Tovastin

Tovastin

atorvastatin

Manufacturer:

T. O. Chemicals

Distributor:

T. O. Chemicals
Full Prescribing Info
Contents
Atorvastatin calcium.
Description
Each film-coated tablet contains Atorvastatin calcium equivalent to Atorvastatin 40 mg.
Action
Pharmacology: Pharmacodynamics: Atorvastatin calcium is a selective competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme that catalyzes the conversion of HMG-CoA to mevalonate in cholesterol biosynthesis. The inhibition of HMG-CoA reductase results in reduction of hepatic cholesterol biosynthesis then lead to a compensatory increase in the expression of low-density lipoprotein (LDL) receptors on hepatic cell surfaces and increased hepatic uptake and clearance of the blood.
Atorvastatin decreases elevated serum total cholesterol (total-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), and triglyceride (TG) concentrations, and to increase high-density lipoprotein-cholesterol (HDL-C) concentrations in patients with primary hypercholesterolemia or mixed dyslipidemia. In patient with hypertriglyceridemia who treatment with atorvastatin resulted in median reductions of total-C, LDL-C, TG, VLDL-C, non-HDL-C concentrations, and a median increment of HDL-C concentrations. Atorvastatin also reduces combined intermediate-density lipoprotein (IDL) and VLDL-cholesterol in patients with primary dysbetalipoproteinemia.
Pharmacokinetics: Absorption: After oral administration, Atorvastatin is rapidly absorbed and extensive first-pass metabolism in Gastrointestinal mucosa and liver. The peak plasma concentrations (Cmax) are reached within 1 to 2 hours following administration of the tablets. The absolute bioavailability of atorvastatin is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.
Distribution:
Atorvastatin is distributed mainly to the liver, the primary site of action and principal site of cholesterol synthesis and LDL-cholesterol clearance. It is greater than or equal to 98% bound to plasma protein and the volume of distribution is approximately 381 liters. Therapeutic response is observed within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during long-term therapy.
Metabolism: Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 to active ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by the active ortho- and parahydroxylated metabolites is similar to that by atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Elimination: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolite; however, the drug does not appear to undergo enterohepatic recirculation. The mean plasma elimination half-life of atorvastatin in human 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% is recovered in urine as unchanged drug.
Special patient populations: Pediatric population: In a double-blind, placebo-controlled study (followed by an open-label phase), 187 boys and postmenarchal girls 10 to 17 years of age with heterozygous familial hypercholesterolemia or severe hypercholesterolemia and baseline LDL-C concentration of 219 to 230 mg/dL were randomized to receive either atorvastatin 10 to 20 mg daily. During the 26-week, treatment with atorvastatin resulted in mean reductions of total-C, LDL-C, apo B, and TG concentrations, and in increment of HDL-C.
Geriatric: The peak plasma concentration and area under the plasma concentration-time curve (AUC) of atorvastatin were higher in geriatric than younger patients. In addition, mean reductions in LDL-C concentrations appear to be higher in geriatric receiving any dose of atorvastatin compared with younger patients.
Patients with hepatic impairment: Atorvastatin is metabolized predominantly in the liver and potentially may accumulate in the plasma of patients with hepatic impairment; however, there are no specific recommendations for dosage adjustment in patient with hepatic impairment. Peak plasma concentration and AUC of atorvastatin are increased by 4-fold in patients with Child-Pugh class A disease and by approximately 16-fold, respectively, in patients with Child-Pugh class B disease.
Patients with renal impairment: The renal impairment does not affect plasma concentrations or anti-lipidemic effects of atorvastatin; therefore, dosage modification in patients with renal impairment is not necessary. However, because history of renal impairment may be a risk factor for development of rhabdomyolysis, patient with renal impairment should be monitored more closely for diverse musculoskeletal effects.
Patients with 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.
Indications/Uses
Atorvastatin is used as an adjunct to nondrug therapies, which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, for prevention cardiovascular events and for the management of dyslipidemias. Drug therapy should be continued when drug therapy is initiated.
Prevention of cardiovascular events: In patient without clinical evidence of coronary heart disease (CHD) who have multiple risk factors such as age, smoking, hypertension, low HDL-C concentration and family history of early CHD, atorvastatin is indicated to reduce the risk of myocardial infarction (MI), stroke, or angina and to reduce the risk of undergoing revascularization procedures. In addition, patient without CHD who have type 2 diabetes mellitus and multiple risk factors for CHD such as retinopathy, albuminuria, smoking, hypertension, atorvastatin is indicated to reduce the risk of MI or stroke.
In patient with clinical evidence of CHD, atorvastatin is indicated to reduce the risk of nonfatal MI, fatal and nonfatal stroke, angina, or hospitalization for congestive heart failure (CHF), and to reduce the risk of undergoing revascularization procedures.
Hypercholesterolemia: Atorvastatin indicated for the reduction of total-C, LDL-C, apoB and TG and the increment of HDL in patients with primary hypercholesterolaemia (heterozygous familial and nonfamilial hypercholesterolaemia), mixed hyperlipidemia (Fredrickson types IIa and IIb), and patient with primary dysbetalipoproteinemia (Fredrickson type III) who do not respond adequately to diet. Atorvastatin also used in treatment of elevated TG in patient with hypertriglyceridemia (Fredrickson type IV) and reduced total-C and LDL-D in patient with homozygous familial hypercholesterolemia.
Dosage/Direction for Use
General: The patient should be placed on a standard cholesterol-lowering diet before receiving atorvastatin by appropriate diet, exercise and weight reduction in obese patients, and to treat the underlying medical problems and should continue remain on this diet during treatment with atorvastatin. The dosage range is 10 mg to 80 mg once daily. Starting and maintenance dosage should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response. Lipid levels should be determined within 2 to 4 weeks following initiation and/or titration of atorvastatin, and dosage should be adjusted accordingly.
Primary hypercholesterolaemia (heterozygous familial and non-familial) and mixed hyperlipidemia: The majority of patients are controlled with atorvastatin 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Primary hypercholesterolaemia (heterozygous familial and non-familial) in paediatric patient (10 -17 years of age): The recommended initial dosage is 10 mg once daily and the maximum recommended dosage is 20 mg daily. The dosages exceeding 20 mg daily have not been studied for safety and efficacy in this patient population. Adjustments should be made at 106 intervals of 4 week or more.
Homozygous familial hypercholesterolaemia: The usual dosage is 10 to 80 mg once daily and should be used as an adjunct to other lipid-lowering therapies or when such therapies are unavailable.
Use in patients with renal impairment: Dosage modification is not necessary.
Use in patients with hepatic impairment: Atorvastatin should be used with caution in patients with hepatic impairment and contraindicated in patients with active liver disease, including unexplained, persistent elevations in hepatic aminotransferase concentrations.
Use in patients with Geriatric: No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population. If an increase in AST or ALT of 3 times the ULN or grater persists, withdrawal or a reduction of dose of atorvastatin is recommended.
Use in concomitant with other medicinal compounds: The dosage of atorvastatin should not exceed 10 mg when concomitant with cyclosporine, telaprevir, or the combination tipranavir/ritonavir.
MODE OF ADMINISTRATION: TOVASTIN must be administered orally and swallowed whole with liquid anytime with or without food.
Overdosage
Symptoms: Myopathy such as unexplained muscle pain, weakness, or tenderness with creatine phosphokinase values above 10 times the upper limit of normal.
Treatment: Specific treatment is not available for Atorvastatin overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
Contraindications
TOVASTIN is contraindicated in persons with a history of hypersensitivity reaction to atorvastatin, any of its components or atorvastatin.
TOVASTIN is contraindicated in patient with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.
TOVASTIN is contraindicated in patients during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate.
Warnings
Warning according to notification of Ministry of Public Health: Do not use this medication in pregnant women and nursing women.
Do not use this medication in patients with hepatic impairment.
Stop taking this medication and see the doctors in patients with musculoskeletal disorder such as muscles pain, back pain or limb pain.
Should monitor the liver function test in 6-week and 12-weeek before and after taking this medication. For the patient who continually taking this medication should monitor every 6 month or following the recommendation of doctor. Stop taking this medication and see the doctors, if the transaminase enzyme level is higher than three times of the upper normal limit.
This medication should be used with caution in combination with digoxin, warfarin because those medication level in serum will increase.
The concomitant use of this medication with azole antifungals (e.g. ketoconazole, itraconazole), macrolides (e.g. erythromycin, clarithromycin), HIV protease inhibitors (e.g. indinavir ritonavir, nelfinavir, saquinavir), verapamil, diltiazem, gemfibrozil, nicotinic acid, cyclosporine, amiodarone resulted in increased risk of myopathy or rhabdomyolysis.
Using this medication in patients with renal or hepatic impairment or alcoholism or hypothyroidism may increase the risk of rhabdomyolysis.
Used with caution in concomitant use with colchicines especially geriatric patients or the patient with renal impairment because of the risk of myopathy or rhabdomyolysis.
This medication may increase the risk of hyperglycemia.
Special Precautions
Hepatic effects: Statins have been associated with biochemical abnormalities of liver function. Elevations in hepatic transaminases were dose dependent. Liver function tests should be performed before the initiation of treatment and periodically thereafter. The US Food and Drug Administration (FDA) concluded that serious statin-related liver injury is rate and unpredictable in individual patients and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. The ACC/AHA cholesterol management guideline recommends that baseline measurement of transaminase (ALT) levels should be performed before initiating statin therapy. In addition, the FDA has indicated that if the baseline hepatic transaminases are normal, further hepatic monitoring is not needed. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise such as unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of the skin or sclera. Persistent increases in transaminases of greater than 3 times the upper limit of normal (ULN), reduction of dose or withdrawal of atorvastatin is recommended. The incidence of these abnormalities with atorvastatin was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, atorvastatin therapy should be promptly interrupted. If an alternate etiology is not found, atorvastatin therapy should not be restarted.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease, or who have signs suggestive of liver disease such as unexplained aminotransferase elevations, and jaundice. Active liver disease or unexplained persistent transaminase elevations are contraindications for the use of HMG-CoA reductase inhibitors.
Musculoskeletal effects: Myalgia, myositis, and myopathy have been reported occasionally in patients receiving statins, including atorvastatin and may lead to rhabdomyolysis which presented by increased creatine kinase (CK) levels exceeding 10 times the upper limit of normal (ULN). Rhabdomyolysis with acute renal failure secondary to myoglobinuria also has been reported rarely.
In addition, Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patient treatment with statins. IMNM is clinically characterised by proximal muscle weakness and elevated CK concentration, which persist despite discontinuation of statin treatment.
The risk of myopathy is increased in geriatric patients (65 years of age or older) and patients with uncontrolled hypothyroidism or renal impairment. Those patients should be more closely monitored for adverse musculoskeletal effects. The risk of myopathy 176 may also be increased with the concomitant use of cyclosporine, gemfibrozil and other fibric acid derivates, potent inhibitors of CYP3A4; azole antifungals, boceprevir, erythromycin, niacin, or HIV protease inhibitors and its combination (tipranavir/ritonavir). In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended. Patients should be asked to promptly report unexplained muscle pain, tenderness, weakness or brown urine, especially if accompanied by malaise or fever.
Furthermore, the ACC/AHA cholesterol management guideline recommends against routine measurement of CK in individuals receiving statin therapy. However, baseline CK concentration measurement is reasonable in adults at increased risk of developing adverse musculoskeletal events before initiation of statin therapy. Those events include patient with personal or family history of statin intolerance or muscle disease, patient receiving concomitant therapy with myotoxic drugs. During statin therapy, it is useful to measure CK concentration in adults who experiencing muscle symptoms such as pain, tenderness, stiffness, cramping, weakness, generalized fatigue. The National Heart, Lung, and Blood Institute (NHLB1)-appointed expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that baseline CK concentrations should be obtained before initiating statin therapy in pediatric patients. In addition, routine monitoring for muscle toxicity is strongly recommended in children and adolescents receiving statin therapy.
Endocrine effects: Increase in HbA1C and fasting serum glucose levels have been reported. and the ACC/AHA cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus according to current diabetes screening guidelines. If diabetes mellitus develops during statin therapy, patient should be encouraged to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of atherosclerotic cardiovascular disease (ASCVD).
Caution should be exercised if a statin is used concomitantly with drugs that may decrease the concentrations or activity of endogenous steroid hormones such as spironolactone, and cimetidine.
Use in patients with recent stroke or transient ischemic attack: In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in hypercholesterolemic patients without coronary heart disease (CHD) who had a stroke or transient ischemic attack (TIA), there was a higher incidence of hemorrhagic stroke in patients initiated on atorvastatin 80 mg compared with placebo. The incidence of nonfatal hemorrhagic stroke was substantially higher with atorvastatin compared with placebo. The increased risk of developing hemorrhagic stroke was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry.
Use In Pregnancy & Lactation
Pregnancy: Category X according to US pregnancy category; studies in animals and pregnant women have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. It is unknown if atorvastatin or its active metabolites cross the placenta in humans. Atorvastatin is unlikely to cross the placenta because of its relatively high molecular weight and extensive protein binding. However, HMG-CoA inhibitors should be discontinued prior to pregnancy (ADA 2013). If treatment of dyslipidemias is needed in pregnant women or in women of reproductive age, other agents are preferred (Berglund 2012; Stone 2013).
Labor and delivery: The effects of Atorvastatin on labor and delivery in pregnant woman are unknown.
Lactation: Atorvastatin is probably distributed into human milk because a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions in nursing infants, women who require atorvastatin therapy should not breast-feed their infants.
Adverse Reactions
Very common effects (>1:10): Gastrointestinal disorders: diarrhea.
Musculoskeletal and connective tissue disorders: arthralgia.
Respiratory disorders: nasopharyngitis.
Common effects (>1:100 to <1:10): Cardiovascular: hemorrhagic stroke.
Central nervous system disorders: insomnia.
Metabolism and nutrition disorders: hyperglycemia.
Gastrointestinal disorders: nausea, dyspepsia.
Immune system disorders: allergic reaction.
Nervous system disorders: headache.
Respiratory disorders: pharyngolaryngeal pain.
Hepatobiliary disorders: abnormal liver function test, increased serum transaminases.
Musculoskeletal and connective tissue disorders: myalgia, muscle spasm, limb pain.
Uncommon effects (>1:1,000 to <1:100): Metabolism and nutrition disorders: hypoglycemia, weight gain, anorexia.
Nervous system disorders: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia (reversible).
Eye disorders: blurred vision.
Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders: vomiting, abdominal pain, eructation, pancreatitis.
Skin and subcutaneous tissue disorders: Uncommon: skin rash, urticaria, pruritus, alopecia.
Musculoskeletal and connective tissue disorders: neck pain, muscle fatigue.
General disorders and administration site conditions: pyrexia, malaise chest pain, peripheral edema, fatigue.
Drug Interactions
Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4). Concomitant administration of medicinal products that are inhibitors of CYP3A4 may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The potent CYP3A4 inhibitors such as cyclosporine, clarithromycin, itraconazole, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, should be avoided if possible. Moreover, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.
Furthermore, atorvastatin and its metabolites are substrate to transport proteins such as the hepatic uptake transporter organic anion transport polypeptide (OATP) 1B1. The drug that inhibit OATP1B1 such as cyclosporine. Concomitant use of atorvastatin (10 mg daily for 20 days) and cyclosporine (5.2 mg/kg daily), atorvastatin peak plasma concentration and AUC were increased by 10.7- and 8.7-fold, respectively.
Otherwise, concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 such as efavirenz, rifampin, St. John's Wort, can lead to variable reductions in plasma concentrations of atorvastatin.
The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy. Nevertheless, if concomitant administration cannot be avoided, a dose reduction and clinical carefully monitoring for efficacy is recommended.
Clarithromycin/ Erythromycin: Concomitant use of atorvastatin (80 mg daily for 8 days) and clarithromycin (500 mg twice daily for 9 days), atorvastatin peak plasma concentration and AUC were increased by 5.4- and 4.4-fold, respectively. Following concomitant use of atorvastatin (10 mg single dose) and erythromycin (500 mg 4 times daily for 7 days), atorvastatin peak plasma concentration and AUC were increased by 38 and 33%, respectively. However, concomitant use should be weight between the benefit and the risk of myopathy.
During the clarithromycin therapy, the lowest necessary dosage of atorvastatin should not exceed 20 mg daily and should be carefully monitored for manifestations of muscle pain, tenderness, or weakness.
Rifampin: Administration of rifampin (600 mg once daily for 5 days) followed by delayed administration of atorvastatin (40 mg as a single dose) resulted in 40 and 80% decreased in atorvastatin peak plasma concentration and AUC, respectively, while simultaneous administration of the drugs (rifampin 600 mg once daily for 7 days with atorvastatin 40 mg as a single dose) resulted in 2.7-fold and 30% increases in atorvastatin peak plasma concentration and AUC, respectively. Therefore, if atorvastatin and rifampin are used concomitantly, these drugs should be administered simultaneously.
Fibric acid derivatives: The use of Fibric acid derivatives such as gemfibrozil, fenofibrate with atorvastatin increases the risk of myopathy, including rhabdomyolysis. Concomitant administration should be avoided and weighed the benefits of concomitant use against the possible risk of myopathy. The lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should be appropriately monitored for muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug. The ACC/AHA cholesterol management guideline states that the combination of fenofibrates and low- or moderate-intensity statin therapy may be considered only if the benefits from atherosclerotic cardiovascular disease (ASCVD) risk reduction or triglyceride lowering (when triglyceride concentrations exceed 500 mg/dL) outweigh the potential risk of adverse effects.
Itraconazole: Concomitant use of atorvastatin (40 mg as a single dose) and itraconazole (200 mg once daily for 4 days), atorvastatin peak plasma concentration and AUC were increased by 20% and 3.3-fold, respectively. During the itraconazole therapy, the lowest necessary dosage of atorvastatin should not exceed 20 mg daily.
Antacid: Coadministration with aluminum hydroxide/magnesium hydroxide suspension decreased atorvastatin levels by approximately 35% but LDL-C reduction was not altered.
Colestipol: Atorvastatin co-administered with colestipol decreased plasma concentrations of atorvastatin approximately 25%. However, LDL-C reduction was greater when co-administration than when either medicinal product was given alone.
Colchicine: Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Digoxin: Concomitant use of atorvastatin (80 mg once daily for 14 days) and digoxin (0.25 mg once daily for 20 days) resulted in 20 and 15% increases in digoxin peak plasma concentration and AUC, respectively. Therefore, patient receiving such concomitant therapy should be monitored digoxin levels and adjusted the dosage as needed.
Oral contraceptives: Concomitant use of atorvastatin (40 mg once daily for 22 days) and an oral contraceptive (ethinyl estradiol 35 mcg with norethindrone 1 mg for 2 months) resulted in 30 and 19% increases in ethinyl estradiol peak plasma concentration and AUC, respectively, and 23 and 28% increases in norethindrone peak plasma concentration and AUC, respectively. This interaction should be considered when selecting oral contraceptives for patients receiving atorvastatin.
Warfarin: Atorvastatin had no clinically important effect on prothrombin time (PT) when administered to patients receiving long-term warfarin therapy.
Grapefruit juice: Because grapefruit juice contains some components that inhibit CYP3A4, ingestion of grapefruit juice may lead to increase atorvastatin concentration. Concomitant use of atorvastatin (40 mg as a single dose) with grapefruit juice (240 ml once daily), atorvastatin peak plasma concentration and AUC were increased by 16 and 37%, respectively. Therefore, avoid concomitant use atorvastatin with large quantities of grapefruit juice (at least one liter daily) may result in increased plasma levels of atorvastatin and risk of myopathy.
Storage
Store below 30°C.
ATC Classification
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab 40 mg (white, oval, biconvex film-coated tablets with half-scored line between debossed "T" and "O" on one side 18 and "40" on the other side) x 3 x 10's, 10 x 10's.
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