Lipitor

Atorvastatin calcium.

Lipitor contains the following inactive ingredients: Calcium carbonate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, polysorbate 80, hydroxypropyl cellulose, magnesium stearate, Opadry White YS-1-7040, Antifoam AF Emulsion Medical.
Atorvastatin calcium is (C₃₃H₃₄FN₂O₅)₂Ca·3H₂O with a molecular weight of 1209.42.
Atorvastatin calcium is a white to off-white crystalline powder, practically insoluble in aqueous solution of pH <4. It is very slightly soluble in distilled water, pH 7.4 phosphate buffer and acetonitrile, slightly soluble in ethanol and freely soluble in methanol.

Atorvastatin calcium is a synthetic lipid-lowering agent, which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Pharmacology: Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that coverts of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B). Atorvastatin also reduces very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG), and produces variable increases in high-density lipoprotein cholesterol (HDL-C). Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL in patients with homozygous familial hypercholesterolemia, a population that has not normally responded to lipid-lowering medication.
In a dose-response study, atorvastatin, (10-80 mg) reduced total-C (30-46%), LDL-C (41-61%), apolipoprotein B (34-50%) and triglycerides (14-33%). These results are consistent in patients with heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.
In patients with isolated hypertriglyceridemia, atorvastatin reduces total-C, LDL-C, VLDL-C, apo-B, TG, and non-HDL-C, and increases HDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C).
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median percent increases from baseline in HDL-C for atorvastatin (10 mg-80 mg) were 5.1% to 8.7% in a non-dose-related manner. Additionally, analysis of this pooled data demonstrated significant dose related decreases in total-C/HDL-C and LDL-C/HDL-C ratios, ranging from -29% to -44% and -37% to -55%, respectively.
The effects of atorvastatin on ischemic events and total mortality were studied in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study (MIRACL). This multicenter, randomized, double-blind, placebo-controlled study followed 3086 patients with acute coronary syndromes; unstable angina or non-Q wave myocardial infarction (MI). Patients were treated with standard care, including diet, and either atorvastatin 80 mg daily or placebo for a median duration of 16 weeks. The final LDL-C, total-C, HDL-C and TG levels were 72 mg/dL, 147 mg/dL, 48 mg/dL, 139 mg/dL, respectively, in the atorvastatin group, and 135 mg/dL, 217 mg/dL, 46 mg/dL, and 187 mg/dL, respectively, in the placebo group. Atorvastatin significantly reduced the risk of ischemic events and death by 16%. The risk of experiencing rehospitalization for angina pectoris with documented evidence of myocardial ischemia was significantly reduced by 26%. Atorvastatin reduced the risk of ischemic events and death to a similar extent across the range of baseline LDL-C. In addition, atorvastatin reduced the risk of ischemic events and death to similar extents in patients with non-Q wave MI and unstable angina, as well as in males and females and in patients ≤65 years of age and >65 years of age.
Prevention of Cardiovascular Complications: In the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal coronary heart disease (CHD) was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean age 63 years), without a previous MI and with total-C levels <6.5 mmol/L (251 mg/dL). Additionally all patients had at least three of the following cardiovascular (CV) risk factors: male gender, age >55 years, smoking, diabetes, history of CHD in a first-degree relative, total C: HDL >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific electrocardiogram (ECG) abnormality, proteinuria/albuminuria. In this double-blind, placebo-controlled study, patients were treated with antihypertensive therapy (goal BP <140/90 mm Hg for non-diabetic patients, <130/80 mm Hg for diabetic patients) and allocated to either atorvastatin 10 mg daily (n=5168) or placebo (n=5137). As the effect of atorvastatin treatment compared to placebo exceeded the significance threshold during an interim analysis, the ASCOT-LLA was terminated early at 3.3 years instead of 5 years. Additionally, blood pressure was well controlled and similar in patients assigned atorvastatin and placebo. These changes persisted throughout the treatment period.
Atorvastatin significantly reduced the rate of the following events: see Table 1.


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The total mortality and CV mortality have not been significantly reduced although a favorable trend was observed. In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on fatal and non-fatal cardiovascular disease (CVD) was assessed in 2838 patients with type 2 diabetes 40 to 75 years of age, without prior history of CVD and with LDL ≤4.14 mmol/L (160 mg/dL) and TG ≤6.78 mmol/L (600 mg/dL). Additionally, all patients had at least one of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.
In this randomized, double-blind, multicenter, placebo-controlled trial, patients were treated with either atorvastatin 10 mg daily (n=1428) or placebo (n=1410) for a median follow-up of 3.9 years. As the effect of atorvastatin treatment on the primary endpoint reached the predefined stopping rules for efficacy, CARDS was terminated 2 years earlier than anticipated.
The absolute and relative risk reduction effects of atorvastatin are as follows: see Table 2.


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There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A relative risk reduction in death of 27% (82 deaths in the placebo group compared to 61 deaths in the treatment arm) has been observed with a borderline statistical significance (p=0.0592).
The overall incidence of adverse events or serious adverse events was similar between the treatment groups.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients: In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia or severe hypercholesterolemia were randomized to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥190 mg/dL or 2) a baseline LDL-C ≥160 mg/dL and positive family history of familial hypercholesterolemia or documented premature CVD in a first- or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the atorvastatin group compared to 230.0 mg/dL (range: 160.0-324.5 mg/dL) in the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >130 mg/dL. The number of atorvastatin-treated patients who required up-titration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C, TG, and apo B during the 26-week double-blind phase (see Table 3).


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The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26 week double-blind phase.
In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual cycle length in girls. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Pharmacodynamics: Atorvastatin and some of its metabolites are pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which is the principal site of cholesterol synthesis and LDL clearance. LDL-C reduction correlates better with drug dose than it does with systemic drug concentration. Individualization of drug dosage should be based on therapeutic response (see Dosage & Administration).
Pharmacokinetics: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1-2 hrs. 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 C_max and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C_max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same whatever the time of day for drug administration (see Dosage & Administration).
Distribution: Mean volume of distribution of atorvastatin is approximately 381 L. 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 (see Contraindications and Precautions).
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various β-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 hepatic cytochrome P-450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme (see Precautions and Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, Lipitor does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hrs, but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hrs due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters MDR1 and BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.
Special Populations: Elderly: Plasma concentrations of atorvastatin are higher (approximately 40% for C_max and 30% for AUC) in healthy, elderly subjects (age >65 years) than in young adults.
Pediatric: Pharmacokinetic studies have not been conducted in the pediatric population.
Gender: Plasma concentrations of atorvastatin in women differ (approximately 20% higher for C_max and 10% lower for AUC) from those in men. However, there were no clinically significant differences in lipid effects between men and women.
Renal Insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin. Thus, dose adjustment in patients with renal dysfunction is not necessary (see Dosage & Administration).
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 Insufficiency: Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in C_max and 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B) (see Contraindications). C_max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C_max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease.
Drug Interactions: The effect of co-administered drugs on the pharmacokinetics of atorvastatin as well as the effect of atorvastatin on the pharmacokinetics of co-administered drugs are summarized as follows (see Precautions and Interactions). (See Table 4 and Table 5.)


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Adjunct to diet for the reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolemia, combined (mixed) hyperlipidemia, and heterozygous and homozygous familial hypercholesterolemia when response to diet and other nonpharmacological measures are inadequate.
Prevention of Cardiovascular Complications: In patient with hypertension (≥40 years) and dyslipidemia with at least 3 risk factors for future cardiovascular events eg, left ventricular hypertrophy (LVH), ECG abnormalities, non-insulin-dependent diabetes mellitus (NIDDM), peripheral vascular disease, post-history of cerebrovascular events including transient ischemic attack (TIA) ≥3 months previously, microalbuminuria/proteinuria, smoking (regular smoker within the last year of 20 cigarettes or cigars/week), TC/HDL-ratio ≥6, and history of coronary artery disease event in a first degree relative before age 55 (males) or 60 (women), atorvastatin is indicated to: Reduce the risk of fatal coronary heart disease and nonfatal myocardial infarction; stroke; revascularization procedures and angina pectoris.
Pediatric Patients (10-17 years): Adjunct to diet to reduce total-C, LDL-C and apo-B levels in boys and postmenarchal girls, 10-17 years, 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 cardiovascular disease or ≥2 other cardiovascular disease (CVD) risk factors are present in the pediatric patient.

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 underlying medical problems. The patient should continue on a standard cholesterol-lowering diet during treatment with atorvastatin. The usual starting dose is 10 mg once a day. The dosage range is 10-80 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 atorvastation, lipid levels should be analyzed within 2-4 weeks, and dosage adjusted accordingly.
Primary Hypercholesterolemia and Combined (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 response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Homozygous Familial Hypercholesterolemia: Adults: In a compassionate-use study of patients with homozygous familial hypercholesterolemia, most patients responded to 80 mg atorvastatin.
Heterozygous Familial Hypercholesterolemia: Children (10-17 years): The recommended starting dose of atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (dose >20 mg have not been studied in this patient population). Dose should be individualized according to the recommended goal of therapy (see Pharmacology: Pharmacodynamics under Actions and Indications). Adjustment should be made at intervals of 4 weeks or more.
Children: Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80 mg daily for 1 year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients.
Patients with Renal Insufficiency: Renal disease has no influence on the plasma concentrations or on the LDL-C reduction of atorvastatin; thus, no adjustment of the dose is required.
Patients with Hepatic Dysfunction: See Contraindications and Precautions.
Elderly: No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Use in Combination with Other Medicinal Compounds: In cases where co-administration of atorvastatin with cyclosporine, 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 Precautions and Interactions).

There is no specific treatment for atorvastatin overdosage. Should an overdosage occur, 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.

Patients who are hypersensitive to any component of Lipitor; have active liver disease or unexplained persistent elevations of serum transaminases >3 times the upper limit of normal (ULN).
Patients who are pregnant, breastfeeding 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.
Use in pregnancy & lactation: Atorvastatin is contraindicated in pregnancy. Women of childbearing potential should use 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. If the patient becomes pregnant while taking this drugs, therapy should be discontinued and the patient appraised of the potential hazard to the fetus.
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 hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women, therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.
Atorvastatain is contraindicated while breastfeeding. It is not known whether this drug is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking atorvastatin should not breastfeed.

Hepatic Effects: As with other lipid-lowering agents of the same class, moderate [>3 x upper limit of normal (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 given at doses of 10, 20, 40 and 80 mg.
Persistent increases in serum transaminases (>3 x ULN on ≥2 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 10, 20, 40, 80 mg doses, respectively. One patients in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were 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. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of Lipitor.
Liver function tests should be performed before the initiation of treatment and at 12 weeks following both the initiation therapy and any evaluation of dose, and periodically (semiannually) 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 times the upper limit of normal 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 aching 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 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 P-450 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, letermovir, HCV NS5A/NS5B or lipid-lowering 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 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 has been reported. A history of renal impairment may be a risks 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 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).
Hemorrhagic Stroke: A post-hoc analysis of a clinical study in 4731 patients without CHD who had a stroke or 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).
Information for Patient: Patient should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Adolescent females and women of childbearing potential should be counseled on appropriate contraceptive methods while on atorvastatin therapy (see Use in pregnancy & lactation under Contraindications).
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.

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 other underlying medical problems.
Information for the Patient: Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Atorvastatin was not carcinogenic in rats. The maximum dose used was 63-fold higher than the highest human dose (80 mg/day) on a mg/kg body weight basis and 8- to 16-fold higher based on AUC (0-24) values. In a 2-year study in mice, incidences of hepatocellular adenomas in males and hepatocellular carcinomas in females were increased at the maximum dose used, which was 250-fold higher than the biggest human dose on a mg/kg body weight basis. Systemic exposure was 6- to 11-fold higher based on AUC_(0-24).
All other chemically similar drugs in this class have induced tumors in both mice and rats at multiples of 12-125 times their highest recommended clinical doses, on a mg/kg body weight basis.
Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro test with and without metabolic activation or in 1 in vivo assay. It was negative in the Ames test with Salmonella typhimurium and Escherichia coli, and in vitro HGPRT forward mutation assay in Chinese hamster lung cells. Atorvastatin did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay and was negative in the in vivo mouse micronucleus test.
No adverse effects on fertility or reproduction were observed in male rats given doses of atorvastatin up to 175 mg/kg/day or in female rats given doses up to 225 mg/kg/day. These doses are 100-140 times the maximum recommended human dose on a mg/kg basis. Atorvastatin caused no adverse effects on sperm or semen parameters, or on reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years.
Use in Children: Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80 mg/day for 1 year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients.

Atorvastatin is contraindicated in pregnancy. Women of childbearing potential should use 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. If the patient becomes pregnant while taking this drugs, therapy should be discontinued and the patient appraised of the potential hazard to the fetus.
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 hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women, therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.
Atorvastatain is contraindicated while breastfeeding. It is not known whether this drug is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking atorvastatin should not breastfeed.

Atorvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. Less than 2% of patients were discontinued from clinical trials due to side effects attributed to atorvastatin. In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 Lipitor vs 7311 placebo) patient treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
The most frequent (≥1%) adverse effects associated with atorvastatin therapy, in patients participating in controlled clinical studies were: Infections and Infestations: nasopharyngitis.
Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, epistaxis.
Psychiatric Disorders: insomnia, nightmare.
Nervous System Disorders: headache.
Gastrointestinal Disorders: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal and Connective Tissue Disorders: myalgia, arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, joint swelling.
Investigations: liver function test abnormal, blood creatine phosphokinase increased.
General Disorders and Administration Site Conditions: asthenia.
The following additional adverse effects have been reported in atorvastatin clinical trials: Eye Disorders: vision blurred.
Metabolism and Nutrition Disorders: hypoglycaemia, hyperglycemia, anorexia.
Nervous System Disorders: peripheral neuropathy, paresthesia.
Ear and Labyrinth Disorders: tinnitus.
Gastrointestinal Disorders: pancreatitis, vomiting, abdominal discomfort, eructation.
Hepatobiliary Disorders: hepatitis, cholestatic jaundice.
Skin and Subcutaneous Tissue Disorders: alopecia, pruritus, rash, urticaria.
Musculoskeletal and Connective Tissue Disorders: myopathy, myositis, muscle cramps, muscle fatigue, neck pain.
Reproductive System and Breast Disorders: impotence.
General Disorders and Administration Site Conditions: angioneurotic edema, malaise, pyrexia.
Cardiovascular: angina.
Investigations: white blood cells urine positive. Not all effects listed previously have been causally associated with atorvastatin therapy.
Pediatric Patients (10-17 years): Patients treated with atorvastatin had an adverse experience profile generally similar to that patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections.
In post-marketing experiences, 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 (eg, erythromycin and azole antifungals) (see Warnings).
Inhibitors of CYP 3A4: Atorvastatin is metabolized by cytochrome P-450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P-450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on CYP 3A4.
Erythromycin/Clarithromycin: Co-administration of atorvastatin and erythromycin (500 mg 4 times daily), or clarithromycin (500 mg twice daily) known inhibitors of cytochrome P-450 3A4, was associated with higher plasma concentrations of atorvastatin.
Protease Inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of CYP 3A4, was associated with increased plasma concentrations of atorvastatin.
Diltiazem Hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin.
Cimetidine: An atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen.
Itraconazole: Concomitant administration of atorvastatin (20-40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC.
Grapefruit Juice: Contains ≥1 components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L/day).
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 CYP3A4, thus it increases exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Dosage & Administration).
Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Co-administration of glecaprevir/pibrentasvir is not recommended. (see 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 Dosage & Administration).
The magnitude of CYP 3A4 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 Dosage & Administration).
Inducers of CYP 3A4: Concomitant administration of atorvastatin with inducers of CYP 3A4 (eg, efavirenz, rifampicin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, (CYP 3A4 induction and inhibiton of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations.
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased atorvastatin plasma concentrations by 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 were lower (approximately 25%) 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 atorvastatin 10 mg were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with atorvastatin 80 mg daily. Patients taking digoxin should be monitored appropriately.
Azithromycin: Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Oral Contraceptives: Co-administration with an oral contraceptive containing norethindrone and ethinyl estradiol increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: An atorvastatin interaction studies 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 and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin 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.
Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patient. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if an HMG-CoA reductase inhibitor as administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones eg, ketoconazole, spironolactone, and cimetidine.

Store below 25°C.
Shelf-Life: 36 months.

Dyslipidaemic Agents

C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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