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LIPSAVA-20

Quick Overview

Our aim is to reach out to the globe within shortest possible time frame


To promote this objective, not only we distribute and market our cardiovascular  range of products globally through our distribution channels but we also undertake ‘contract manufacturing’& ‘formulation development ’of our wide range of generic products such as Lipsava which contain  Atorvastatin Calcium Equivalent to Atorvastatin 20 mg.


This Lipsava 20 contaisn same active ingredient as Lipitor from Pfizer.


 


 

Lipsava-20

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Details

LIPSAVA-20

Each film coated tablet contains:

Atorvastatin Calcium

Equivalent to Atorvastatin 20 mg

Excipients q.s.

Colour: Titanium Dioxide BP

Chemical Name:

(3R,5R)-7-[2-(4-fluorophenyl)- 3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)- 1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid.

Category:

Atorvastatin works by inhibiting HMG-CoA reductase.

Description:

White to off-white film-coated oval shape tablet ‘20’ engraved on

one side and breakline on another side.

Pharmacology

Pharmacodynamics

Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the synthesis of cholesterol. The primary site of action of HMG-CoA reductase inhibitors is the liver. Inhibition of cholesterol synthesis in the liver leads to up regulation of LDL-receptors and an increase in LDL-catabolism.

There is also some reduction of LDL-production as a result of inhibition of hepatic synthesis of very low density lipoprotein (VLDL), the precursor of LDL-cholesterol. Atorvastatin reduces total cholesterol, LDL-cholesterol and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, non familial forms of hypercholesterolemia and mixed dyslipidemias. Atorvastatin also reduces VLDL-cholesterol and triglycerides and produces variable increases in HDL-cholesterol and apolipoprotein A1. Atorvastatin reduces total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, triglycerides, and non-HDL-cholesterol, and increases HDLcholesterol in patients with isolated hypertriglyceridemia.

Atorvastatin also reduces intermediate density lipoprotein (IDL) cholesterol in patients with dysbetalipoproteinemia.

Atorvastatin as well as some of its metabolites are pharmacologically active in humans. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. Individualization of drug dosage should be based on therapeutic response.

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is = 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk.

Metabolism:

 Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bilefollowing hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Special Populations

Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age = 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults.

Paediatric: Pharmacokinetic data in the paediatric population are not available.

Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10%  lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.

Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.

Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-PughA disease.

Indications

LIPSAVA is indicated as an adjunct to diet for reduction of elevated total-cholesterol, LDL cholesterol, apolipoprotein-B, and triglyceride levels in patients with

• primary hypercholesterolaemia

• mixed dyslipidaemia

• heterozygous familial hypercholesterolaemia.

LIPSAVA is indicated to reduce total-C and LDL-C in patients with

• homozygous familial hypercholesterolaemia (As an adjunct to other lipid-lowering treatments (e.g. LDL

aphaeresis) or if such treatments are unavailable) Important Prior to initiating therapy with LIPSAVA, secondary causes for hypercholesterolemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, and alcoholism) should be excluded, and a lipid profile performed to measure total- C, LDL-C, HDL-C, and TG. Therapy with lipid-lowering agents should be a component of multiple-risk-factor intervention in individuals at increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate.

Contra-indications

• Hypersensitivity to any component of this medication.

• Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS and SIDE EFFECTS ANDSPECIAL PRECAUTIONS)

• Pregnancy

• In breast feeding mothers

• In women of childbearing potential not using adequatecontraceptive measures. (An interval of one month should be allowed from stopping LIPSAVA treatment to conception in the event of planning a pregnancy)

• In children the safety and efficacy have not yet been established.

Warnings

Liver Effects

•Persistent elevations (> 3 times the upper limit of normal (ULN) occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received Atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0, 2%, 0.6% and 2.3% for 10, 20, 40 and 80 mg respectively.

•It is recommended that liver function tests be performed before the initiation of treatment, following each dosage increase, and periodically thereafter. Liver enzyme changes mostly commence in the first 4 months of treatment with Atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of > 3 times ULN persist, withdrawal of Atorvastatin is recommended.

•Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contra-indications to the use of

Skeletal Muscle

•Rhabdomyolysis with or without renal impairment has been reported with the use of HMG-CoA reductase inhibitors.

•Myalgia has been reported in patients treated with Atorvastatin Myopathy, defined as muscle

aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values greater than 10 times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. LIPSAVA therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

•As with other HMG-CoA reductase inhibitors, the risk of myopathy during treatment with Atorvastatin is increased with concurrent administration of immunosuppressive drugs, including cyclosporine, fibric acid derivatives, nicotinic acid, azole antifungals or erythromycin. (see PRECAUTIONS: Interactions).

•Atorvastatin therapy should be withdrawn in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Dosage and directions for use

The patient should be placed on a standard cholesterol-lowering diet before receiving LIPSAVA and should continue on this diet during treatment with LIPSAVA. The usual starting dose is 10 mg once a day. Doses should be individualised according to the baseline LDL-C levels, the goal of therapy, and patient response. Adjustment of dosage should only be made after an interval of 4 weeks or more. The maximum recommended dose is 40 mg once a day. Doses may be given at any time of day with or without food.

Primary Non-familial Hypercholesterolemia and Combined (Mixed) Hyperlipidaemia The majority of patients are controlled with 10 mg LIPSAVA once a day. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy. Heterozygous Familial Hypercholesterolemia Patients should be started with LIPSAVA 10 mg daily.

 Doses should be individualised and adjusted every 4 weeks to 40 mg daily.Thereafter, a bile acid sequestrant (e.g. colestipol) may be combined with 40 mg LIPSAVA. Homozygous Familial Hypercholesterolemia

Adults: In a compassionate-use, uncontrolled study of 29 patients with homozygous familial hypercholesterolemia, most patients responded to a dose of 80 mg of Atorvastatin, with a mean reduction in LDL-C of 20% (range 7% - 53%), although in some patients an increase of LDL-C occurred.

Children: Treatment experience in the homozygous familial hypercholesterolemia paediatric population with Atorvastatin is limited.

 

Description:

White to off-white film-coated oval shape tablet ‘20’ engraved on

one side and breakline on another side.

Pharmacology

Pharmacodynamics

Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3- methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the synthesis of cholesterol. The primary site of action of HMG-CoA reductase inhibitors is the liver. Inhibition of cholesterol synthesis in the liver leads to up regulation of LDL-receptors and an increase in LDL-catabolism. There is also some reduction of LDL-production as a result of inhibition of hepatic synthesis of very low density lipoprotein (VLDL), the precursor of LDL-cholesterol. Atorvastatin reduces total cholesterol, LDL-cholesterol and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, non familial forms of hypercholesterolemia and mixed dyslipidemias. Atorvastatin also reduces VLDL-cholesterol and triglycerides and produces variable increases in HDL-cholesterol and apolipoprotein A1. Atorvastatin reduces total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, triglycerides, and non-HDL-cholesterol, and increases HDLcholesterol in patients with isolated hypertriglyceridemia. Atorvastatin also reduces intermediate density lipoprotein (IDL) cholesterol in patients with dysbetalipoproteinemia. Atorvastatin as well as some of its metabolites are pharmacologically active in humans. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. Individualization of drug dosage should be based on therapeutic response.

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is = 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk.

Metabolism:

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the +ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Special Populations

Geriatric: Plasma concentrations of atorvastatin are higher(approximately 40% for Cmax and 30% for AUC) in healthy elderlysubjects (age = 65 years) than in young adults. Clinical datasuggest a greater degree of LDL-lowering at any dose of drug in theelderly patient population compared to younger adults.

Paediatric: Pharmacokinetic data in the paediatric population arenot available.

Gender: Plasma concentrations of atorvastatin in women differ rom those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.

Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.

Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh

A disease. Indications LIPSAVA is indicated as an adjunct to diet for reduction of elevated total-cholesterol, LDL cholesterol, apolipoprotein-B, and triglyceride levels in patients with

• primary hypercholesterolaemia

• mixed dyslipidaemia

• heterozygous familial hypercholesterolaemia. LIPSAVA is indicated to reduce total-C and LDL-C in patients with

• homozygous familial hypercholesterolaemia (As an adjunct to other lipid-lowering treatments (e.g. LDL

aphaeresis) or if such treatments are unavailable) Important Prior to initiating therapy with LIPSAVA, secondary causes for hypercholesterolemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, and alcoholism) should be excluded, and a lipid profile performed to measure total- C, LDL-C, HDL-C, and TG. Therapy with lipid-lowering agents should be a component of multiple-risk-factor intervention in individuals at increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate.

 

Dosage in Patients with Renal Insufficiency

Renal disease has no influence on the plasma concentrations nor on lipid effects of LIPSAVA; thus, no adjustment of dose required.

Side-Effects and Special Precautions

The most frequent adverse effects associated with Atorvastatin therapy, in patients participating in controlled clinical studies were: diarrhoea, constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, arthralgia, asthenia, insomnia and rash.

The following side-effects have also been reported in clinical trials:

muscle cramps, myositis, myopathy, paraesthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, impotence, hyperglycaemia and hypoglycaemia. Allergic reactions have been reported rarely. Atorvastatin may cause elevation of creatine phosphokinase and dose-related increases in transaminase levels may occur.

Interactions

As with other HMG-CoA reductase inhibitors the risk of myopathy during treatment with LIPSAVA is increased with concurrent administration of immunosuppressive drugs, fibric acid derivatives, macrolide antibiotics, e.g. erythromycin, azole antifungals, e.g. clotrimazole, or niacin (nicotinic acid)

Antacid: Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides with Atorvastatin decreased plasma concentrations of atorvastatin approximately 35%; however, LDL C reduction was not altered.

Antipyrine: Because Atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.

Colestipol: Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and LIPSAVA were coadministered. However, LDL C reduction was greater when Atorvastatin and colestipol were co-administered than when either

drug was given alone.

Cholestyramine: No data is available.

Cimetidine: Atorvastatin plasma concentrations and LDL C reduction were not altered by co-administration of cimetidine.

Digoxin: Co-administration of multiple doses of Atorvastatin and digoxin increased steady-state plasma digoxin concentrations by approximately 20%. Patients taking digoxin should be monitored appropriately.

Erythromycin: In healthy individuals, plasma concentrations of Atorvastatin increased approximately 40% with co-administration of Atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4  Oral contraceptives: Co-administration of Atorvastatin and an oral contraceptive increased AUC values of norethindrone and ethinyl estradiol approximately 30% and 20%, respectively. These increases should be considered when selecting an oral

contraceptive for a woman taking atorvastatin.

Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving combined Atorvastatin and warfarin therapy for two weeks. Nevertheless, patients receiving LIPSAVA should be closely monitored when Atorvastatin is combined with warfarin therapy.

Other Concomitant Therapy: In clinical studies, Atorvastatin was used concomitantly with antihypertensive agents and oestrogen replacement therapy without evidence of clinically significant

adverse interactions. Interaction studies with specific agents have not been conducted.

Known Symptoms of Over dosage and Particulars of its Treatment There is no specific treatment for atorvastatin over-dosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Presentation

10 tablets in a blister, such three blister strips are in a mono carton.

Storage

Store in a dry place below 30°C. Protect from light.

Keep out of reach of children.

Shelf Life: 36 months from the date

 
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