with the use of statins, including simvastatin.
There have been reports of cognitive impairment (e.g. memory loss, forgetfulness, memory impairment, confusion) associated with the use of statins, including simvastatin. In general, the cases were mild and reversible, and resolved after discontinuation of the statin.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use, has been reported very rarely. IMMNM is characterized by proximal muscle weakness and elevated plasma creatine kinase that persist despite discontinuation of statins; evidence of necrotizing myopathy on muscle biopsy without significant inflammation; and improvement after immunosuppressive therapy.
The following additional side effects have been reported with some statins: sleep disorders, including nightmares; sexual dysfunction; diabetes mellitus: the frequency of occurrence depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/l, body mass index 30 kg/m2, elevated TG, history of hypertension).
Special instructions
Myopathy/rhabdomyolysis. Simvastatin, like other HMG-CoA reductase inhibitors, can cause myopathy, characterized by muscle pain, tenderness, or weakness, accompanied by an increase in creatine kinase activity to more than 10 times the upper limit of normal. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure due to myoglobinuria; very rarely, fatalities have been reported. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose-dependent.
In patients taking simvastatin at a dose of 80 mg, the risk of myopathy is higher than with other statins with similar efficacy in lowering LDL-C. Therefore, simvastatin at a dose of 80 mg should be used only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications who have not achieved a therapeutic effect with the use of lower doses, and also if the expected benefits outweigh the potential risks. For patients taking simvastatin at a dose of 80 mg who require the appointment of a drug that interacts with simvastatin, a lower dose of simvastatin should be used or an alternative statin with a less pronounced potential for interaction with other drugs should be prescribed (see Measures to reduce the risk of myopathy due to drug interactions).
Reduced function of transport proteins. Reduced function of hepatic transport proteins of the OATP family may increase systemic exposure to simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function may occur as a result of inhibition by interacting agents (e.g., cyclosporine) or in patients who are carriers of the SLCO1B1 (p.521T C) genotype.
Patients carrying the SLCO1B1 gene allele (c.521T C), which encodes a less active OATP1B1 protein, have increased systemic exposure to simvastatin acid and an increased risk of myopathy. Without genetic testing, the overall risk of myopathy associated with high doses (80 mg) of simvastatin is approximately 1%.
The results of the SEARCH study show that homozygous carriers of the C allele (designated as SS) taking simvastatin at a dose of 80 mg have a 15% risk of developing myopathy within a year, while the risk in heterozygous carriers of the C allele (ST) is 1.5%.
Creatine kinase measurement. Creatine kinase should not be measured after strenuous exercise or in the presence of any possible alternative causes for elevated creatine kinase, as this makes interpretation of the results difficult. If creatine kinase levels are significantly elevated at baseline (more than 5 times the upper limit of normal), a repeat test should be performed in 5 to 7 days to confirm the results.
Before starting treatment. All patients starting treatment with simvastatin or increasing the dose of simvastatin should be informed of the risk of myopathy and of the need to seek immediate medical attention if unexplained muscle pain, tenderness or weakness occurs.
The drug should be used with caution in patients with predisposing factors for rhabdomyolysis. In order to establish a baseline value, creatine kinase levels should be determined before starting treatment in the following cases:
advanced age (≥65 years); female gender; impaired renal function; uncontrolled hypothyroidism; personal or family history of hereditary muscle disorders; history of muscle toxicity with statins or fibrates; alcohol abuse.
In such situations, the risk of treatment should be weighed against the potential benefit, and clinical monitoring is recommended. If a patient has previously experienced muscle disorders during treatment with fibrates or statins, treatment with different drugs of this class should be initiated with caution.
If baseline creatine kinase levels are significantly elevated (more than 5 times the upper limit of normal), treatment should not be initiated.
During treatment. If a patient experiences pain, weakness or cramps while taking a statin, creatine kinase levels should be checked. If, in the absence of strenuous exercise, these levels are found to be significantly elevated (more than 5 times the upper limit of normal), treatment should be discontinued. If symptoms are severe and cause daily discomfort, even if creatine kinase levels are less than 5 times the upper limit of normal, discontinuation of treatment should be considered. If myopathy is suspected for any other reason, treatment should be discontinued.
If symptoms resolve and creatine kinase levels return to normal, consideration may be given to reintroducing a statin or an alternative statin at the lowest dose and under close monitoring.
Myopathy is most commonly seen in patients who have had their dose increased to 80 mg. Periodic monitoring of creatine kinase levels is recommended as this may help to detect subclinical cases of myopathy. However, such monitoring may not always prevent the development of myopathy.
Treatment with simvastatin should be temporarily discontinued a few days before scheduled major surgery, as well as after medical or surgical interventions.
Measures to reduce the risk of myopathy due to drug interactions (see Interactions with other drugs). The risk of myopathy and rhabdomyolysis is significantly increased when simvastatin is used concomitantly with potent CYP 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, as well as gemfibrozil, cyclosporine and danazol. The use of these drugs is contraindicated (see Adverse Reactions).
The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, verapamil, or diltiazem with certain doses of simvastatin (see USAGE, Interactions). The risk of myopathy, including rhabdomyolysis, may be increased by concomitant use of fusidic acid and statins (see Interactions with other drugs).
Therefore, regarding CYP 3A4 inhibitors, the use of simvastatin with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see Adverse Reactions, Interactions). If therapy with potent CYP 3A4 inhibitors (drugs that increase AUC by approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be discontinued for the duration of these drugs (or an alternative statin should be considered). Furthermore, caution should be exercised when simvastatin is administered in combination with some other less potent CYP 3A4 inhibitors: fluconazole, verapamil, diltiazem (see Interactions with other drugs). Concomitant administration of grapefruit juice and simvastatin should be avoided.
Simvastatin should not be used concomitantly with fusidic acid. Rhabdomyolysis (including some fatalities) has been reported in patients receiving this combination (see Interactions with other medicinal products and other forms of interaction). In patients requiring systemic fusidic acid, simvastatin should be discontinued for the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if any symptoms such as muscle weakness, pain or tenderness occur. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid therapy is required, e.g. for the treatment of severe infections, the need for concomitant use of simvastatin and fusidic acid should only be considered on an individual basis and under close medical supervision.
The combined use of simvastatin at doses exceeding 20 mg/day with amiodarone, amlodipine, verapamil, or diltiazem should be avoided (see USAGE, Interactions).
Patients taking other drugs that have a moderate inhibitory effect on CYP 3A4, concomitantly with simvastatin, especially with high doses of simvastatin, may be at increased risk of developing myopathy. When simvastatin is used concomitantly with a moderate inhibitor of CYP 3A4 (drugs that increase AUC approximately 2-5 times), a dose adjustment of simvastatin may be necessary. For some moderate inhibitors of CYP 3A4, such as diltiazem, a maximum dose of 20 mg of simvastatin is recommended (see Dosage & Administration).
Rare cases of myopathy/rhabdomyolysis have been associated with the concomitant use of HMG-CoA reductase inhibitors and niacin (nicotinic acid) at lipid-modifying doses (≥1 g/day); the use of either drug alone may cause myopathy.
Physicians considering combination therapy with simvastatin and lipid-modifying doses of niacin (nicotinic acid) (≥1 g/day) or other niacin-containing drugs should carefully consider the potential benefits and risks and monitor patients closely for signs or symptoms of muscle pain, tenderness, or weakness, especially during the first months of treatment and when the dose of either drug is increased.
Caution should be exercised when simvastatin (especially at doses of 40 mg or higher) is administered concomitantly with lipid-modifying doses of niacin (nicotinic acid) (≥1 g/day) or niacin-containing products. Since the risk of myopathy with statins is dose-dependent, simvastatin 80 mg should not be administered concomitantly with lipid-modifying doses of niacin (nicotinic acid) (≥1 g/day) or niacin-containing products in patients of Chinese ethnicity. It is not known whether the risk of myopathy is increased in other patients of Mongoloid race when simvastatin is administered concomitantly with lipid-modifying doses of niacin (nicotinic acid) (≥1 g/day) or niacin-containing products.
Liver Effects: Persistent elevations of serum transaminases (greater than 3 times the upper limit of normal) have been observed in a few adult patients receiving simvastatin. Transaminase levels generally slowly returned to baseline after temporary interruption or discontinuation of simvastatin.
It is recommended to check liver function tests before starting treatment and, if clinically indicated, during treatment. Patients who are planning to increase the dose to 80 mg/day should have additional tests performed before the dose increase, 3 months after the increase to 80 mg and then periodically (e.g. every 6 months) during the first year of treatment. Particular attention should be paid to patients who develop elevated plasma transaminase levels. In such patients, liver function tests should be repeated promptly and more frequently thereafter.
If transaminase levels continue to rise, particularly to 3 times the upper limit of normal, and are persistent, simvastatin should be discontinued. It should be remembered that ALT levels may vary with the state of the muscular system, so an increase in ALT and creatine kinase may indicate myopathy.
Rare cases of fatal and non-fatal hepatic failure have been reported in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, therapy should be discontinued immediately. Unless an alternative etiology is identified, the drug should not be restarted.
The drug should be used with caution in patients who abuse alcohol.
Diabetes mellitus. Some evidence suggests that statins as a class increase blood glucose levels and in some patients at high risk of future diabetes mellitus may cause an increase in blood glucose levels in which treatment of diabetes mellitus is recommended. However, the benefit of reducing the risk of developing cardiovascular disease with statins outweighs this risk and should not be a reason to discontinue treatment. There is evidence for periodic clinical and biochemical monitoring of glycemia in patients at risk (fasting glucose 5.6-6.9 mmol/L, body mass index 30 kg/m2, elevated TG, hypertension) in accordance with current guidelines.
Interstitial lung disease. Cases of interstitial lung disease have been reported with some statins, including simvastatin, particularly with long-term therapy. Manifestations may include dyspnea, nonproductive cough, and worsening of general condition (fatigue, weight loss, and fever). If a patient is suspected of developing interstitial lung disease, statin treatment should be discontinued.
Ophthalmological examination. In the absence of any medical treatment, an increase in the area of lens opacities is considered a consequence of the aging process. Currently available data do not indicate a harmful effect of simvastatin on the human lens.
Use in the Elderly. The efficacy of simvastatin in the treatment of patients over 65 years of age treated in controlled clinical trials was evaluated in terms of reducing total and LDL-cholesterol levels and was similar to that in the general population. There was no increase in the incidence of adverse events, either clinically or by laboratory parameters.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy. Simvastatin is contraindicated during pregnancy, as the safety of the drug in pregnant women has not been established. Controlled clinical studies involving pregnant women have not been conducted. Rarely, congenital malformations have been reported following intrauterine exposure to HMG-CoA reductase inhibitors. However, in a follow-up analysis of approximately 200 pregnant women exposed to simvastatin or other similar HMG-CoA reductase inhibitors during the first trimester of pregnancy, the incidence of congenital malformations was comparable to that in the general population. The number of pregnancies observed was statistically sufficient to exclude an increase in the incidence of congenital malformations of 2.5 or more times the baseline.
Although there is no evidence that the incidence of congenital malformations in children of patients treated with simvastatin or other similar HMG-CoA reductase inhibitors differs from that in the general population, maternal treatment with simvastatin may be associated with a decrease in fetal levels of mevalonate, a precursor for cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy usually has little effect on the long-term risk associated with primary hypercholesterolemia. For these reasons, simvastatin should not be prescribed to pregnant women, to women planning to become pregnant, or to women suspected of being pregnant. Treatment with simvastatin should be suspended for the duration of pregnancy or until pregnancy has been confirmed.
Breastfeeding. It is not known whether simvastatin and its metabolites are excreted in human milk. Because a significant amount of drugs are excreted in human milk and because of the high risk of serious adverse reactions, women taking simvastatin should not breast-feed.
Ability to influence the speed of reactions when driving vehicles or using other mechanisms. Simvastatin has no or negligible influence on the ability to drive vehicles and mechanisms. However, when driving vehicles or using other mechanisms, it should be taken into account that dizziness has been rarely reported during post-marketing studies.
Interactions
Interaction studies were conducted only with the participation of adults.
pharmacodynamic interaction
Pharmacokinetic interaction. The table below summarizes recommendations for prescribing interacting drugs (see USAGE, Contraindications, Special Precautions for Use).
Interaction with other drugs associated with an increased risk of myopathy/rhabdomyolysis
| Drug interactions | relevant recommendations |
| Potent CYP 3A4 inhibitors, such as: itraconazole ketoconazole Posaconazole voriconazole erythromycin clarithromycin telithromycin HIV protease inhibitors (e.g. nelfinavir) boceprevir telaprevir nefazodone cyclosporine danazol gemfibrozil | Contraindicated when using simvastatin |
| Other fibrates (excluding fenofibrate) | Do not exceed a dose of 10 mg of simvastatin per day. |
| fusidic acid | Not recommended with simvastatin |
| amiodarone amlodipine verapamil diltiazem | Do not exceed a dose of 20 mg of simvastatin per day. |
| Grapefruit juice | Avoid drinking grapefruit juice when taking simvastatin. |
|
Effects of other medicinal products on simvastatin
Interaction with CYP 3A4 inhibitors. Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing plasma concentrations of HMG-CoA reductase inhibitory activity during simvastatin treatment. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir and nefazodone. Concomitant use of itraconazole results in a greater than 10-fold increase in exposure to simvastatin acid (the active β-hydroxyacid metabolite). Telithromycin results in an 11-fold increase in exposure to simvastatin acid.
Combinations with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone, as well as gemfibrozil, cyclosporine and danazol are contraindicated (see Adverse Reactions). If therapy with potent CYP 3A4 inhibitors (drugs that increase AUC by approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be discontinued for the duration of these drugs. Simvastatin should be administered with caution in combination with other less potent CYP 3A4 inhibitors: fluconazole, verapamil or diltiazem (see USAGE, Special Precautions for Use).
Fluconazole: Rhabdomyolysis has been reported rarely in association with the concomitant use of fluconazole and simvastatin.
Cyclosporine: The risk of myopathy/rhabdomyolysis is increased when cyclosporine is used concomitantly with simvastatin, therefore use with cyclosporine is contraindicated.
