Mosten Simvastatin USP Tablets

MOSTEN® – 20
Simvastatin Tablets USP 20 mg.
COMPOSITION

Each film coated tablet contains:

Simvastatin USP 20mg

Excipients q.s.

 

DESCRIPTION

Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, Is hydrolyzed to the corresponding (beta)-hydroxyacid form. This is an inhibitor of 3-hydroxy-3- methyl-gutaryl-coenzyme A(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin is butanoic acid, 2,2-dimethyl-1,2,3,7,8,8a-hexahydro-3,7- dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2- yl)ethyl]-1-naphthalenyl ester, [1 S -(1(alpha),3(alpha), 7(beta), 8(beta)(2 S* ,4 S*),8a(beta)]]. 2,2-Dimethylbutyricacid, 8-ester with (4R,6R)-6-2-((1S,2S,6R,8S, 8(aIpha) R)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6- dimethyl-1-naphthyqethyl]tetrahydro-4-hydroxy-2H-pyran-2-one -[79902-63-9]. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57.

 

PHARMACOLOGY

The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemlological studies have established that high LDL-C, low high-density lipoprotein cholesterol (HDL-C), and high plasma triglycerides (TG) are risk factors for coronary heart disease (CHD). Cholesterol-enriched TG-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C and small LDL particles, as well as in association with non-lipid metabolic risk factors for CHD. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Simvastatin may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apolipoprotein B (Apo B) also falls substantially during treatment with Simvastatin. As each LDL particle contains one molecule of Apo B, and since in patients with predominant elevations in LDL-C (without accompanying elevation in VLDL) little Apo B is found in other lipoproteins, this strongly suggests that Simvastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, Simvastatin reduces VLDL and TG and increases HDL-C. The effects of Simvastatin on Lp(a), fibrinogen, and certain other independent biochemical risk markers for CHD are unknown. Simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.

 

INDICATION

MOSTEN is indicated as an adjunct to diet in patients with primary hypercholesterolemia (type lla and llb hyperlipoproteinemia) caused by elevated low density lipoprotein (LDL) cholesterol concentrations in patients with a significant risk of coronary artery disease, who have not responded to diet or otherwmeasures alone.

MOSTEN is also indicated for reduction of elevated LDL cholesterol levels in patients with combined hypercholesterolemia and hypertriglyceridemia.

 

RECOMMENDED DOSE

The recommended starting dose is 5-10mg per day in the evening. The maximum recommended dose is 40mg/day.

Dose should be individualized according to patient’s response.

 

CONTRAINDICATION

MOSTEN Tablets are contraindicated in individuals with a known history of hypersensitivity to the drug, in Individuals having active liver disease, unexplained persistent elevation of liver function tests. It is also contraindicated in pregnant women and in nursing mothers.

 

WARNINGS AND PRECAUTIONS

 

Skeletal Muscle

Simvastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy, which is manifested as muscle pain or weakness associated with grossly elevated creatine kinase (CK) (> 10X the upper limit of normal [ULN]). Rhabdomylysis, with or without acute renal failure secondary to myoglobinuria, has been reported rarely. In 45, there was one case of myopathy among 1,399 patients taking simvastatin 20 mg and no cases among 822 patients taking 40 mg/day for a median duration of 5.4 years. In two 6-month controlled clinical studies, there was one case of myopathy among 436 patients taking 40mg and 5 cases among 669 patients taking 80mg. 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, such as 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 is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that are potent inhibitors of this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics ezythromycin and clarithromycin, HIV protease inhibitors, and the 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 CK level above 10X ULN in a patient with unexplained muscle symptoms indicates myopathy. Simvastatin therapy should be discontinued if myopathy is diagnosed or suspected. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved.
Of the patients with rhabdomyolysis, many had complicated medical histories. Some had pre-existing 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 months of therapy and during any periods of upward dosage titration of either drug. Periodic CK 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 is likely to 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 studies with careful monitoring. Addition of these drugs to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. If one of these drugs must be used with simvastatin, clinical experience suggests that the risk of myopathy is less with niacin than with the fibrates.

In patients taking concomitant cyclosporine, fibrates or niacin, the dose of simvastatin should generally not exceed 10mg, as the risk of myopathy increases substantially at higher doses. Interruption of simvastatin therapy during a course of treatment with a systemic antifungal azole or a macrolide antibiotic should be considered.

 

Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin. When drug treatment is interrupted or discontinued, the kansaminase levels usually falls slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose. It is recommended that liver function test be performed before the initiation of treatment, and periodically thereafter (e.g. semiannually) for the first year of treatment or until one year after the last elevation in dose. Patients titrated to the 80mg dose should receive an additional test at 3 months. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3X ULN or greater persist, withdrawal of therapy with simvastatin is recommended. The drug should be used with caution for patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin. As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after Initiation of therapy with simvastatin, we often transient, were not accompanied by any symptoms and did not require interruption of treatment.

 

Precaution General

Simvastatin may cause elevation of CK and transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with simvastatin.

 

INTERACTIONS WITH OTHER MEDICAMENTS

Cyclosporine, erythromycin, niacin, gemfibrozil; severe myopathy or rhabdomyolysis.

Propranolol: Decrease in antihyperlipidaemic activity.

Itraconazole: Plasma levels of lovastatin increased 20-folds.

Warfarin: Anticoagulant effect increased chances of bleeding.

 

ADVERSE/SIDE EFFECTS

Simvastatin is generally well tolerated. However a few gastrointestinal symptoms have been reported viz., flatulence, diarrhoea, constipation, nausea, abdominal pain, cramps, heartburn and dysgeusia. Rarely myopathy, characterised by myalgia and muscle weakness has been reported. Rhabodomyolysis with acute renal failure may also occur.

Asymptomatic elevations of the plasma concentration of the muscle Isozyme of creatine phosphokinase occur in up to 11% of patients taking simvastatin.

Ocular symptoms may rarely include blurring & vision and lens opacities. Other adverse effects include headache, dizziness, rashes/pruritus, impotence and insomnia.

 

PREGNANCY AND LACTATION

Pregnancy

Safety in pregnant women has not been established.

Simvastatin has no teratogenic in rats at doses of 25mg/kg/day or in rabbits at doses up to 10 mg/kg daily. These doses resulted in 3 times (rabbit) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/still births did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with simvastatin during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized. Simvastatin should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.

Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their Infants.

 

UNDESIRABLE EFFECTS

Commonly found adverse effects with MOSTEN are constipation, diarrhoea, nausea, dyspepsia, flatulence, dizziness, skin rash, fatigue, myopathy.

 

OVERDOSE AND TREATMENT

Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with simvastatin have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 450mg. Until further experience is obtained, no specific treatment of overdosage with simvastatin can be recommended.

The dialyzability of simvastatin and its metabolites in man is not known at present.

 

STORAGE CONDITION

Store in a cool & dry place, below 25°C.

Protect from light and moisture.

Keep all medicines away from children.

 

DOSAGE

As directed by the physician.

 

PRESENTATION

Blister pack of 2 x 10 tablets.
NAFDAC Regn. No.: A4-3557

 

Manufactured by

Osaka Pharmaceuticals Pvt. Ltd.

Old National Highway No. 8, Sankarda – 391 350,

Dist. Vadodara, Gujarat, India.

 

Marketed by

SEAGREEN PHARMACEUTICALS LTD.

3, Okunfolami Street, Anthony Village,

Lagos, Nigeria.

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