ADCO-SIMVASTATIN 10 mg Tablets
ADCO-SIMVASTATIN 20 mg Tablets
ADCO-SIMVASTATIN 40 mg Tablets
(and dosage form):
ADCO-SIMVASTATIN 10 mg Tablets
ADCO-SIMVASTATIN 20 mg Tablets
ADCO-SIMVASTATIN 40 mg Tablets
Each ADCO-SIMVASTATIN 10 mg tablet contains 10 mg Simvastatin.
Each ADCO-SIMVASTATIN 20 mg tablet contains 20 mg Simvastatin.
Each ADCO-SIMVASTATIN 40 mg tablet contains 40 mg Simvastatin.
Each tablet contains: Butylhydroxyanisole 0,019 % m/m as an anti-oxidant.
A 7.5 Serum-cholesterol reducers
The cholesterol-lowering agent, SIMVASTATIN, is synthetically obtained from lovastatin, which is derived from a fermentation process. The inactive lactone, SIMVASTATIN, is hydrolyzed to beta-hydroxyacid (active form), after oral ingestion. Beta-hydroxyacid is a principal metabolite and inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. This conversion is an early and rate limiting step in the production of cholesterol within the body. The effect of this inhibition, is that SIMVASTATIN reduces total plasma cholesterol, by decreasing very low-density lipoprotein (VLDL)- and low-density lipoprotein (LDL)- cholesterol concentrations, as well as Apolipoprotein B and plasma triglyceride concentrations. An increase in high-density lipoprotein (HDL)-cholesterol concentrations is also noted.
Reduction of elevated total and LDL-cholesterol levels in patients with primary hypercholesterolaemia, in whom response to diet and other non-pharmaceutical measures have been inadequate.
ADCO-SIMVASTATIN is indicated to lower elevated cholesterol levels in patients with a combination of primary hypercholesterolaemia and primary hypertriglyceridaemia, where the hypercholesterolaemia is of primary concern.
Coronary Heart Disease
Patients with established coronary heart disease and hypercholesterolaemia in whom dietary measures have been inadequate or ineffective.
ADCO-SIMVASTATIN is indicated to lower :
the risk of total mortality by decreasing coronary death, the risk of non-fatal myocardial
infarction and the risk of undergoing myocardial revascularization procedures (coronary
artery bypass grafting and percutaneous transluminal coronary angioplasty).
ADCO-SIMVASTATIN is also indicated to delay the progression of coronary atherosclerosis.
Hypersensitivity to simvastatin or any of the excipients used in the tablet.
Simvastatin should not be given to patients with acute liver disease or unexplained persistent raised serum-amino transferase concentrations or those with porphyria.
Pregnancy and lactation.
Female patients of childbearing potential should not use ADCO-SIMVASTATIN, as the active metabolite is fetotoxic and teratogenic in rats.
As safety and efficacy have not yet been established, use in paediatric patients is not advised.
ADCO-SIMVASTATIN is ineffective for the treatment of homozygous familial hypertriglyceridaemia or hypercholesterolaemia.
Concomitant use of immunosuppressive drugs (especially cyclosporine), fibric acid derivatives and/or niacin with HMG-CoA reductase inhibitors has resulted in rhabdomyolysis, sometimes with acute renal failure.
FDA Class Warnings for Lipid Lowering Agents of the Statin Class
The following effects have been reported with medicines in this class; not all effects listed below have necessarily been associated with ADCO-SIMVASTATIN therapy.
Skeletal: myopathy, muscle cramps, rhabdomyolysis, arthralgias, myalgia.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, memory loss, vertigo, paraesthesia, peripheral neuropathy, peripheral nerve palsy, anxiety, insomnia, depression, psychic disturbances.
Hypersensitivity reactions: An apparent hypersensitivity syndrome has been reported that included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopaenia, leukopaenia, haemolytic anaemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnoea, toxic epidermal necrolysis, erythema multiforme including Stevens Johnson syndrome.
Gastro-intestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis and hepatoma, anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes, (eg. nodules, discolouration, dryness of skin/mucous membranes, changes to hair/nails), have been reported.
Reproductive: gynaecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory abnormalities: elevated transaminases, creatine kinase, alkaline phosphatase, y-glutamyl transpeptidase and bilirubin, thyroid function abnormalities.
DOSAGE AND DIRECTIONS FOR USE:
Prior to, and throughout treatment with ADCO-SIMVASTATIN, the patient should be placed on a standard cholesterol-lowering diet.
The usual initial dose is 10 mg/day given as a single dose in the evening. The dosage may be adjusted, if needed, but at intervals of not less than 4 weeks. The maximum dosage that may be given is 40 mg daily as a single dose in the evening.
If LDL-cholesterol levels fall below 1,94 mmol/L (75 mg/dL) or total plasma cholesterol levels fall below 3,6 mmol/L (140 mg/dL) consideration should be given to a reduction in dose of ADCO-SIMVASTATIN.
Coronary Heart Disease
A starting dose of 20 mg/day may be given as a single dose in the evening.
The dosage may be adjusted, if needed, in accordance with the instructions under Hypercholesterolaemia.
Dosage in Renal Insufficiency
Patients with moderate renal insufficiency may not require dosage adjustments due to the fact that ADCO-SIMVASTATIN does not undergo significant renal excretion.
Implementation of dosages above 10 mg/day require careful consideration and caution in patients with severe renal insufficiency (creatine clearance <30 mL/min).
ADCO-SIMVASTATIN is effective as a single agent. It is also effective when used in combination with bile-acid sequestrants but it should be given either one hour prior to, or four hours after cholestyramine administration.
The lowest recommended dosage of HMG-CoA reductase inhibitors and immunosuppressive agents should be used if these drugs are taken together, as the incidence of myopathy in such patients has increased. (see SPECIAL PRECAUTIONS Muscle Effects),
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Gastro-intestinal disturbances, such as abdominal pain, cramps, constipation and flatulence may occur. Other side-effects include, asthenia, headache, nausea, diarrhoea, skin rashes, dyspepsia, pruritus, anaemia, fatigue, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, paraesthesia, vomiting, blurred vision, insomnia, dysgeusia, mass gain, peripheral neuropathy and neutropaenia.
Rhabdomyolysis, hepatitis/jaundice, pancreatitis and myopathy have been reported less frequently.
There have been less frequent reports of an apparent hypersensitivity syndrome. Some of the features of this syndrome include: lupus-like syndrome, fever, malaise, vasculitis, polymyalgia rheumatica, angioedema, eosinophilia, thrombocytopaenia, arthritis, urticaria, increased erythrocyte sedimentation rate, arthralgia, photosensitivity, flushing and dyspnoea.
Laboratory Test Findings
Liver function test abnormalities have been mild and transient. Significant and persistent increases of serum transaminases, elevated serum creatine kinase (CK) levels (derived from skeletal muscle), elevated alkaline phophatase and elevated gamma-glutamyl transpeptidase have been reported. (see SPECIAL PRECAUTIONS).
Marked, persistent elevations in serum transaminases (to more than 3 times the upper limit of normal) have occurred. Upon discontinuation or interruption of SIMVASTATIN treatment, the elevated transaminase levels in these patients slowly dropped to pretreatment levels.
All patients are advised to undergo liver function tests prior to initiation of therapy, and periodically thereafter, as hepatitis, an indicator of which is an increase in liver enzymes, has also been reported.
Caution should be exercised in patients who develop elevated serum transaminase levels. Measurements should be repeated promptly and then performed more frequently in such patients. Discontinue treatment with ADCO-SIMVASTATIN if the transaminase levels continue to rise, particularly if they rise to three times the upper limit of normal and are persistent. Patients who consume substantial quantities of alcohol and/or have a history of liver disease should use ADCO-SIMVASTATIN with caution. The use of simvastatin is contra-indicated in patients with active liver diseases or in patients that have unexplained increases in transaminase levels.
An increase in the prevalence of lens opacities is expected with time as a result of ageing and not necessarily due to the use of simvastatin.
No relationship exists between the use of simvastatin and adverse effects on the human lens.
Increased creatine kinase (CK) levels (from skeletal muscles) have been frequently reported. Marked elevations of CK, muscle tenderness and/or diffuse myalgia are symptoms of myopathy. This condition should be considered in any patient presenting with such symptoms. In addition, any unexplained muscle pain, tenderness or weakness should be reported immediately.
If there is a potential diagnosis of myopathy, or if there is a significant increase in CK levels, treatment with ADCO-SIMVASTATIN should be discontinued immediately.
Concomitant use of ADCO-SIMVASTATIN together with immunosuppressive agents including cyclosporine, fibric acid derivatives or lipid lowering doses of niacin (nicotinic acid) could increase the risk of myopathy. The risk / benefit profile of these combinations should therefore be carefully considered.
Patients on HMG-CoA reductase inhibitor therapy have experienced rhabdomyolysis with or without renal impairment. A renal transplant patient on cyclosporine and simvastatin experienced muscle fatigue together with a significant increase of CK, after the introduction of therapy with the systemic antifungal agent itraconazole. Cholesterol biosynthesis is inhibited at different stages in the biosynthetic pathway by the HMG CoA reductase inhibitors and the azole derivative antifungal agents. Simvastatin treatment should therefore be temporarily discontinued in patients receiving cyclosporine and simvastatin, who also require systemic azole derivative antifungal therapy. Patients only receiving simvastatin require careful monitoring if systemic azole derivative antifungal therapy is initiated.
Simvastatin 20-40 mg/day slightly enhances the effect of coumarin anticoagulants, as indicated by the prothrombin times [reported as International Normalized Ratio (INR)], which increased from a baseline of 1,7 to 1,8 in normal volunteers and from a baseline of 2,6 to 3,4 in hypercholesterolaemic patients.
In order to ensure that no significant changes to prothrombin times occur in patients taking coumarin anticoagulants, the prothrombin time should be determined prior to starting simvastatin therapy and at frequent intervals during early treatment with simvastatin.
Prothrombin times may be monitored at the intervals usually indicated for patients on coumarin anticoagulants, once it has stabilised and been documented. Any dosage alterations to simvastatin should follow the same procedure. Patients taking simvastatin have not experienced bleeding or changes in prothrombin time, in the absence of anticoagulant therapy.
Simvastatin elevates digoxin levels.
Fibric Acid Derivatives
See SPECIAL PRECAUTIONS Muscle Effects.
Other Concomitant Therapy
ADCO-SIMVASTATIN when used simultaneously with immunosuppressant therapy, itraconazole or niacin, should be monitored cautiously. (See SPECIAL PRECAUTIONS Muscle Effects).
Concomitant administration of a single dose of SIMVASTATIN and propranolol in healthy male volunteers, showed a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors. The clinical importance of this finding is unclear. The enantiomers of propranolol remain unchanged in terms of their pharmacokinetic properties.
Raised concentrations of simvastatin have also occurred in patients given mibefradil.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE EFFECTS and SPECIAL PRECAUTIONS):
General measures should be adopted and liver function tests should be performed.
Treatment of overdosage is symptomatic and supportive.
ADCO-SIMVASTATIN 10 mg Tablets:
White, oblong, biconvex film-coated tablets, scored on both sides. The tablets are embossed with SVTand 10on one side.
ADCO-SIMVASTATIN 20 mg Tablets:
White, oblong, biconvex film-coated tablets, scored on both sides. The tablets are embossed with SVTand 20on one side.
ADCO-SIMVASTATIN 40 mg Tablets:
White, oblong, biconvex film-coated tablets, scored on both sides. The tablets are embossed with SVTand 40on one side.
ADCO-SIMVASTATIN 10 mg, 20 mg & 40 mg Tablets:
The white blister packs of PVC/PE/PVDC/Al and the blister packs of PVC/PE/PVDC/Al in Al sachets, are both available as cartons of 10, 20, 30, 50 or 100 tablets, where the tablets are enclosed in blister strips of 10 tablets or 15 tablets each. The white blister packs of PVC/PE/PVDC/Al and the blister packs of PVC/PE/PVDC/Al in Al sachets, are also available as cartons of 14 or 28 tablets, where the tablets are enclosed in blister strips of 14 tablets each. The 75 mL white HDPE tablet containers with child resistant Polypropylene closures contain 100 or 300 tablets.
Keep well closed. Store in a dry place, below 25°C in the original package.
KEEP OUT OF REACH OF CHILDREN.
ADCO-SIMVASTATIN 10 mg: 35/7.5/0277
ADCO-SIMVASTATIN 20 mg: 35/7.5/0278
ADCO-SIMVASTATIN 40 mg: 35/7.5/0279
NAME AND BUSINESS ADDRESS OF APPLICANT:
Adcock Ingram Limited
Adcock Ingram Park
17 Harrison Avenue
Private Bag X69
DATE OF PUBLICATION OF THIS PACKAGE INSERT:
New addition to this site: April 2004
Source: Pharmaceutical Industry
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