APO-ATORVASTATIN (atorvastatin calcium) is indicated as an adjunct to lifestyle changes, including diet, for the reduction of elevated total cholesterol (total-C), LDL-C, triglycerides (TG) and apolipoprotein B (apo B), the Total-C/HDL-D ratio and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, including:

• Primary hypercholesterolemia (Type IIa);
• Combined (mixed) hyperlipidemia (Type IIb), including familial combined hyperlipidemia, regardless of whether cholesterol or triglycerides are the lipid abnormality of concern;
• Dysbetalipoproteinemia (Type III);
• Hypertriglyceridemia (Type IV);
• Familial hypercholesterolemia (homozygous and heterozygous). For homozygous familial hypercholesterolemia, APO-ATORVASTATIN should be used as an adjunct to treatments such as LDL apheresis, or as monotherapy if such treatments are not available.
• An adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia, if after an adequate trial of diet therapy the following findings are still present:
  • LDL-C remains >4.9 mmol/L (190 mg/dL) or
  • L-C remains >4.1 mmol/L (160 mg/dL) and:
    • there is a positive family history of premature cardiovascular disease or
    • two or more other CVD risk factors are present in the pediatric patient

Prior to initiating therapy with APO-ATORVASTATIN, secondary causes should be excluded for elevations in plasma lipid levels (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, and alcoholism), and a lipid profile performed to measure total cholesterol, LDL-C, HDL-C, and TG. For patients with TG <4.52 mmol/L (<400 mg/dL), LDL-C can be estimated using the following equation:

LDL-C (mmol/L) = total - C - [(0.37 x (TG) + HDL-C)]

LDL-C (mg/dL) = total - C - [(0.2 x (TG) + HDL-C)]

For patients with TG levels >4.52 mmol/L (>400 mg/dL), this equation is less accurate and LDL-C concentrations should be measured directly or by ultracentrifugation.

Patients with high or very high triglyceride levels, i.e. >2.2 mmol/L (200 mg/dL) or >5.6 mmol/L (500 mg/dL), respectively, may require triglyceride-lowering therapy (fenofibrate, bezafibrate or nicotinic acid) alone or in combination with APO-ATORVASTATIN.

In general, combination therapy with fibrates must be undertaken cautiously and only after risk- benefit analysis (see WARNINGS AND PRECAUTIONS, Muscle Effects, Pharmacokinetic Interactions and INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION).

Elevated serum triglycerides are most often observed in patients with the metabolic syndrome (abdominal obesity, atherogenic dyslipidemia {elevated triglycerides, small dense LDL particles and low HDL- cholesterol}, insulin resistance with or without glucose intolerance, raised blood pressure and prothrombic and proinflammatory states).

When drugs are prescribed attention to therapeutic lifestyle changes (reduced intake of saturated fats and cholesterol, weight reduction, increased physical activity, ingestion of soluble fibers) should always be maintained and reinforced.

Prevention of Cardiovascular Disease

APO-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, type 2 diabetes, left ventricular hypertrophy, other specified abnormalities on ECG, microalbuminuria or proteinuria, ratio of plasma total cholesterol to HDL-cholesterol >6, or premature family history of coronary heart disease.

APO-ATORVASTATIN is also indicated to reduce the risk of myocardial infarction and stroke in adult patients with type 2 diabetes mellitus and hypertension without clinically evident coronary heart disease, but with other risk factors such as age ≥55 years, retinopathy, albuminuria or smoking.

APO-ATORVASTATIN is indicated to reduce the risk of myocardial infarction in patients with clinically evident coronary heart disease.

Patients should be placed on a standard cholesterol-lowering diet before receiving APO- ATORVASTATIN, and should continue on this diet during treatment with APO-ATORVASTATIN. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with APO-ATORVASTATIN, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

Primary Hypercholesterolemia and Combined (Mixed) Dyslipidemia, Including Familial Combined Hyperlipidemia

The recommended starting dose of APO-ATORVASTATIN is 10 or 20 mg once daily, depending on patient’s LDL-C reduction required. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of APO-ATORVASTATIN is 10 to 80 mg once daily. Doses can be given at any time of the day with or without food, and should preferably be given in the evening. A significant therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 2-4 weeks. The response is maintained during chronic therapy. Adjustments of dosage, if necessary, should be made at intervals of 2 to 4 weeks. The maximum dose is 80 mg/day.

The dosage of APO-ATORVASTATIN should be individualized according the baseline LDL-C, total- C/HDL-C ratio and/or TG levels to achieve the recommended desired lipid values at the lowest dose needed to achieve LDL-C desired level. Lipid levels should be monitored periodically and, if necessary, the dose of APO-ATORVASTATIN adjusted based on desired lipid levels recommended by guidelines.

Severe Dyslipidemias

In patients with severe dyslipidemias, including homozygous and heterozygous familial hypercholesterolemia and dysbetalipoproteinemia (Type III), higher dosages (up to 80 mg/day) may be required (see WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions, Muscle Effects; INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION).

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age)

In this population, the recommended starting dose of APO-ATORVASTATIN is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg/day have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy (see THERAPEUTIC INDICATIONS and PHARMACOLOGY, Clinical Studies). Adjustments should be made at intervals of 4 weeks or more.

Prevention of Cardiovascular Disease

Clinical trials conducted that evaluated atorvastatin in the primary prevention of myocardial infarction used a dose of 10 mg atorvastatin once daily.

For secondary prevention of myocardial infarction, 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.

Concomitant Therapy

See INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION.

Dosage in Patients with Renal Insufficiency

(See WARNINGS AND PRECAUTIONS)

General

Before instituting therapy with APO-ATORVASTATIN (atorvastatin calcium), an attempt should be made to control elevated serum lipoprotein levels with appropriate diet, exercise, and weight reduction in overweight patients, and to treat other underlying medical problems (see THERAPEUTIC INDICATIONS). Patients should be advised to inform subsequent physicians of the prior use of APO- ATORVASTATIN or any other lipid-lowering agents.

Pharmacokinetic Interactions

The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are co-administered with drugs that inhibit the cytochrome P-450 enzyme system. Atorvastatin is metabolized by cytochrome P-450 isoform 3A4 and as such may interact with agents that inhibit this enzyme. (See WARNINGS AND PRECAUTIONS, Muscle effects, and INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION).

Muscle Effects

Effects on skeletal muscle such as myalgia, myopathy and rarely, rhabdomyolysis have been reported in patients treated with atorvastatin.

Rare cases of rhabdomyolysis, with acute renal failure secondary to myoglobinuria, have been reported with atorvastatin and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. APO-ATORVASTATIN therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

Pre-disposing Factors for Myopathy/Rhabdomyolysis: APO-ATORVASTATIN, as with other HMG- CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• Personal or family history of hereditary muscular disorders
• Previous history of muscle toxicity with another HMG-CoA reductase inhibitor
• Concomitant use of a fibrate, or niacin
• Hypothyroidism
• Alcohol abuse
• Excessive physical exercise
• Age > 65 years
• Renal impairment
• Hepatic impairment
• Diabetes with hepatic fatty change
• Surgery and trauma
• Frailty
• Situations where an increase in plasma levels of active ingredient may occur

The risk of myopathy and rhabdomyolysis during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of drugs that interfere with metabolism of atorvastatin via CYP 3A4, such as cyclosporin, fibric acid derivatives, erythromycin, clarithromycin, niacin (nicotinic acid), azole antifungals, nefazodone, colchicine, the hepatitis C protease inhibitor telaprevir, boceprevir, HIV protease inhibitor fosamprenavil and each of the following HIV protease inhibitor combinations: saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir and fosamprenavil plus ritonavir. The combined therapy with APO-ATORVASTATIN and cyclosporine, gemfibrozil, telaprevir or tipranavir plus ritonavir should be avoided. APO-ATORVASTATIN dose restriction or caution is recommended for combined therapy with other CYP 3A4 inhibitors (see Pharmacokinetic Interactions; INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION, Drug-Drug Interactions; DETAILED PHARMACOLOGY, Human Pharmacokinetics).

In cases where co-administration of APO-ATORVASTATIN with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg. Temporary suspension of atorvastatin during fusidic acid therapy is recommended (see INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION, Drug-Drug Interactions).

Although patients with renal impairment are known to be predisposed to the development of rhabdomyolysis with administration of HMG-CoA reductase inhibitors (also known as statins), those with a history of renal impairment may also be predisposed to the development of rhabdomyolysis. Such patients merit close monitoring for skeletal muscle effects.

APO-ATORVASTATIN therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (such as sepsis, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

APO-ATORVASTATIN therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

Cardiovascular

Hemorrhagic Stroke in Patients with Recent Stroke or Transient Ischemic Attack (TIA)

A post-hoc analysis of a clinical study in 4,731 patients without coronary heart disease (CHD) who had a stroke or TIA within the preceding six months revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg group compared to placebo. Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke. The potential risk of hemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin in patients with recent (1-6 months) stroke or TIA.

Effect on Ubiquinone (CoQ10)Levels

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure (see REFERENCES).

Endocrine and Metabolism

Endocrine Function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with atorvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.

Increases in fasting glucose and HbA1c levels have been reported with inhibitors of HMG-CoA reductase as a class. For some patients, at high risk of diabetes mellitus, hyperglycemia was sufficient to shift them to the diabetes status. The benefit of treatment continues to outweigh the small increased risk. Periodic monitoring of these patients is recommended.

Effect on Lipoprotein (a)

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on atorvastatin therapy (see REFERENCES).

Patients with Severe Hypercholesterolemia

Higher drug dosages (80 mg/day) required for some patients with severe hypercholesterolemia (including familial hypercholesterolemia) are associated with increased plasma levels of atorvastatin. Caution should be exercised in such patients who are also severely renally impaired, elderly, or are concomitantly being administered digoxin or CYP 3A4 inhibitors (see WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions, Muscle Effects; INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION; DOSAGE AND ADMINISTRATION).

Hepatic/Biliary/Pancreatic

Hepatic Effects

In clinical trials, persistent increases in serum transaminases greater than three times the upper limit of normal occurred in <1% of patients who received atorvastatin. When the dosage of atorvastatin was reduced, or when drug treatment was interrupted or discontinued, serum transaminase levels returned to pretreatment levels. The increases were generally not associated with jaundice or other clinical signs or symptoms. Most patients continued treatment with a reduced dose of atorvastatin without clinical sequelae. If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, particularly if they rise to greater than 3 times the upper limit of normal and are persistent, the dosage should be reduced or the drug discontinued.

Liver function tests should be performed before the initiation of treatment, and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with APO-ATORVASTATIN,  promptly interrupt therapy. If an alternate etiology is not found, do not restart APO-ATORVASTATIN.

APO-ATORVASTATIN, as well as other HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of atorvastatin; if such a condition should develop during therapy, the drug should be discontinued.

Ophthalmologic

Effect on the Lens

Current long-term data from clinical trials do not indicate an adverse effect of atorvastatin on the human lens.

Renal

Renal Insufficiency

Plasma concentrations and LDL-C lowering efficacy of atorvastatin was shown to be similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of APO-ATORVASTATIN should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see WARNINGS AND PRECAUTIONS, Muscle Effects; INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION). Refer also to DOSAGE AND ADMINISTRATION.

Sensitivity/Resistance

Hypersensitivity

An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included 1 or more of the following features: anaphylaxis, angioedema, lupus erythematous- like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Although to date hypersensitivity syndrome has not been described as such, APO-ATORVASTATIN should be discontinued if hypersensitivity is suspected.

Special Populations

Pediatric Use: Safety and effectiveness of atorvastatin in patients 10-17 years of age (N=140) with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin had a safety and tolerability profile generally similar to that of placebo. Doses greater than 20 mg have not been studied in this patient population.

Safety and effectiveness of atorvastatin in pediatric patients has not been determined in the prevention of myocardial infarction.

Atorvastatin had no effect on growth or sexual maturation in boys and in girls. The effects on menstrual cycle were not assessed [see PHARMACOLOGY, Clinical Studies section; UNDESIRABLE EFFECTS, Pediatric Patients; and DOSAGE AND ADMINISTRATION for Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age)].

Adolescent females should be counselled on appropriate contraceptive methods while on

APO-ATORVASTATIN therapy (see CONTRAINDICATIONS and PRECAUTIONS, Use in

Pregnancy). Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.

Doses of atorvastatin up to 80 mg/day for 1 year have been evaluated in 8 pediatric patients with homozygous familial hypercholesterolemia (see Clinical Studies - Heterozygous Familial Hypercholesterolemia in pediatric patients).

Geriatric Use: Treatment experience in adults 70 years or older (N=221) with doses of atorvastatin up to 80 mg/day has demonstrated that the safety and effectiveness of atorvastatin in this population was similar to that of patients <70 years of age. Pharmacokinetic evaluation of atorvastatin in subjects over the ag        e of 65 years indicates an increased AUC. As a precautionary measure, the lowest dose should be administered initially (see DETAILED PHARMACOLOGY, Human Pharmacokinetics; REFERENCES).

Elderly patients may be more susceptible to myopathy (see WARNINGS - Muscle Effects - Predisposing Factors for Myopathy/Rhabdomyolysis).

Pharmacokinetic interaction studies conducted with drugs in healthy subjects may not detect the possibility of a potential drug interaction in some patients due to differences in underlying diseases and use of concomitant medications (see also WARNINGS AND PRECAUTIONS, Special Populations; Renal Insufficiency; Patients with Severe Hypercholesterolemia; Geriatric Use).

Concomitant Therapy with Other Lipid Metabolism Regulators: Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates, and lipid-modifying doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see WARNINGS -Muscle Effects). The concomitant use of APO-ATORVASTATIN with gemfibrozil should be avoided. The combined therapy with other fibrates and niacin should be used with caution; lower starting and maintenance doses of atorvastatin should be considered.

Cytochrome P-450-mediated Interactions: Atorvastatin is metabolized by the cytochrome P-450 isoenzyme, CYP 3A4. Erythromycin, a CYP 3A4 inhibitor, increased atorvastatin plasma levels by 40%. Coadministration of CYP 3A4 inhibitors, such as grapefruit juice, some macrolide antibiotics (i.e. erythromycin, clarithromycin), immunosuppressants (cyclosporine), azole antifungal agents (i.e. itraconazole, ketoconazole), protease inhibitors, or the antidepressant, nefazodone, have the potential to increase plasma concentrations of HMG CoA reductase inhibitors, including atorvastatin (see Drug-Drug Interactions, REFERENCES).  Concomitant use of APO-ATORVASTATIN with cyclosporine, gemfibrozil, telaprevir or the combination of tipranavir with ritonavir should be avoided. Other CYP 3A4 inhibitors should be used with APO-ATORVASTATIN dose restriction or caution, and patients should be monitored closely for musculoskeletal effects (see WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions, Muscle Effects, Renal Insufficiency and Endocrine Function; Drug-Drug Interactions, Table 2 – Established or Potential Drug-Drug Interactions; REFERENCES).

Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have been noted with HIV protease inhibitors (lopinavir plus ritonavir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir and nelfinavir), Hepatitis C protease inhibitor (boceprevir), clarithromycin and itraconazole. Caution should be used when co-prescribing atorvastatin and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see Drug-Drug Interactions, Table 2 - Established or Potential Drug-Drug Interactions).

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 (see DETAILED PHARMACOLOGY, Human Pharmacokinetics).

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 resulted in a mean increase in Cmax and AUC of atorvastatin of 12 and 190%, respectively. In contrast, a delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction (approximately 80%) in atorvastatin plasma concentrations.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interactions studies, case reports, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated). Interactions with other drugs have not been established.

Table 2: Established or Potential Drug -Drug Interactions

Legend:             HC = hypercholesterolemia; TG = triglycerides; PK = pharmacokinetics; BP = Blood Pressure; HR = Heart Rate; AUC = Area under the curve

* Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change).

Drug-Food Interactions

Coadministration of grapefruit juice has the potential to increase plasma concentrations of HMG-CoA reductase inhibitors, including atorvastatin. The equivalent of 1.2 litres per day resulted in a 2.5 fold increase in AUC of atorvastatin. Consumption of excessive grapefruit juice with atorvastatin is not recommended.

Drug-Herb Interactions 

Interactions with herbal products have not been established.

Drug/Laboratory Test Interactions

APO-ATORVASTATIN may elevate serum transaminase and creatine kinase levels (from skeletal muscle). In the differential diagnosis of chest pain in a patient on therapy with APO-ATORVASTATIN, cardiac and noncardiac fractions of these enzymes should be determined.

Use in Pregnancy: (pregnancy category X)

APO-ATORVASTATIN is contraindicated during pregnancy (see CONTRAINDICATIONS). There are no data on the use of atorvastatin during pregnancy. APO-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. If the patient becomes pregnant while taking APO-ATORVASTATIN, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

Use in Nursing Mothers:

In rats, milk concentrations of atorvastatin are similar to those in plasma. It is not known whether this drug is excreted in human milk. Because of the potential for Undesirable effects in nursing infants, women taking APO-ATORVASTATIN should not breast-feed.

No or negligible influence.

Undesirable effects with atorvastatin have usually been mild and transient. In the atorvastatin placebo- controlled clinical trial database of 16,066 (8755 Lipitor versus 7311 placebo) patients treated for a median period of 53 weeks , 5.2% of patients on atorvastatin discontinued due to Undesirable effects compared to 4.0% of the patients on placebo.

Adverse experiences occurring at an incidence ≥1% in patients participating in placebo-controlled clinical studies of atorvastatin and reported to be possibly, probably or definitely drug related are shown in Table 1 below:

Table 1: Associated Adverse Events Reported in ≥1 % of Patients in Placebo Controlled Clinical Trials

*alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, hepatic enzyme increased, liver function test abnormal and transaminases increased.

The following additional adverse events were reported in placebo-controlled clinical trials during atorvastatin therapy: Muscle cramps, myositis, muscle fatigue, myopathy, paresthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, cholestasis, anorexia, vomiting, abdominal discomfort, alopecia, pruritus, rash, urticaria , erectile dysfunction, nightmare, vision blurred, tinnitus, eructation, neck pain, malaise, pyrexia and white blood cells urine positive.

In summary, the adverse events occurring at a frequency <1% are listed below:

General disorders and administration site conditions: malaise; pyrexia

Gastrointestinal disorders: abdominal discomfort, eructation

Hepatobiliary disorders: hepatitis, cholestasis

Musculoskeletal and connective tissue disorders: muscle fatigue, neck pain

Psychiatric disorders: nightmare

Skin and subcutaneous tissue disorders: urticaria

Eye disorders: vision blurred

Ear and labyrinth disorders: tinnitus

Investigations: white blood cells urine positive

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (ages 10-17 years):

In a 26-week controlled study in boys and postmenarchal girls (n=187, where 140 patients received atorvastatin), the safety and tolerability profile of atorvastatin 10 to 20 mg daily was similar to that of placebo. The adverse events reported in >1% of patients were as follows: abdominal pain, depression and headache (see PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Pediatric Use).

Laboratory Changes and Adverse Events

The criteria for clinically significant laboratory changes were >3 X the upper limit of normal (ULN) for liver enzymes, and >5 X ULN for creatine kinase. A total of 8 unique subjects met one or more of these criteria during the double-blind phase. Hence, the incidence of patients who experienced abnormally high enzymatic levels (AST/ALT and creatine kinase) was >4% (8/187).

Five atorvastatin and one placebo subjects had increases in CK >5 X ULN during the double-blind phase; two of the five atorvastatin treated subjects had increases in CK >10 X ULN.

There were 2 subjects who had clinically significant increases in ALT.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Tests: Increases in serum transaminase levels and serum glucose have been noted in clinical trials (see WARNINGS AND PRECAUTIONS, UNDESIRABLE EFFECTS).

Post-Market Adverse Drug Reactions

The following adverse events have also been reported during post-marketing experience with atorvastatin, regardless of causality assessment:

Rare reports: severe myopathy with or without rhabdomyolysis (see WARNINGS AND PRECAUTIONS, Muscle Effects, Renal Insufficiency and INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION).

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

Isolated reports: Gynecomastia, thrombocytopenia, arthralgia and allergic reactions including urticaria, angioneurotic edema, anaphylaxis and bullous rashes (including erytheme multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), fatigue, back pain, chest pain, malaise, dizziness, amnesia, peripheral edema, weight gain, abdominal pain, insomnia, hypoesthesia, tinnitus, tendon rupture, pancreatitis and dysgeusia.

Ophthalmologic observations: see WARNINGS AND PRECAUTIONS.

Cases of erectile dysfunction have been reported in association with the use of statins. The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares;
• Mood related disorders, including depression;
• Very rare cases of interstitial lung disease, especially with long term therapy. If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Endocrine disorders: Increases in fasting glucose and HbA1c levels have been reported with APO-ATORVASTATIN.

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).

-  To report any side effect(s)

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 (see UNDESIRABLE EFFECTS)

The lowering of total cholesterol, LDL-C and ApoB have been shown to reduce the risk of cardiovascular events and mortality.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. In both subjects and in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and dysbetalipoproteinemia, atorvastatin has been shown to reduce levels of total cholesterol (total-C), LDL-C, apo B and total TG, and raises HDL-C levels.

Epidemiologic and clinical studies have associated the risk of coronary artery disease (CAD) with elevated levels of total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Like LDL, cholesterol-enriched 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 (metabolic syndrome). Clinical studies have also shown that serum triglycerides can be an independent risk factor for CAD. CAD risk is especially increased if the hypertriglyceridemia is due to increased intermediate density lipoproteins (IDL) or associated with decreased HDL or increased LDL-C. In addition, high TG levels are associated with an increased risk of pancreatitis. Although epidemiological and preliminary clinical evidence link low HDL-C levels and high triglyceride levels with coronary artery disease and atherosclerosis, the independent effect of raising HDL or lowering TG on the risk of coronary and cerebrovascular morbidity and mortality has not been demonstrated in prospective, well-controlled outcome studies. Other factors, e.g. interactions between lipids/lipoproteins and endothelium, platelets  and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications. Regardless of the intervention used (low-fat/low-cholesterol diet, partial ileal bypass surgery or pharmacologic therapy), effective treatment of hypercholesterolemia/ dyslipidemia has consistently been shown to reduce the risk of CAD.

Atorvastatin reduces LDL-C and the number of LDL particles, lowers Very Low Density Lipoprotein- Cholesterol (VLDL-C) and serum triglyceride, reduces the number of apo B containing particles, and also increases HDL-C. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a condition that rarely responds to any other lipid-lowering medication. In addition to the above effects, atorvastatin reduces IDL-C and apolipoprotein E (apo E) in patients with dysbetalipoproteinemia (Type III).

In patients with type II hyperlipidemia, atorvastatin improved endothelial dysfunction. Atorvastatin significantly improved flow-mediated endothelium-dependent dilatation induced by reactive hyperemia, as assessed by brachial ultrasound (p<0.01).

Mechanism of Action

Atorvastatin is a synthetic lipid-lowering agent. It is a selective, competitive inhibitor of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

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 Low Density Lipoprotein (LDL) receptors on the cell-surface for enhanced uptake and catabolism of Low Density Lipoprotein (LDL).

Atorvastatin reduces LDL-Cholesterol (LDL-C) and the number of LDL particles. Atorvastatin also reduces Very Low Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High Density Lipoprotein-Cholesterol (HDL-C). Elevated serum cholesterol due to elevated LDL-C is a major risk factor for the development of cardiovascular disease. Low serum concentration of HDL-C is also an independent risk factor.  Elevated plasma TG is also a risk factor for cardiovascular disease, particularly if due to increased IDL, or associated with decreased HDL-C or increased LDL-C.

Epidemiologic, clinical and experimental studies have established that high LDL-C, low HDL-C and high plasma TG promote human atherosclerosis and are risk factors for developing cardiovascular disease.

Some studies have also shown that the total (TC):HDL-C ratio (TC:HDL-C) is the best predictor of coronary artery disease. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.

Absorption: Atorvastatin is rapidly absorbed after oral administration; maximal plasma concentrations occur within 1 to 2 hours. Extent of absorption and plasma atorvastatin concentrations increase in proportion to atorvastatin dose. Atorvastatin tablets are 95-99% bioavailable compared to solutions. The absolute bioavailability (parent drug) of atorvastatin is approximately 12% 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 first-pass metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, as assessed by Cmax and AUC respectively, LDL-C reduction and HDL-C elevation are similar when atorvastatin is given with and without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following drug administration in the evening compared with morning dosing.

However, LDL-C reduction and HDL-C elevation are the same regardless of the time of drug administration.

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

Metabolism: Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives by cytochrome P-450 3A4 (CYP 3A4) and to various beta-oxidation products. In vitro, inhibition of HMG- CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin.

Approximately 70% of circulating inhibitory activity for HMG- CoA reductase is attributed to active metabolites. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Atorvastatin and its metabolites are eliminated by biliary excretion.

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

Special Populations and Conditions

Pediatrics: Assessment of pharmacokinetic parameters such as Cmax, AUC and bioavailability of atorvastatin in pediatric patients (>10 to <17 years old, postmenarche) was not performed during the 6- month, placebo-controlled trial referred to earlier (see Clinical Studies - Heterozygous Familial Hypercholesterolemia in Pediatric Patients and PRECAUTIONS - Pediatric Use).

Geriatrics: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age 65 years or older) compared with younger individuals. LDL-C reduction, however, is comparable to that seen in younger patient populations.

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

Race: Plasma concentrations of atorvastatin are similar in black and white subjects.

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).

Renal Insufficiency: Plasma concentrations and LDL-C lowering efficacy of atorvastatin are similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of atorvastatin should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see WARNINGS AND PRECAUTIONS, Muscle Effects; INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION; DOSAGE AND ADMINISTRATION).

Acute Toxicity

The acute toxicity of atorvastatin following single doses was evaluated in mice, rats and dogs by oral and intravenous routes, and the results are summarized below:

Table 20:  Acute Oral and Intravenous Toxicity Studies with Atorvastatin

The acute toxicity of atorvastatin in rodents and dogs is low. Oral median lethal doses in mice and rats are greater than 5000 mg/kg.

Subacute and Chronic Toxicity Studies

The target organs affected by atorvastatin in multiple dose toxicity studies in rats (2 weeks to 52 weeks), and dogs (2 weeks to 104 weeks) are summarized in the table below. The spectrum of effects observed is not unexpected in view of the magnitude of the dose levels used, potency of atorvastatin in inhibiting mevalonate synthesis and the essential role of HMG-CoA reductase in maintaining cellular homeostasis.

Table 21: Atorvastatin: Target Organs Affected in Animal Studies

* Occurred after administration of high, intolerable doses (280 mg/kg)

The following table summarizes the significant adverse changes observed during long-term toxicology studies in rats (52 weeks) and dogs (104 weeks):

Table 22: Atorvastatin: Significant Adverse Changes in Chronic Studies

(1) Present only at Week 26; not observed at Week 52.

(2) Findings occurred in Week 7 or 9.

(3) Findings occurred at Week 52 or in moribund dogs, were less pronounced after a 12-week withdrawal period (Week 64), and were not observed after 104 weeks of dosing.

ND = Not determined.

The results of the long-term toxicology studies with atorvastatin indicated that similar to other HMG-CoA reductase inhibitors, the liver is the primary target organ. This is expected since the liver is the primary site of the pharmacologic action of atorvastatin and it is subject to the greatest drug exposure following oral administration. In both the rat and dog studies, the hepatic changes diminished with time (i.e. effects were less pronounced at the end of the 52-week and 104-week studies) suggesting an adaptive response.

Brain hemorrhage, optic nerve degeneration, lenticular opacities and testicular degeneration were not seen in dogs treated for 104-weeks with atorvastatin up to 120 mg/kg/day. Carcinogenicity and Genotoxicity Studies

Atorvastatin was not carcinogenic in rats given 10, 30 or 100 mg/kg/day for 2 years. The 100 mg/kg dose is 63-fold higher than the maximum recommended human dose of 80 mg (1.6 mg/kg, based on a 50 kg human) and AUC (0-24 hr) values were 8-to 16-fold higher.

In a 2-year study in mice given 100, 200 or 400 mg/kg/day, incidences of hepatocellular adenoma in  males and hepatocellular carcinoma in females were increased at 400 mg/kg. This dose is 250 times the maximum recommended human dose on a mg/kg basis and systemic exposure based on AUC (0-24 hr) was 6 to 11 times higher. There was no evidence of treatment-related increases in tumor incidences at the lower doses of 100 and 200 mg/kg/day (i.e. up to 125 times the maximum recommended human dose on a mg/kg basis and systemic exposures of 3 times higher based on AUC (0-24 hr).

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.

Reproductive and Teratogenicity Studies

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 did not cause any adverse effects on sperm or semen parameters, or in reproductive organ histopathology in dogs given doses of 10, 40 or 120 mg/kg for 2 years. Atorvastatin was not teratogenic in either rats or rabbits.

This medicinal product must not be mixed with other medicinal products.

Store below 25°C.

Alu/Alu blister (Silver cold form foil and silver plain foil) pack.

10 mg: Available in bottles of 90, 100, 500, and 1000 tablets, blisters of 30.

20 mg: Available in bottles of 90, 100, 500, and 1000 tablets, blisters of 30.

40 mg: Available in bottles of 90, 100, 500, and 1000 tablets, blisters of 30.

80 mg: Available in bottles of 90, 100 and 500 tablets, blisters of 30. Not all packs sizes may be marketed.

No special requirements.