Apo-Atorvastatin

Atorvastatin calcium.

Each tablet contains either 11 mg (or 22 mg, or 88 mg) atorvastatin calcium propylene glycol solvate, equivalent to 10 mg, 20 mg, and 80 mg free acid respectively, as the active ingredient.
Excipients/Inactive Ingredients: calcium acetate, croscarmellose sodium, sodium carbonate, microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, titanium dioxide.

Pharmacology: Pharmacodynamics: 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.
The empirical formula of Atorvastatin calcium is (C₃₃H₃₄FN₂O₅)₂Ca∙3H₂O) and its molecular weight is 1209.42.
Atorvastatin calcium is a white to off-white crystalline powder, practically insoluble in aqueous solutions of pH 4 and below. It is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol and freely soluble in methanol.
Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In patients with homozygous and heterozygous familial hypercholesterolemia (FH), non-familial forms of hypercholesterolemia, and mixed dyslipidemia, Atorvastatin reduces total-C (total cholesterol), LDL-C (low-density lipoprotein cholesterol), and apo B (apolipoprotein B). Atorvastatin also reduces VLDL-C (very-low-density lipoprotein cholesterol) and TG (triglycerides) and produces variable increases in HDL-C (high-density lipoprotein cholesterol).
Triglycerides and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
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%), apo B (34%-50%), and TG (14%-33%). These results are consistent in patients with heterozygous familial hypercholesterolemia, non-familial 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 IDL-C (intermediate density lipoprotein cholesterol).
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 (10-80 mg) were 5.1-8.7% 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.
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).
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 was assessed in 10,305 hypertensive patients 40-80 years of age (mean of 63 years), without a previous myocardial infarction (MI) and with total cholesterol (TC) levels ≤6.5 mmol/l (251 mg/dl). Additionally all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age ≥55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL ≥6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormalities (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study patients were treated with anti-hypertensive 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). Patients were followed for a median duration of 3.3 years. Blood pressure control throughout the trial was similar in patients assigned to Atorvastatin and placebo. (See Table 1.)

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The primary endpoint examined in ASCOT was the rate of fatal coronary heart disease or non-fatal (symptomatic and silent) myocardial infarction. These coronary events occurred in 1.9% of Atorvastatin treated patients compared to 3% of placebo treated subjects, a relative risk reduction of 36% (p=0.0005). There was no significant difference between groups for cardiovascular mortality (p=0.51) and all-cause mortality (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of Atorvastatin on fatal and non-fatal cardiovascular disease was assessed in 2838 patients with type 2 diabetes 40-75 years of age, without prior history of cardiovascular disease 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 1 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 effect of Atorvastatin is as follows: See Table 2.

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Secondary Prevention of Cardiovascular Events: In the Treating to New Targets Study (TNT), the effect of Atorvastatin 80 mg/day vs. Atorvastatin 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with Atorvastatin 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of Atorvastatin and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98 and 47 mg/dL during treatment with 80 mg of Atorvastatin and 99, 177, 152, 129 and 48 mg/dL during treatment with 10 mg of Atorvastatin.
Treatment with Atorvastatin 80 mg/day significantly reduced the rate of major cardiovascular events (MCVE) (434 events in the 80 mg/day group vs 548 events in the 10 mg/day group) with a relative risk reduction of 22%. (See Table 3.)

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There was no significant difference between the treatment groups for all-cause mortality: 282 (5.6%) in the Atorvastatin 10 mg/day group vs. 284 (5.7%) in the Atorvastatin 80 mg/day group. The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke were numerically smaller in the Atorvastatin 80 mg group than in the Atorvastatin 10 mg treatment group. The proportions of subjects who experienced non-cardiovascular death were numerically larger in the Atorvastatin 80 mg group than in the Atorvastatin 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with Atorvastatin 80 mg/day was compared to treatment with simvastatin 20-40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45 and 100 mg/dL during treatment with 80 mg of Atorvastatin and 105, 179, 142, 47 and 132 mg/dL during treatment with 20-40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI and resuscitated cardiac arrest): 411 (9.3%) in the Atorvastatin 80 mg/day group vs. 463 (10.4%) in the simvastatin 20-40 mg/day group, HR 0.89, 95% CI (0.78, 1.01), p=0.07.
There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the Atorvastatin 80 mg/day group vs. 374 (8.4%) in the simvastatin 20-40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the Atorvastatin 80 mg group and the simvastatin 20-40 mg group.
There were more serious adverse events and discontinuations due to adverse events in the high-dose Atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively). Persistent transaminase elevations (≥3x ULN twice within 4-10 days) occurred in 62 (1.3%) individuals with Atorvastatin 80 mg and in nine (0.2%) individuals with Atorvastatin 10 mg. Elevations of CK (≥10 x ULN) were low overall, but were higher in the high-dose Atorvastatin treatment group (13, 0.3%) compared to the low-dose Atorvastatin group (6, 0.1%).
Paediatric Population: Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old: An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of Atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥2.
The initial dose of Atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL-C of <3.35 mmol/L at Week 4 and if Atorvastatin was well tolerated.
Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old: In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and post-menarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to Atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received Atorvastatin for 26 weeks. 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 >3.36 mmol/l. Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase. The mean achieved LDLC value was 3.38 mmol/l (range: 1.81-6.26 mmol/l) in the Atorvastatin group compared to 5.91 mmol/l (range: 3.93-9.96 mmol/l) in the placebo group during the 26-week double-blind phase.
An additional paediatric study of Atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-18 years demonstrated that Atorvastatin (N=25) caused a significant reduction in LDL-C at week 26 (p<0.05) compared with colestipol (N=31).
A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to response (some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDLcholesterol was lowered by 36%.
The long-term efficacy of Atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Pharmacokinetics: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within one to two hours. Extent of absorption and plasma Atorvastatin concentrations increase in proportion to Atorvastatin dose. Atorvastatin tablets are 95% to 99% bioavailable compared with solutions. The absolute bioavailability of Atorvastatin is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9% respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether Atorvastatin is given with or without food. Plasma Atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration (see Dosage & Administration).
Distribution: Mean volume of distribution of Atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A red blood cell/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of Atorvastatin metabolism by hepatic cytochrome P450 3A4, consistent with increased plasma concentrations of Atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme. In vitro studies also indicate that Atorvastatin is a weak inhibitor of cytochrome P450 3A4. Atorvastatin coadministration did not produce a clinically significant effect in plasma concentrations of terfenadine, a compound predominantly metabolized by cytochrome P450 3A4; therefore, it is unlikely that Atorvastatin will significantly alter the pharmacokinetics of other cytochrome P450 3A4 substrates (see 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, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Atorvastatin is recovered in urine following oral administration.
Special Populations: Elderly: Plasma concentrations of Atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy, elderly subjects (aged ≥65 years) than in young adults. The ACCESS study specifically evaluated elderly patients with respect to reaching their NCEP treatment goals. The study included 1087 patients under 65 years of age, 815 patients over 65 years of age, and 185 patients over 75 years of age. No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Paediatric: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage ≥2 (N=24) paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated atorvastatin tablets once daily, respectively. Body weight was the only significant covariate in atorvastatin population PK model. Apparent oral clearance of atorvastatin in paediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of atorvastatin and o-hydroxyatorvastatin exposures.
Gender: Plasma concentrations of Atorvastatin in women differ (approximately 20% higher for Cmax 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 Cmax and 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B) (see Contraindications).
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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Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, 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 highest 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 to 125 times their highest recommended clinical doses, on a mg/kg body-weight basis.
Atorvastatin did not demonstrate mutagenic or clastogenic potential in four in vitro tests with and without metabolic activation or in one in vivo assay. It was negative in the Ames test with Salmonella typhimurium and Escherichia coli, and in the 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 to 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 two years.

Atorvastatin is indicated as an adjunct to lifestyle changes, including diet, for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, or combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb), elevated serum triglyceride levels (Fredrickson Type IV), and for patients with dysbetalipoproteinemia (Fredrickson Type III) when response to diet and other non-pharmacological measures is inadequate.
Atorvastatin also raises HDL-cholesterol and lowers the LDL/HDL and total cholesterol/HDL ratios.
Atorvastatin is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
Prevention of Cardiovascular Disease: Atorvastatin is indicated to reduce the risk of myocardial infarction in adult hypertensive patients without clinically evident coronary heart disease, but with at least three additional risk factors for coronary heart disease such as age ≥55 years, male sex, smoking, left ventricular hypertrophy, other specified abnormalities on ECG, microalbuminia or proteinuria, ratio of plasma total cholesterol to HDL-cholesterol ≥6, or premature family history of coronary heart disease.
In adults with type 2 diabetes and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking or hypertension, Atorvastatin is indicated to: Reduce the risk of myocardial infarction; Reduce the risk of stroke.
In adults with clinically evident coronary heart disease, Atorvastatin is indicated to: Reduce the risk of non-fatal myocardial infarction; Reduce the risk of fatal and non-fatal stroke; Reduce the risk for revascularization procedures; Reduce the risk of hospitalization for CHF; Reduce the risk of angina.

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 underlying medical problems. The patient should continue on a standard cholesterol-lowering diet during treatment with Atorvastatin. The recommended starting dose of Atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range is 10 to 80 mg once daily.
Atorvastatin can be administered as a single dose at any time of the day, with or without food. The doses 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.
Prevention of Cardiovascular Disease: For primary prevention, the recommended dose is 10 mg once daily. For secondary prevention, optimal dosing may range from 10 mg to 80 mg Atorvastatin once daily, to be given at the discretion of the prescriber, taking into account the expected benefit and safety considerations relevant to the patient to be treated (see Pharmacology: Pharmacodynamics: Secondary Prevention of Cardiovascular Events under Actions).
Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia: The majority of patients are controlled with 10 mg Atorvastatin once a day. A therapeutic response is evident within two weeks, and the maximum response is usually achieved within four 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 of Atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).
Use in Patients with Hepatic Insufficiency: (See Contraindications and Precautions).
Use in 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. (See Precautions).
Paediatric use, Hypercholesterolaemia: Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress. For patients aged 10 years and above, the recommended starting dose of Atorvastatin is 10 mg per day with titration up to 20 mg per day. Titration should be conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, corresponding to about 0.5 mg/kg, is limited.
There is limited experience in children between 6-10 years of age (See Pharmacology: Pharmacodynamics under Actions). Atorvastatin is not indicated in the treatment of patients below the age of 10 years.
Treatment experience in a pediatric population is limited to doses of Atorvastatin up to 80 mg/day for one year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients.
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, or the combination tipranavir/ritonavir is necessary, the dose of Atorvastatin should not exceed 10 mg. In patients taking clarithromycin or in patients with HIV taking a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, for doses of Atorvastatin exceeding 20 mg appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Atorvastatin is employed.
THE FOLLOWING TREATMENT GUIDELINES MAY BE USED TO ESTABLISH TREATMENT GOALS: (See Table 6.)

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After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL (2.2 mmol/L), non HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL (0.8 mmol/L) higher than LDL-C goals for each risk category.

There is no specific treatment for Atorvastatin overdosage. Should an overdose 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.

Atorvastatin is contraindicated in patients who have: Hypersensitivity to any component of this medication, active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal, 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 (>3x 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 (>3x 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 10, 20, 40 and 80 mg 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 greater than three 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 >10x 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 during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, azole antifungals, colchicines, telaprevir, or the combination of tipranavir/ritonavir. Many of these drugs inhibit cytochrome P450 3A4 metabolism and/or drug-transport. CYP 3A4 is the primary hepatic isoenzymes known to be involved in the biotransformation of Atorvastatin. Physicians considering combined therapy with Atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals, 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. Temporary suspension of Atorvastatin may be appropriate during fusidic acid therapy (See Interactions). Periodic creatine phosphokinase (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 creatine phosphokinase (see Adverse Reactions).
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 having 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).
Endocrine Functions: Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Atorvastatin.
Hemorrhagic Stroke: A post-hoc analysis of a clinical study in 4,731 patients without CHD who had a stroke or TIA within the preceding 6 months and were 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).
Information for the Patient: Patients 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).
Effects on Ability to Drive and Use Machines: None known.

Atorvastatin is contraindicated in pregnant, breast-feeding, or of childbearing potential who are not using adequate contraceptive measures.
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.
Atorvastatin is contraindicated while breast-feeding. 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 breast-feed.

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 Atorvastatin 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 the 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.
Psychiatric disorders: insomnia.
Nervous system disorders: headache.
Gastrointestinal disorders: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, myalgia, joint swelling.
General disorders and administration site conditions: asthenia.
Investigations: liver function test abnormal, blood creatine phosphokinase increased.
Additional adverse effects reported in Atorvastatin placebo-controlled clinical trials include: Metabolism and nutrition disorders: hypoglycemia, hyperglycemia, anorexia.
Psychiatric disorders: nightmare.
Eye disorders: vision blurred.
Ear and labyrinth disorders: tinnitus.
Nervous system disorders: peripheral neuropathy, paresthesia.
Gastrointestinal disorders: abdominal discomfort, eructation, pancreatitis, vomiting.
Hepatobiliary disorders: hepatitis, cholestasis.
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: malaise, pyrexia.
Investigations: white blood cells urine positive.
Not all effects listed previously have been causally associated with Atorvastatin therapy.
Paediatric Population: The clinical safety database includes safety data for 249 paediatric patients who received Atorvastatin, among which 7 patients were <6 years old, 14 patients were in the age range of 6 to 9, and 228 patients were in the range of 10 to 17.
Nervous system disorders: Common: Headache.
Gastrointestinal disorders: Common: Abdominal pain.
Investigations: Common: Alanine aminotransferase increased, blood creatine phosphkinase increase.
Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in adults. There is currently limited experience with respect to long-term safety in the paediatric population.
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, erythema multiforme, bullous rashes.
Musculoskeletal and connective tissue disorders: rhabdomyolysis, back pain.
General disorders and Administration site conditions: chest pain, peripheral edema, fatigue.
There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

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 cytochrome P450 3A4 inhibitors (e.g erythromycin and azole antifungals) (see the following and also Use in Combination with Other Medicinal Compounds under Dosage & Administration and Skeletal Muscle Effects under Precautions).
Inhibitors of cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of Atorvastatin with inhibitors of cytochrome P450 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 cytochrome P450 3A4.
Transporter Inhibitors: Atorvastatin and Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the bioavailability of Atorvastatin. Concomitant administration of Atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an 8.7-fold increase in Atorvastatin AUC. In cases where co-administration of Atorvastatin with cyclosporine is necessary, the dose of Atorvastatin should not exceed 10 mg.
Clarithromycin: Concomitant administration of Atorvastatin 80 mg with clarithromycin (500 mg twice daily) resulted in a 4.4-fold increase in Atorvastatin AUC (see Skeletal Muscle Effects under Precautions, and Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Erythromycin: In healthy individuals, plasma concentrations of Atorvastatin increased approximately 40% with co-administration of Atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see Skeletal Muscle Effects under Precautions).
Protease inhibitors: Concomitant administration of Atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) resulted in a 3-fold increase in Atorvastatin AUC. Concomitant administration of Atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) resulted in a 5.9-fold increase in Atorvastatin AUC (see Pharmacology: Pharmacokinetics under Actions and Use in Combination with Other Medicinal Compounds under Dosage & Administration).
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 to 40 mg) and itraconazole (200 mg) was associated with a 2.5-3.3-fold increase in Atorvastatin AUC.
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 liters per day).
Inducers of cytochrome P450 3A: Concomitant administration of Atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin) can lead to variable reductions in plasma concentrations of Atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 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.
Antacids: Co-administration of Atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides, decreased Atorvastatin plasma concentrations 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 10 mg Atorvastatin were co-administered, steady- state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% 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) 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 study with warfarin was conducted, and no clinically significant interactions were seen.
Amlodipine: In a drug-drug interaction study in healthy subjects, co-adminstration 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, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination. Patients should be closely monitored and temporary suspension of Atorvastatin treatment may be appropriate.
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 Colchicines.
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.
Paediatric population: Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The previously-mentioned interactions for adults and the warning in Precautions should be taken into account for the paediatric population.

Dyslipidaemic Agents

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

POM