Priacin

Simvastatin.

Each tablet also contains the following excipients: Core: Lactose monohydrate, pregelatinised starch, microcrystalline cellulose, butylated hydroxyanisole, ascorbic acid, citric acid monohydrate, magnesium stearate and purified water. Coating: Hydroxypropylmethyl cellulose, hydroxypropyl cellulose, titanium dioxide (E171), talc and red iron oxide (E172).
Priacin 10 mg and 20 mg  also contains yellow iron oxide (E172).

Pharmacotherapeutic Group: HMG-CoA reductase inhibitor. ATC Code: C10A A01.
Pharmacology: Pharmacodynamics: After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active β-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin has been shown to reduce both normal and elevated low-density lipoprotein cholesterol (LDL-C) concentrations. Low-density lipoprotein (LDL) is formed from very low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B (apo B) also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases high-density lipoprotein cholesterol (HDL-C) and reduces plasma triglycerides (TG). As a result of these changes, the ratios of total- to HDL-C and LDL- to HDL-C are reduced.
High Risk or Existing Coronary Heart Disease (CHD): In the heart protection study (HPS), the effects of therapy with Priacin were assessed in 20,536 patients (40-80 years), with or without hyperlipidaemia and with CHD other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6793 patients (33%) had LDL-C levels <116 mg/dL; 5063 patients (25%) had levels between 116 mg/dL and 135 mg/dL and 8680 patients (42%) had levels >135 mg/dL.
Treatment with Priacin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality [1328 (12.9%) for simvastatin-treated patients versus 1507 (14.7%) for patients given with placebo; p=0.0003], due to an 18% reduction in coronary death rate [587 (5.7%) versus 707 (6.9%); p=0.0005; absolute risk reduction of 1.2%]. The reduction in nonvascular deaths did not reach statistical significance. Priacin also decreased the risk of major coronary events [a composite endpoint comprised of nonfatal myocardial infarction (MI) or CHD death] by 27% (p<0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30% (p<0.0001) and 16% (p=0.006), respectively. Simvastatin reduced the risk of stroke by 25% (p<0.0001), attributable to a 30% reduction in ischemic stroke (p<0.0001). In addition, within the subgroup of patients with diabetes, simvastatin reduced the risk of developing macrovascular complications including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations or leg ulcers by 21% (p=0.0293). The proportional reduction in event rate was similar in each subgroup of patients studies, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women those aged either under or >70 years at entry into the study, presence or absence of hypertension and notably those with LDL-C <3 mmol/L at inclusion.
In the Scandinavian simvastatin survival study (4S), the effect of therapy with simvastatin on total mortality was assessed in 4444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients with angina or a previous MI were treated with diet, standard care and either simvastatin 20-40 mg/day (n=2221) or placebo (n=2223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30% (absolute risk reduction of 3.3%). The risk of CHD death was reduced by 42% (absolute risk reduction on 3.3%). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34%. Furthermore, simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28%. There was no statistically significant difference between groups in noncardiovascular mortality.
Primary Hypercholesterolaemia and Combined Hyperlipidaemia: In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30%, 38%, 41% and 47%, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 and 80 mg the median reduction in triglycerides were 28% and 33% (Placebo: 2%), respectively and mean increases in HDL-C were 13% and 16% (Placebo: 3%), respectively.
Pharmacokinetics: Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.
Absorption: In man, simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be <5% of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hrs after administration of simvastatin. Concomitant food intake does not affect the absorption.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.
Distribution: Both simvastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Elimination: Simvastatin is a substrate of cytochrome P-450 3A4 (CYP3A4) (see Contraindications and Interactions). The major metabolites of simvastatin present in human plasma are the β-hydroxyacid and 4 additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hrs. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile, as well as unabsorbed medicinal product. Following an IV injection of the β-hydroxyacid metabolite, its t_½ averaged 1.9 hrs. An average of only 0.3% of the IV dose was excreted in urine as inhibitors.
Toxicology: Preclinical Safety Data: Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, simvastatin produced no foetal malformations and had no effects on fertility, reproductive function or neonatal development.

Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate.
Patients at High Risk or Existing Coronary Heart Disease (CHD): In patients at high risk of coronary events because of existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, Priacin is indicated to reduce the risk of total mortality by reducing CHD deaths; reduce the risk of nonfatal MI and stroke and reduce the need for coronary and noncoronary revascularization procedures.
In hypercholesterolemic patients with CHD, Priacin slows the progression of coronary atherosclerosis, including reducing the development of new lesions and new total occlusions.
Patients with Hyperlipidemia: Adjunct to diet to reduce elevated total-C, LDL-C, TG and 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. Priacin, therefore, lowers LDL-C/HDL-C and total-C/HDL-C ratios.
Adjunct to diet and other nondietary measures for the treatment of patients with homozygous familial hypercholesterolemia to reduce elevated total-C, LDL-C and apo B.

Dosage Range: 5-80 mg/day, given as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not <4 weeks, to a maximum of 80 mg/day given as a single dose in the evening.
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the 1st year of treatment, use of the 80-mg dose of simvastatin should be restricted to patients who have been taking simvastatin 80 mg chronically (eg, for ≥12 months) without evidence of muscle toxicity. Patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
Patients with High Risk or Existing Coronary Heart Disease (CHD): Patients with CHD can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease have been shown to benefit from 40 mg/day and can be started at this dose.
Patients with Hyperlipidemia (Who are Not in the Risk Categories Previously Specified): The patient should be placed on a standard cholesterol-lowering diet before receiving Priacin and should continue on this diet during treatment with Priacin.
The usual starting dose is 10 mg/day given as a single dose in the evening. Patients who require a reduction in LDL-C (>45%) may be started at 40 mg/day given as a single dose in the evening. 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 is 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg and an evening dose of 40 mg. Priacin should be used as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable.
Concomitant Therapy: Priacin is effective alone or in combination with bile acid sequestrants.
In patients taking cyclosporine, danazol, gemfibrozil, other fibrates (except fenofibrate) concomitantly with Priacin, the dose of Priacin should not exceed 10 mg/day. In patients taking amiodarone or verapamil concomitantly with Priacin, the dose of Priacin should not exceed 20 mg/day. In patients taking diltiazem concomitantly with Priacin, the dose of Priacin should not exceed 40 mg/day. (See Precautions and Interactions.)
Renal Insufficiency: Because Priacin 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 >10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

Hypersensitivity to simvastatin or to any of the other components of Priacin.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and lactation.
Concomitant administration of potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone) and gemfibrozil, cyclosporine or danazol (see Interactions).

Hepatic Effects: In clinical studies, persistent increases [to >3 x upper limit of normal (ULN)] in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.
If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.
It is recommended that liver function tests 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 (eg, semi-annually) for the 1st 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 3 x ULN and are persistent, simvastatin should be discontinued.
The product 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 (3 x 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.
Myopathy/Rhabdomyolysis: Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) >10 x ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and rare fatalities has occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Predisposing factors for myopathy include advanced age (≥65 yrs), female gender, uncontrolled hypothyroidism and renal impairment.
As with other statins, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 yrs, 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 80 mg/day (mean follow-up 6.7 yrs), the incidence of myopathy was approximately 1% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the 1st 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. Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the 1st year of treatment, use of the 80-mg dose of simvastatin should be restricted to patients who have been taking simvastatin 80 mg chronically (eg, for ≥12 months) without evidence of muscle toxicity. Patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C lowering treatment(s) that provides greater LDL-C lowering. 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.
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 yrs), 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.
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid modifying doses (>1 g/day) of niacin. In a clinical trial (median follow-up 3.9 yrs) 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, coadministration of simvastatin with lipid modifying doses (>1 g/day) of niacin is not recommended in Asian patients.
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 x ULN indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. 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.
Prescribing recommendations for interacting agents are summarized in the table. (See table.)

Click on icon to see table/diagram/image

Creatine Kinase Measurement: Creatine Kinase (CK) levels should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (>5 x ULN), levels should be re-measured within 5-7 days later to confirm the results.
Before the Treatment: 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.
Caution should be exercised in patients with predisposing factors for rhabdomyolysis. In order to establish a reference baseline value, CK level should be measured before starting treatment in the following situations: Elderly (>65 years); female gender; renal impairment; uncontrolled hypothyroidism; personal or familial history of hereditary muscular disorders; previous history of muscular toxicity with a statin or fibrate; alcohol abuse.
In such situations, the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (>5 x ULN), treatment should not be started.
While on Treatment: If muscular pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (>5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are <5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.
If symptoms resolve and CK levels return to normal then reintroduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close 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.
Measures to Reduce the Risk of Myopathy Caused by Medicinal Product Interactions (see Interactions): The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), as well as gemfibrozil, ciclosporin and danazol (see Dosage & Administration).
The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, lipid-lowering doses of niacin (≥1 g/day) or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see Dosage & Administration and Interactions). There is also a slight increase in risk when diltiazem or amlodipine is used with simvastatin 80 mg. The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with statins (see Interactions).
Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see Contraindications and Interactions). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: Ciclosporin, verapamil, diltiazem (see Dosage & Administration and Interactions).
Concomitant intake of grapefruit juice and simvastatin should be avoided.
The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol, gemfibrozil or lipid-lowering doses (≥1 g/day) of niacin. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), niacin, ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See Dosage & Administration and Interactions.)
Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.
The combined use of simvastatin at doses >20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see Dosage & Administration and Interactions).
In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of ≥40 mg) co-administered with lipid-modifying doses niacin (nicotinic acid ≥1 g/day) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of simvastatin 80 mg with lipid-modifying doses niacin (nicotinic acid ≥1 g/day) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid-modifying doses niacin (nicotinic acid ≥1 g/day) or products containing niacin.
If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see Interactions). Temporary suspension of simvastatin treatment may be considered.
Excipient: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on the Ability to Drive or Operate Machinery: Priacin has no or negligible influence on the ability to drive and use machines.
However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.
Use in pregnancy: Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the 1st trimester to Priacin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a ≥2.5-fold increase in congenital anomalies over the background incidence. Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Priacin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Priacin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Priacin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Priacin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Use in lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Priacin should not breastfeed their infants.

Use in pregnancy: Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the 1st trimester to Priacin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a ≥2.5-fold increase in congenital anomalies over the background incidence. Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Priacin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Priacin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Priacin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Priacin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Use in lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Priacin should not breastfeed their infants.

The frequencies of the following adverse events which have been reported during clinical studies and/or post-marketing use are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4444 patients, respectively (see Pharmacology: Pharmacodynamics under Actions). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed in the following text were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials and there were similar reasonable causally related spontaneous report events, these adverse events are categorized as rare.
In HPS (see Pharmacology: Pharmacodynamics under Actions) involving 20,536 patients treated with Priacin 40 mg/day (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with simvastatin 40 mg and patients treated with placebo over the mean 5 yrs of the study. Discontinuation rates due to side effects were comparable (4.8% in patients treated with simvastatin 40 mg compared with 5.1% in patients treated with placebo). The incidence of myopathy was <0.1% in patients treated with simvastatin 40 mg. Elevated transaminases (>3 x ULN confirmed by repeat test) occurred in 0.21% (n=21) of patients treated with simvastatin 40 mg compared with 0.09% (n=9) of patients treated with placebo.
The frequencies of adverse events are ranked according to the following: 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) including isolated reports.
Blood and Lymphatic System Disorders: Rare: Anaemia.
Nervous System Disorders: Rare: Headache, paresthesia, dizziness, peripheral neuropathy. There has been rare post-marketing reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Very Rare: Memory impairment.
Gastrointestinal Disorders: Rare: Constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis.
Hepatobiliary Disorders: Rare: Hepatitis/jaundice. Very Rare: Hepatic failure.
Skin and Subcutaneous Tissue Disorders: Rare: Rash, pruritus, alopecia.
Musculoskeletal, Connective Tissue and Bone Disorders: Rare: Myopathy, rhabdomyolysis (see Precautions), myalgia, muscle cramps. Myopathy has been rarely reported.
Psychiatric Disorders: Very Rare: Insomnia.
The following adverse events have been reported with some statins: Sleep disturbances including insomnia and nightmares, sexual dysfunction, depression, exceptional cases of interstitial lung disease especially with long-term therapy (see Precautions).
General Disorders and Administration Site Conditions: Rare: Asthenia.
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: Angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.
Investigations: Rare: Increases in serum transaminases (alanine or aspartate aminotransferase, γ-glutamyl transpeptidase) (see Hepatic Effects under Precautions), alkaline phosphatase; serum CK levels (see Precautions). Increases in HbA1c and fasting serum glucose levels have been reported with statins.

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 (eg, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone) is contraindicated.
Other Drug Interactions: Other Fibrates: The risk of myopathy is increased by gemfibrozil 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.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid.
Calcium Channel Blockers: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem or amlodipine.
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.
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.
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.
Ciclosporin: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see Dosage & Administration and Precautions). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the area under the curve (AUC) of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see Dosage & Administration and Precautions).
Gemfibrozil: Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see Dosage & Administration and Precautions).
Amiodarone and Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with simvastatin (see Precautions). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.
An analysis of the available clinical trials showed an approximately 1% incidence of myopahty in patients receiving simvastain 40 or 80 mg and verapamil. In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy/rhabdomyolysis.
Diltiazem: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem and simvastatin 80 mg (see Precautions). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due, to inhibition of CYP3A4. Therefore, the dose of simvastain should not exceed 40 mg daily in patients receiving concomitant medication with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
Effects of Simvastatin on Pharmacokinetics of Other Medicinal Products: Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.
Oral Anticoagulants: In 2 clinical studies 1 in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as international normalized ration (INR), increased from a baseline of 1.7-1.8 and from 2.6-3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastain 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.
Other Interactions: Grapefruit juice contains ≥1 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 large quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during simvastatin therapy.

Store below 25°C. Protect from moisture and light.

Dyslipidaemic Agents

C10AA01 - simvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

POM