LIPITOR Atorvastatin Calcium 20mg Tablet 1's

Atorvastatin is indicated as an adjunct to diet for the treatment of patients with elevated total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and triglycerides (TG) and to increase high density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb), elevated serum TG levels (Fredrickson Type IV), and for patients with dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
Atorvastatin is also indicated for the reduction of total-C and LDL-C in patients with homozygous familial hypercholesterolemia.
Prevention of Cardiovascular Complications: In patients without clinically evident cardiovascular disease (CVD), and with or without dyslipidemia, but with multiple risk factors for coronary heart disease (CHD) such as smoking, hypertension, diabetes, low HDL-C, or a family history of early CHD, atorvastatin is indicated to: Reduce the risk of fatal CHD and non-fatal myocardial infarction (MI); Reduce the risk of stroke; Reduce the risk of revascularization procedures and angina pectoris.
In patients with clinically evident CHD, atorvastatin is indicated to: Reduce the risk of non-fatal MI; Reduce the risk of fatal and non-fatal stroke; Reduce the risk for revascularization procedures; Reduce the risk of hospitalization for congestive heart failure (CHF); Reduce the risk of angina.
As adjunct to lifestyle changes, such as proper diet and exercise, intensive atorvastatin treatment has been shown to halt the progression of atherosclerosis (total atheroma or plaque volume) in patients with coronary artery disease and other individuals who are at high risk for cardiovascular disease.
Chronic Kidney Disease: In patients with diabetes with moderately decreased eGFR, Atorvastatin is indicated to reduce the risk for cardiovascular disease.
In patients with clinically evident coronary heart disease and CKD not requiring dialysis, atorvastatin is indicated to reduce the risk of major cardiovascular events including stroke.
In patients with clinically evident coronary heart disease and/or diabetes with microalbuminuria, atorvastatin is indicated to reduce the rate of GFR decline and progression of CKD.
Pediatric Patients (10-17 years of age): Atorvastatin is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and post-menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if, after an adequate trial of diet therapy, the following findings are present: LDL-C remains ≥190 mg/dL or LDL-C remains ≥160 mg/dL and there is a positive family history of premature CVD or two or more other CVD risk factors are present in the pediatric patient.

 

General: Before instituting therapy with atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise and weight reduction in obese patients, and to treat the underlying medical problems. The patient should continue on a standard cholesterol-lowering diet during treatment with atorvastatin. The dosage range is 10 mg to 80 mg once daily. Doses may be given any time of the day, with or without food. Starting and maintenance dosage should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within 2 to 4 weeks, and dosage adjusted accordingly.
Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia: The majority of patients are controlled with 10 mg atorvastatin once daily. 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.
Homozygous Familial Hypercholesterolemia: In a compassionate-use study of patients with homozygous familial hypercholesterolemia, most patients responded to 80 mg atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).
Severe Dyslipidemias in Pediatric Patients: For patients aged 10 years and above, the recommended starting dose is 10 mg atorvastatin once daily. The dose may be increased to 80 mg daily, according to the response and tolerability. Doses should be individualized according to the recommended goal of therapy (see Indications and Pharmacology: Pharmacodynamics under Actions). Adjustments should be made at intervals of 4 weeks or more.
Experience in pediatric patients younger than 10 years of age is derived from open-label studies (see Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics: Special Populations under Actions).
Use in Patients with Hepatic Insufficiency: See Contraindications and Precautions.
Use in Patients with Renal Insufficiency: Renal disease has no influence on plasma concentrations or on LDL-C reduction with atorvastatin. Thus, no dose adjustment is required (see Precautions).
Use in the Elderly: No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population (see Pharmacology: Pharmacokinetics: Special Populations under Actions).
Use in Combination with Other Medicinal Compounds: In cases where co-administration of atorvastatin with cyclosporine, telaprevir, the combination tipranavir/ritonavir, or glecaprevir/pibrentasvir is necessary, the dose of atorvastatin should not exceed 10 mg.
Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine.
Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have also been noted with other human immunodeficiency virus (HIV) protease inhibitors (lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir and nelfinavir), hepatitis C (HCV) protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), clarithromycin, itraconazole, and letermovir. Caution should be used when co-prescribing atorvastatin, and appropriate clinical assessment is recommended to ensure that the lowest dose of atorvastatin necessary is employed (see Skeletal Muscle Effects under Precautions and Interactions).

 

Overdosage

May be taken with or without food.

Atorvastatin is contraindicated in patients who have: Hypersensitivity to any component of this medication, such as, atorvastatin calcium, calcium carbonate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, polysorbate 80, hydroxypropyl cellulose, purified water, magnesium stearate, opadry white, simethicone emulsion, and candelilla wax.
Active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal (ULN) or who are: Pregnant, breast-feeding, or of childbearing potential who are not using adequate contraceptive measures. Atorvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus.

Hepatic Effects: As with other lipid-lowering agents of the same class, moderate (>3 x ULN) elevations of serum transaminases have been reported following therapy with atorvastatin. Liver function was monitored during pre-marketing as well as post-marketing clinical studies of atorvastatin at doses of 10 mg, 20 mg, 40 mg and 80 mg.
Persistent increases in serum transaminases (>3 x ULN on two or more occasions) occurred in 0.7% of patients who received atorvastatin in these clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for the 10 mg, 20 mg, 40 mg and 80 mg doses respectively.
Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced, or drug treatment interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggesting liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve(s). Should an increase in ALT or AST of >3 x ULN persist, reduction of dose or withdrawal of atorvastatin is recommended. Atorvastatin can cause an elevation in transaminases (see Adverse Reactions).
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 contraindications to the use of atorvastatin (see Contraindications).
Skeletal Muscle Effects: Myalgia has been reported in atorvastatin-treated patients (see Adverse Reactions). Myopathy, defined as muscle ache or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 x ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or if myopathy is diagnosed or suspected. The risk of myopathy is increased with concurrent administration of drugs that increase the systemic concentration of atorvastatin (see Interactions and Pharmacology: Pharmacokinetics under Actions). Many of these drugs inhibit cytochrome P450 3A4 (CYP 3A4) metabolism and/or drug transport. CYP 3A4 is the primary hepatic isozyme known to be involved in the biotransformation of atorvastatin. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals, HIV/HCV protease inhibitors, HCV NS5A/NS5B inhibitors, letermovir, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Therefore, lower starting and maintenance doses of atorvastatin should also be considered when taken concomitantly with the aforementioned drugs (see Dosage & Administration). The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin is advised during fusidic acid therapy (see Interactions). Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Atorvastatin may cause an elevation of CPK (see Adverse Reactions).
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins (see Adverse Reactions). IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment, positive anti-HMG CoA reductase antibody and improvement with immunosuppressive agents.
As with other drugs in this class, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or with a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, (e.g., severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; and uncontrolled seizures).
Hemorrhagic Stroke: A post-hoc analysis of a clinical study in 4731 patients without CHD who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and were initiated on atorvastatin 80 mg revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg group compared to placebo (55 atorvastatin vs. 33 placebo). Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke (7 atorvastatin vs. 2 placebo). However, in patients treated with atorvastatin 80 mg there were fewer strokes of any type (265 vs. 311) and fewer CHD events (123 vs. 204) (see Pharmacology: Pharmacodynamics: Recurrent Stroke under Actions).
Endocrine Function: Increases in hemoglobin A1c (HbA1c) and fasting serum glucose levels have been reported with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, including atorvastatin. The risk of hyperglycemia, however, is outweighed by the reduction in vascular risk with statins.
Effects on Ability to Drive and Use Machines: None known.

 

Use In Pregnancy & Lactation

Atorvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Lipitor vs. 7311 placebo) patients treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of patients on placebo.
The most frequent (≥1%) adverse effects that may be associated with atorvastatin therapy, reported in patients participating in placebo-controlled clinical studies include: Infections and infestations: Nasopharyngitis.
Metabolism and nutrition disorders: Hyperglycemia.
Respiratory, thoracic and mediastinal disorders: Pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders: Diarrhea, dyspepsia, nausea, flatulence.
Musculoskeletal and connective tissue disorders: Arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.
Investigations: Liver function test abnormal, blood creatine phosphokinase increased.
Additional adverse effects reported in atorvastatin placebo-controlled clinical trials include: Psychiatric disorders: Nightmare.
Eye disorders: Vision blurred.
Ear and labyrinth disorders: Tinnitus.
Gastrointestinal disorders: Abdominal discomfort, eructation.
Hepatobiliary disorders: Hepatitis, cholestasis.
Skin and subcutaneous tissue disorders: Urticaria.
Musculoskeletal and connective tissue disorders: Muscle fatigue, neck pain.
General disorders and administration site conditions: Malaise, pyrexia.
Investigations: White blood cells urine positive.
Not all effects listed previously have been causally associated with atorvastatin therapy.
Pediatric Patients: Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections.
No clinically significant effect on growth and sexual maturation was observed in a 3-year study in children ages 6 and above based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight. The safety and tolerability profile in pediatric patients was similar to the known safety profile of atorvastatin in adult patients.
Post-marketing Experience: In post-marketing experience, the following additional undesirable effects have been reported: Blood and lymphatic system disorders: Thrombocytopenia.
Immune system disorders: Allergic reactions (including anaphylaxis).
Injury, poisoning, and procedural complications: Tendon rupture.
Metabolism and nutrition disorders: Weight gain.
Nervous system disorders: Hypoesthesia, amnesia, dizziness, dysgeusia.
Gastrointestinal disorders: Pancreatitis.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme, bullous rashes.
Musculoskeletal and connective tissue disorders: Rhabdomyolysis, immune mediated necrotizing myopathy, myositis, back pain.
General disorders and administration site conditions: Chest pain, peripheral edema, fatigue.

 

The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying doses of niacin or CYP 3A4/transporter inhibitors (e.g., erythromycin and azole antifungals), (see as follows, also Use in Combination with Other Medicinal Compounds under Dosage & Administration and Skeletal Muscle Effects under Precautions).
Inhibitors of CYP 3A4: Atorvastatin is metabolized by CYP 3A4. Concomitant administration of atorvastatin with inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
Erythromycin/Clarithromycin: Co-administration of atorvastatin with erythromycin (500 mg four times daily) or clarithromycin (500 mg twice daily), known inhibitors of CYP 3A4, was associated with higher plasma concentrations of atorvastatin (see Skeletal Muscle Effects under Precautions and Pharmacology: Pharmacokinetics under Actions).
Protease Inhibitors: Co-administration of atorvastatin with protease inhibitors, known inhibitors of CYP 3A4, was associated with increased plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Diltiazem Hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Cimetidine: An atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen (see Pharmacology: Pharmacokinetics under Actions).
Itraconazole: Concomitant administration of atorvastatin (20-40 mg) with itraconazole (200 mg) was associated with an increase in atorvastatin AUC (see Pharmacology: Pharmacokinetics under Actions).
Grapefruit Juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L/day) (see Pharmacology: Pharmacokinetics under Actions).
Transporter Inhibitors: Atorvastatin is a substrate of the hepatic transporters (see Pharmacology: Pharmacokinetics under Actions).
Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (ratio of AUC: 8.7; see Pharmacology: Pharmacokinetics under Actions). Cyclosporine is an inhibitor of organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, multi-drug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP) as well as CYP 3A4, thus it increases exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29; see Pharmacology: Pharmacokinetics under Actions). Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine.
Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Use with caution and lowest dose necessary (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Inducers of CYP 3A4: Concomitant administration of atorvastatin with inducers of CYP 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin (CYP 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations (see Pharmacology: Pharmacokinetics under Actions).
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides decreased atorvastatin plasma concentrations (ratio of AUC: 0.66); 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 were lower (ratio of concentration: 0.74) when colestipol was administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased (ratio of AUC: 1.15) following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Azithromycin: Co-administration of atorvastatin (10 mg once daily) with azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Oral Contraceptives: Co-administration of atorvastatin with an oral contraceptive containing norethindrone and ethinyl estradiol increased the area under the concentration vs. time curve (AUC) values for norethindrone (ratio of AUC: 1.28) and ethinyl estradiol (ratio of AUC: 1.19). These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: An atorvastatin interaction study with warfarin was conducted, and no clinically significant interactions were seen.
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.
Amlodipine: In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg with amlodipine 10 mg resulted in an increase in exposure to atorvastatin (ratio of AUC: 1.18) which was not clinically meaningful.
Fusidic Acid: Although interaction studies with atorvastatin and fusidic acid have not been conducted, there is an increased risk of rhabdomyolysis in patients receiving a combination of statins, including atorvastatin, and fusidic acid. The mechanism of this interaction is not known. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Other Concomitant Therapy: In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.

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Action

Dyslipidaemic Agents