ATORLIP Tablets (Atorvastatin calcium)

Table of Content

Acute coronary syndrome (ACS) is associated with high rates of morbidity and mortality. The early period after ACS represents a critical stage with a high risk for recurrent events and death due to vessel occlusions from vulnerable coronary plaques. Therefore, strategies to stabilize vulnerable coronary plaques during this period are paramount. Similarly, post-PCI, there is a high risk of peri-procedural injury that needs to be effectively managed. Although treatment strategies, such as antithrombotic therapy and angiotensin-converting enzyme inhibitors, can be used to prevent early events following ACS and post-PCI, the incidence of serious complications remains high.

There is a large body of evidence which demonstrate the benefits of intensive statin therapy in ACS and PCI patients. Treatment with atorvastatin 80 mg has shown to improve outcomes in patients with ACS and patients undergoing invasive strategy and to reduce recurrent cardiovascular events post-PCI, in various trials such as ARMYDA-ACS, IDEAL, REVERSAL, PROVE IT TIMI-22 and TNT.

Thus, atorvastatin 80 mg represents the optimal strength for reducing risk in PCI and ACS patients.

We are pleased to launch Atorlip 80 in addition to the existing Atorlip range 5/10/20/40.

 

Composition

ATORLIP-5

Each film-coated tablet contains:

Atorvastatin Calcium

equivalent to Atorvastatin…… 5 mg

ATORLIP-10

Each film-coated tablet contains:

Atorvastatin Calcium

equivalent to Atorvastatin…… 10 mg

ATORLIP-20

Each film-coated tablet contains:

Atorvastatin Calcium

equivalent to Atorvastatin…… 20 mg

ATORLIP-40

Each film-coated tablet contains:

Atorvastatin Calcium

equivalent to Atorvastatin…… 40 mg

ATORLIP-80

Each film-coated tablet contains:

Atorvastatin Calcium

equivalent to Atorvastatin…… 80 mg

Dosage Form

Film-coated tablet

Pharmacology

Pharmacodynamics

Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin reduces low density lipoprotein (LDL) production and the number of LDL particles. Triglycerides (TG) and cholesterol in the liver are incorporated into very low density lipoprotein (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.

In animal models, 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 to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles. Atorvastatin reduces LDL-C in some patients with homozygous familial hypercholesterolemia (HoFH), a population that rarely responds to other lipid-lowering medication(s).

Atorvastatin has been shown to reduce concentrations of total-C (30%-46%), LDL-C (41%-61%), ApoB (34%-50%), and TG (14%-33%) while producing variable increases in HDL-C and ApoA1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolemia (HeFH), nonfamilial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with noninsulin-dependent diabetes mellitus. Reductions in total-C, LDL-C, and ApoB have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response.

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and area under the curve (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.

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, ATORLIP is likely to be secreted in human milk.

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 cytochrome P450 (CYP) 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic 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 Population

Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults.

Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population pharmacokinetics (PK) model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

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

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.

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 Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease.

Solute carrier organic anion transporter family member 1B1 (SLOC1B1) polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including atorvastatin, involves the organic anion transporter protein B1 (OATP1B1) transporter. In patients with SLCO1B1 polymorphism, there is a risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis. Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients. Possible consequences for the efficacy are unknown.

Indications

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or multiple risk factors for CHD, ATORLIP can be started simultaneously with diet.

Prevention of Cardiovascular Disease

In adult patients without clinically evident CHD, but with multiple risk factors for CHD such as age, smoking, hypertension, low HDL-C, or a family history of early CHD, ATORLIP is indicated to:

  • Reduce the risk of myocardial infarction
  • Reduce the risk of stroke
  • Reduce the risk for revascularization procedures and angina

In patients with type 2 diabetes, and without clinically evident CHD, but with multiple risk factors for CHD such as retinopathy, albuminuria, smoking, or hypertension, ATORLIP is indicated to:

  • Reduce the risk of myocardial infarction
  • Reduce the risk of stroke

In patients with clinically evident CHD, ATORLIP 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 chronic heart failure (CHF)
  • Reduce the risk of angina

Hyperlipidemia

ATORLIP is indicated:

  • As an adjunct to diet to reduce elevated total-C, LDL-C, ApoB and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb);
  • As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
  • For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
  • To reduce total-C and LDL-C in patients with HoFH as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable;
  • As an adjunct to diet to reduce total-C, LDL-C and ApoB levels in pediatric patients, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:
  1. LDL-C remains >190 mg/dL or
  2. LDL-C remains >160 mg/dL and:
  • there is a positive family history of premature CVD or
  • two or more other CVD risk factors are present in the pediatric patient

Limitations of Use

Atorvastatin has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

Dosage and Administration

Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

The recommended starting dose is ATORLIP-10 or ATORLIP-20 once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at ATORLIP-40 once daily. The dosage range of ATORLIP is 10 to 80 mg once daily. ATORLIP can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of ATORLIP should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines). After initiation and/or up-titration of ATORLIP, lipid levels should be analysed within 2 to 4 weeks and the dosage adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 Years of Age)

The recommended starting dose is ATORLIP-10 once daily; the usual dose range is 10 to 20 mg orally once daily. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.

Homozygous Familial Hypercholesterolemia

The dosage of ATORLIP in patients with HoFH is 10 mg to 80 mg daily. ATORLIP should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Prevention of Cardiovascular Disease

In the primary prevention trials the dose was 10 mg/day. Higher doses of ATORLIP may be necessary in order to attain LDL-C levels according to current guidelines.

Concomitant Lipid-lowering Therapy

ATORLIP may be used with bile acid binding resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution.

Dosage in Patients with Renal Impairment

Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment of ATORLIP in patients with renal dysfunction is not necessary.

Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole or Certain Protease Inhibitors

In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with ATORLIP should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing ATORLIP and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with ATORLIP should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of ATORLIP is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with ATORLIP should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of ATORLIP is employed.

Contraindications

  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
  • Hypersensitivity to any component of this medication
  • Pregnancy and in women of child-bearing potential not using appropriate contraceptive measures
  • Nursing mothers

Warnings and Precautions

Drug Interactions

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors and itraconazole).

Strong Inhibitors of CYP3A4: Atorvastatin is metabolized by CYP4503A4. Concomitant administration of ATORLIP with strong inhibitors of CYP3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on CYP3A4.

Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the ATORLIP dose exceeds 20 mg.

Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of ATORLIP should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing ATORLIP and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of ATORLIP should not exceed 20 mg and should be used with caution. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of ATORLIP should not exceed 40 mg and close clinical monitoring is recommended.

Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, caution should be used when the ATORLIP dose exceeds 20 mg.

Moderate CYP3A4 Inhibitors: (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.

Rifampin or other Inducers of CYP3A4: Concomitant administration of atorvastatin with inducers of CYP3A4 (e.g. efavirenz, rifampin, St. John's

Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of ATORLIP with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Grapefruit Juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters/day).

Cyclosporine: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone. The co-administration of ATORLIP with cyclosporine should be avoided.

Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of ATORLIP with gemfibrozil should be avoided.

Other Fibrates: Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, ATORLIP should be administered with caution when used concomitantly with other fibrates.

Niacin: The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; a reduction in ATORLIP dosage should be considered in this setting.

Ezetimibe: The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and ATORLIP. Appropriate clinical monitoring of these patients is recommended.

Colestipol: Plasma concentrations of atorvastatin and its active metabolites were lower (ratio of atorvastatin concentration: 0.74) when colestipol was co-administered with Atorvastatin. However, lipid effects were greater when Atorvastatin and colestipol were co-administered than when either medicinal product was given alone.

Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, ATORLIP treatment should be discontinued throughout the duration of the fusidic acid treatment.

Digoxin: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased. Patients taking digoxin should be monitored appropriately.

Oral Contraceptives: Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking ATORLIP.

Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing ATORLIP with colchicine. 

Liver Dysfunction

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal occurring on two or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in 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.

One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin.

It is recommended that liver enzyme tests be obtained prior to initiating therapy with ATORLIP 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 ATORLIP, promptly interrupt therapy. If an alternate etiology is not found, do not restart ATORLIP.

ATORLIP 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 persistent transaminase elevations are contraindications to the use of atorvastatin.

Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. 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, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.

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 (CK), which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ATORLIP. ATORLIP 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, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with ATORLIP and fibric acid derivatives, erythromycin, clarithromycin, a combination of ritonavir plus saquinavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or 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. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs. Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

Prescribing recommendations for interacting agents are summarized in Table 1 below.

Table 1: Drug interactions associated with increased risk of myopathy/rhabdomyolysis

Interacting Agents

Prescribing Recommendations

Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)

Avoid atorvastatin

HIV protease inhibitor (lopinavir plus ritonavir)

Use with caution and lowest dose necessary

Clarithromycin, itraconazole,

HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)

Do not exceed 20 mg atorvastatin daily

HIV protease inhibitor (nelfinavir)

Hepatitis C protease inhibitor (boceprevir)

Do not exceed 40 mg atorvastatin daily

* Use with caution and with lowest dose necessary

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.

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 Function

Increases in hemoglobin A1c (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins 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. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

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

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group. 

Central Nervous System (CNS) Toxicity

Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum recommended human dose of 80 mg/day.

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

Interstitial Lung Disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.

Hepatic Impairment

ATORLIP is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels.

Pregnancy

ATORLIP is contraindicated in women who are or may become pregnant since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause fetal harm when administered to a pregnant woman.

Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD)of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses≥ 6 times the MRHD.

Human Data

Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude an at least three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.

Animal Data

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.

Statins may cause fetal harm when administered to a pregnant woman. ATORLIP should be discontinued as soon as pregnancy is recognized.

Lactation

ATORLIP use is contraindicated during breastfeeding. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with ATORLIP.

Females and Males of Reproductive Potential

Contraception

Atorvastatin may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with atorvastatin.

Pediatric Use

Heterozygous Familial Hypercholesterolemia

The safety and effectiveness of atorvastatin have been established in pediatric patients,10 years to 17 years of age, with HeFH as an adjunct to diet to reduce total-C, LDL-C, and ApoB levels when, after an adequate trial of diet therapy, the following are present:

  • LDL-C ≥ 190 mg/dL, or
  • LDL-C ≥ 160 mg/dL and
  • a positive family history of FH, or premature CVD in a first, or second-degree relative, or
  • two or more other CVD risk factors are present

Advise postmenarchal girls of contraception recommendations, if appropriate for the patient.

The long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and efficacy of atorvastatin have not been established in pediatric patients younger than 10 years of age with HeFH.

Homozygous Familial Hypercholesterolemia

Clinical efficacy with doses up to 80 mg/day for 1 year has been evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients.

Geriatric Use

Of the 39,828 patients who received atorvastatin in clinical studies, 15,813 (40%) were >65 years old and 2,800 (7%) were >75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (>65 years) is a predisposing factor for myopathy, ATORLIP should be prescribed with caution in the elderly.

Effects on Ability to Drive and Use Machines

Atorvastatin has negligible influence on the ability to drive and use machines.

Undesirable Effects

The following serious adverse reactions are discussed in greater detail in other sections of the label:

Rhabdomyolysis, myopathy and liver enzyme abnormalities

Clinical Trials Experiences

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).

The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8,755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).

Table 2 below summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials.

Table 2: Clinical adverse reactions occurring in ≥2% in patients treated with any dose of atorvastatin and at an incidence greater than placebo regardless of causality (% of patients)

Adverse Reactions*

Any dose

N=

8,755

10 mg

N=

3,908

20 mg

N=

188

40 mg

N= 604

80 mg

N= 4,055

Placebo

N= 7,311

Nasopharyngitis

8.3

12.9

5.3

7.0

4.2

8.2

Arthralgia

6.9

8.9

11.7

10.6

4.3

6.5

Diarrhea

6.8

7.3

6.4

14.1

5.2

6.3

Pain in extremity

6.0

8.5

3.7

9.3

3.1

5.9

Urinary tract infection

5.7

6.9

6.4

8.0

4.1

5.6

Dyspepsia

4.7

5.9

3.2

6.0

3.3

4.3

Nausea

4.0

3.7

3.7

7.1

3.8

3.5

Musculoskeletal pain

3.8

5.2

3.2

5.1

2.3

3.6

Muscle Spasms

3.6

4.6

4.8

5.1

2.4

3.0

Myalgia

3.5

3.6

5.9

8.4

2.7

3.1

Insomnia

3.0

2.8

1.1

5.3

2.8

2.9

Pharyngolaryngeal pain

2.3

3.9

1.6

2.8

0.7

2.1

* Adverse Reactions ≥2% in any dose greater than placebo

Other adverse reactions reported in placebo-controlled studies include:

  • Body as a Whole: malaise, pyrexia, chest pain, peripheral edema, fatigue, pyrexia.
  • Musculoskeletal and Connective Tissue Disorders: myalgia, arthralgia, pain in extremity, muscle spasms, muscle fatigue, back pain, neck pain, joint swelling, myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture, immune mediated necrotizing myopathy
  • Metabolic and Nutritional System: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, CPK increase, hyperglycemia, hypoglycemia, weight gain, anorexia
  • Nervous System: headache, dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia, peripheral neuropathy
  • Psychiatric Disorders: nightmare, insomnia
  • Respiratory, Thoracic and Mediastinal Disorders: epistaxis, nasopharyngitis, pharyngolaryngeal pain
  • Skin and Appendages: urticaria, skin rash, pruritus, alopecia, angioneurotic edema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Urogenital System: white blood cells urine positive
  • Blood and Lymphatic System Disorders: thrombocytopenia
  • Immune System Disorders: allergic reactions, anaphylaxis
  • Eye Disorders: vision blurred, visual disturbance
  • Ear and Labyrinth Disorders: tinnitus, hearing loss
  • Gastrointestinal Disorders: abdominal discomfort, constipation, flatulence, dyspepsia, nausea, diarrhea, vomiting, abdominal pain upper and lower, eructation, pancreatitis
  • Hepatobiliary Disorders: hepatitis, cholestasis, hepatic failure
  • Reproductive System and Breast Disorders: gynecomastia

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT involving 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.

Collaborative Atorvastatin Diabetes Study (CARDS)

In CARDS involving 2,838 subjects (age range 39–77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.

Treating to New Targets Study (TNT)

In TNT involving 10,001 subjects (age range 29–78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), there were more serious adverse reactions and discontinuations due to adverse reactions 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) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x 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%).

Incremental Decrease in Endpoints through Aggressive Lipid-lowering Study (IDEAL)

In IDEAL involving 8,888 subjects (age range 26–80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin 80 mg/day (n=4,439) or simvastatin 20–40 mg daily (n=4,449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL involving 4,731 subjects (age range 21–92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or TIA within the previous 6 months treated with atorvastatin 80 mg (n=2,365) or placebo (n=2,366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥3 x ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke .

There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

Pediatric Patients (Age 10-17 Years)

In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and ApoB levels, was generally similar to that of placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, and pancreatitis.

There have been rare reports of IMNM associated with statin use.

There have been rare postmarketing 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 nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

There is no specific treatment available for ATORLIP overdosage. In the event of an overdose, 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.

Incompatibility

None

Shelf-Life

3 years

Storage and Handling Instructions

Store in a cool, dry place. Protect from light.

Packaging

ATORLIP-5: Strip of 10 tablets

ATORLIP-10: Strip of 10 tablets

ATORLIP-20: Strip of 10 tablets

ATORLIP-40: Strip of 10 tablets

ATORLIP-80: Strip of 7 tablets

Last Updated:  January 2019

Last Reviewed: January 2019