Corstat

Simvastatin.

Pharmacology: Pharmacodynamics: The involvement of LDL cholesterol in arthrogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have been established that high LDL (low-density lipoprotein) and HDL (high-density lipoprotein) cholesterol are both risk factors for coronary heart disease.
Corstat has been shown to reduce both normal and elevated LDL-cholesterol concentrations. LDL is formed from VLDL and is catabolised predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of Corstat may involve both reduction of VLDL-cholesterol concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL cholesterol. Apolipoprotein B also falls substantially during treatment with Corstat. Since each LDL particles contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that Corstat does not merely cause cholesterol to be lost from LDL but also reduces the concentration of circulating LDL particles. In addition, Corstat increases HDL cholesterol and reduces plasma triglycerides. As a result of these changes the ratios of total to HDL cholesterol and LDL to HDL cholesterol are reduced. In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily, the mean reductions of LDL-C where 30%, 38%, 41% and 47%, respectively. The percent reduction in LDL-C was essentially independent of baseline. In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolaemia received simvastatin 40 mg/day in a single dose or in 3 divided doses or 80 mg/day in 3 divided doses. The mean LDL-cholesterol reductions for the 40- and 80-mg doses were 14% and 25%, respectively. One patient with absent LDL-cholesterol receptor function had an LDL-cholesterol reduction of 41% with the 80-mg dose.
In the Scandinavian Simvastatin Survival Study (45), the total mortality of therapy with Corstat for a median of 5.4 years was assessed in 4444 patients with coronary heart disease (CHD) and baseline total cholesterol 5.5-8 mmol/L. In this multicentre, randomised, double-blind, placebo-controlled study, Corstat reduced the risk of death by 30%, of CHD death by 42%, and of having a hospital-verified non-fatal myocardial infarction by 37%. Furthermore, Corstat reduced the risk for myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty) by 37%. In a post-hoc analysis performed on fatal plus non-fatal cerebrovascular events (stroke and transient ischaemic attacks), there were 75 patients with such events in the Corstat group and 102 in the placebo group (risk reduction 28%, p=0.033). In a multicentre, placebo-controlled clinical trial in 404 patients using quantitative coronary angiography, Corstat slowed the progression of coronary atherosclerosis and reduced the development of both new lesions and new total occlusions, whereas coronary atherosclerosis lesions steadily worsened over 4 years in patients receiving standard care. Corstat is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyses the conversion of HMG-CoA to mevalonate. However, at therapeutic doses, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with Corstat would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolised readily back to acetyl CoA, which participates in many biosynthetic processes in the body.
Pharmacokinetics: Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding β-hydroxy acid, L-654,969 a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxy acid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors). Both are measured in plasma following administration of simvastatin. In a disposition study with ¹⁴C-labelled simvastatin, 100 mg (20 uCi) of simvastatin was administered as capsules (5 x 20 mg) and blood, urine and in faeces collected. 13% of the radioactivity was recovered in the urine and 60% in the faeces. The latter represents absorbed drug equivalents excreted in bile as well as any unabsorbed drug. Less than 0.5% of the dose was recovered in urine as HMG-CoA reductase inhibitors. In plasma, the inhibitors account for 14% and 28% (active and total inhibitors) of the AUC of total radioactivity, indicating that the majority of chemical species present were inactive or weak inhibitors.
The major metabolites of simvastatin present in human plasma are L-654,969 and 4 additional active metabolites. Both simvastatin and L-654,969 are highly bound to human plasma proteins (>94%). The availability of L-654,969 to the systemic circulation following an oral dose of simvastatin was estimated using IV reference dose of L-654,969; the value was found to be <5% of the dose. By analogy to the dog model, simvastatin is well absorbed and undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the general circulation is low. In dose-proportionality studies, utilising doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all the aforementioned pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3- to 2.4-hrs post-dose.

Treatment of coronary heart disease.
Patients with coronary heart disease with a plasma cholesterol level of ≥5.5 mmol/L, Corstat is used in the reducing the risks of the following conditions: mortality of patient; coronary death and non-fatal myocardial infarction; undergoing myocardial revascularisation procedures (coronary artery bypass) grafting and percutaneous transluminal angioplasty); and slow the progression of coronary atherosclerosis, including the development of new lesions and new total occlusions.
Hyperlipidaemia: As an adjunct to diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolaemia, heterozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia when response to diet and other non-pharmacological measures is inadequate. Corstat increases HDL-cholesterol and, therefore lowers the LDL/HDL and total cholesterol/HDL ratios. As with any cholesterol-lowering therapy, other modifiable risk factors should also be considered when treatment is started.
Homozygous Familial Hypercholesterolaemia: As an adjunct to diet and other non-dietary measures in reducing elevated total cholesterol, LDL-cholesterol and apolipoprotein B in patients with homozygous familial hypercholesterolaemia when response to these measures is inadequate.

The patient should be placed on a standard cholesterol-lowering diet before receiving Corstat and should continue on this diet during treatment with Corstat.
Coronary Heart Disease: Patients with coronary heart disease can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Adjustment of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening, depending on the patient's individual response.
If LDL-cholesterol levels fall <1.94 mmol/L or total serum cholesterol levels fall <3.6 mmol/L consideration should be given to reducing the dose of Corstat.
Hyperlipidaemia: Recommended Dose: 10 mg once daily taken in the evening. The dose range is 10-80 mg a day in single doses taken in the evening. A marked response to Corstat is seen within 2 weeks and the maximum therapeutic response occurs within 4-6 weeks. The response is maintained during continuation of therapy. When therapy with Corstat is stopped, total cholesterol has been shown to return to pretreatment levels. Adjustment of dosage, if required, should be made as previously specified.
Homozygous Familial Hypercholesterolaemia: Based on the results of a controlled clinical study, the recommended dosage for patients with homozygous familial hypercholesterolaemia is 40 mg/day taken as a single dose in the evening, or 80 mg/day in 3 divided doses of 20-, 20- and 40-mg dose taken in the evening. Corstat 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: Corstat is effective alone or in combination with bile acid sequestrants. In patients taking cyclosporin, fibrates or niacin concomitantly with Corstat, the maximum recommended dosage is 10 mg/day.
Renal Insufficiency: Because Corstat 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.
Elderly: Although experience in elderly patients is limited, efficacy using standard doses appears similar to that seen in the population as a whole. There is no apparent increase in the frequency of clinical or laboratory adverse findings.
Children: Studies to show safety and effectiveness in children have not been carried out.

A few cases of overdosage have been reported; no patient had any specific symptoms and all patients recovered without sequelae. The maximum dosage taken was 450 mg. General measures should be adopted. The maximum plasma concentration of inhibitors occurred within 1.3-2.4 hrs of administration.

Hypersensitivity to Corstat; active liver disease or unexplained persistent elevations of serum transaminases; porphyria; pregnancy and lactation (see also Precautions).

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.

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.

Corstat is generally well tolerated, for the most part, side effects have been usually mild and transient in nature. Less than 2% on Corstat were discontinued from controlled clinical studies due to side effects attributable to Corstat.
In the premarketing controlled studies, adverse effects occurring with a frequency of ≥1% and considered by the investigator as possibly, probably or definitely drug-related were: Abdominal pain, constipation and flatulence. Other side effects occurring in 0.5-0.9% of patients were asthenia and headache. Myopathy has been reported rarely.
In the Scandinavian Simvastatin Survival Study (4S) involving 4444 patients treated with Corstat 20-40 mg/day (n=2221) or placebo (n=2223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study. The following additional side effects were reported either in long-term extension studies or in marketed use: Nausea, diarrhoea, rash, dyspepsia, pruritus, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, paraesthesia, peripheral neuropathy, vomiting and anaemia. Rarely, rhabdomyolysis and hepatitis/jaundice occurred. An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: Angioedema, lupus-like syndrome, polymyalgia rheumatica, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.
Laboratory Test Findings: Marked and persistent increases of serum transaminase have been reported infrequently. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum creatine phosphokinase (CPK) levels derived from skeletal muscle have been reported. Side effects-causal relationship unknown: The following side effects have been reported; however, a causal relationship to therapy with Corstat has not been established: Depression, erythema multiforme including Stevens-Johnson syndrome, leucopenia and purpura.

Interactions with Other Medicaments and Other Forms of Interaction: Gemfibrozil and Other Fibrates, Lipid-Lowering Dose (1g/day) of Niacin (nicotinic acid): These drugs increase the risk of myopathy when given concomitantly with simvastatin, probably because they can produce myopathy when given alone (see Muscle Effect under Precautions).
CYP3A4 Interactions: Simvastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect plasma levels of the drugs metabolised by CYP3A4. However, simvastatin itself is a substrate for CYP3A4. Potent inhibitors of CYP3A4 may increase the risk of myopathy by increasing the plasma levels of HMG-CoA reductase activity during simvastatin therapy. These include cyclosporin, itraconazole, ketoconazole erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone (see Muscle Effects under Precautions).
Grape fruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolised by CYP3A4. The effect of typical consumption (one 240 mL glass daily) is minimal (13% increase in the active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-curve) and of no clinical relevance. However, very large quantities (over 1 L daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided. Amounts of grapefruit juice between 240 mL and 1 L have not been studied.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of Corstat and propranolol.
Digoxin: Concomitant administration of Corstat and digoxin resulted in a slight elevation (>0.3 ng/mL) in drug concentration (as measured by a digoxin radio immunoassay) in plasma compared to concomitant administration of placebo and digoxin.
Coumarin Derivatives: In 2 clinical studies, one 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 Normalised Ratio (INR), increased from patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin occurs. Once a stable prothrombin time has been documented, prothrombin time can be monitored at the intervals usually recommended for patients on coumarin anticoagulants.
Other Concomitant Therapy: In clinical studies, Corstat was used concomitantly with ACE inhibitors β-blockers, calcium antagonists, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.
Incompatibilities: None known.

Instruction for Use and Handling: Not applicable.

Store in a dry place below 25°C.
Shelf-Life: 3 years.

Dyslipidaemic Agents

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

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