ATORLIP CV Capsules (Atorvastatin calcium + Clopidogrel)

Table of Content

Black Box Warning: Diminished Effectiveness of Clopidogrel in Poor Metabolizers

The effectiveness of clopidogrel is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers

Composition

ATORLIP CV 10

Each hard gelatin capsule contains:

Atorvastatin Calcium equivalent to Atorvastatin …………… 10 mg

(As Pellets)

Clopidogrel Bisulphate IP equivalent to Clopidogrel….…… 75 mg

(As Pellets)

Dosage Form

Capsule

Description

ATORLIP CV Capsules are a fixed-dose combination of atorvastatin and clopidogrel.

Pharmacology

Pharmacodynamics

Atorvastatin

Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts 3-HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides (TG) circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions. TG and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor.

Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C) and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-cholesterol (HDL-C) are associated with a decreased cardiovascular risk. Like LDL, cholesterol-enriched TG-rich lipoproteins, including VLDL, IDL and remnants, can also promote atherosclerosis. Elevated plasma TGs 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 (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

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 total-C, LDL-C and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia and mixed dyslipidemia. Atorvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C and apo A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG and non-HDL-C and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces IDL cholesterol (IDL-C) in patients with dysbetalipoproteinemia.

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.

Clopidogrel

Clopidogrel is a thienopyridine class inhibitor of P2Y12 adenosine diphosphate (ADP) platelet receptors. It is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

Clopidogrel must be metabolized by cytochrome P (CYP) 450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of ADP to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition.

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

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 (GI) 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 the Cmax and area under 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.

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast. ATORLIP CV can be administered with or without food.

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood to 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.

Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range.

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 (CY) P450 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.

Clopidogrel is extensively metabolized in the liver by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.

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.

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

Pharmacogenomics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel’s active metabolite.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and *3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function alleles in white (85%) and Asian (99%) poor metabolizers. Other alleles associated with absent or reduced metabolism are less frequent, and include, but are not limited to, CYP2C19*4, *5, *6, *7, and *8. A patient with poor metabolizer status will possess two loss-of-function alleles as defined above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype.

The relationship between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in retrospective analyses of clopidogrel-treated subjects in CHARISMA (n=2,428) and TRITON-TIMI 38 (n=1,477), and in several published cohort studies. In TRITON-TIMI 38 and the majority of the cohort studies, the combined group of patients with either intermediate or poor metabolizer status had a higher rate of cardiovascular events or stent thrombosis compared to extensive metabolizers. In CHARISMA and one cohort study, the increased event rate was observed only in poor metabolizers.

Special Populations

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. Elderly (>75 years) and young healthy subjects had similar effects on platelet aggregation with clopidogrel.

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. In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, with clopidogrel.

Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin. After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients. Thus, dose adjustment of ATORLIP CV in patients with renal dysfunction may not be 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. After repeated doses of 75 mg clopidogrel   per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.

Race: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism of clopidogrel differs according to race/ethnicity. From literature, limited data for clopidogrel in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

Indications

ATORLIP CV (atorvastatin and clopidogrel) is indicated in patients for whom treatment with both atorvastatin and clopidogrel is appropriate.

Atorvastatin

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 CHD or multiple risk factors for CHD, atorvastatin 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, atorvastatin is indicated to

  • reduce the risk of myocardial infarction (MI)
  • 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, atorvastatin is indicated to

  • reduce the risk of MI
  • reduce the risk of stroke

In patients with clinically evident CHD, atorvastatin is indicated to:

  • reduce the risk of non-fatal MI
  • reduce the risk of fatal and non-fatal stroke
  • reduce the risk for revascularization procedures
  • reduce the risk of hospitalization for CHF
  • reduce the risk of angina

Hyperlipidemia

Atorvastatin is indicated:

  • As an adjunct to diet to reduce elevated total-C, LDL-C, apo B 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 dysbetalipoproteinaemia (Fredrickson Type III) who do not respond adequately to diet;
  • To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolaemia 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 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 present:
    • a. LDL-C remains >190 mg/dL or
    • b. 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).

Clopidogrel

Acute Coronary Syndrome

  • For patients with non-ST-segment elevation ACS , including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
  • For patients with ST-elevation myocardial infarction (STEMI), clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

Dosage and Administration

Patients should be placed on an appropriate lipid-lowering diet before receiving ATORLIP CV, and should continue this diet during treatment. The recommended dosage is one capsule once daily.

The dose of atorvastatin can be individualized according to baseline LDL-C levels, the goal of therapy and patient response. The usual starting dose is 10mg once daily. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80mg once daily.

The dosage of clopidogrel in unstable angina (UA) / Non-ST-elevated myocardial infarction (NSTEMI) is 75 mg daily after a single loading dose. In patients with STEMI, recent MI, stroke or peripheral artery disease, the recommended dose of clopidogrel is 75 mg once daily.

Avoid using omeprazole or esomeprazole with ATORLIP CV. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.

Contraindications

  • Hypersensitivity to atorvastatin, clopidogrel or any component of this medication
  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
  • Active pathological bleeding such as peptic ulcer or intracranial hemorrhage
  • Women who are pregnant or may become pregnant
  • Lactation

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 CYP450 3A4. Concomitant administration of ATORLIP CV 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. Co-administration of ritonavir, lopinavir, darunavir, atazanavir, indinavir, ketoconazole, voriconazole, posaconazole, delavirdine, stiripentol and telithromycin with atorvastatin should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended 

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 dose of atorvastatin 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 CV should be avoided. In patients taking the HIV protease inhibitor, lopinavir plus ritonavir, caution should be exercised when prescribing ATORLIP CV 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 atorvastatin 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 atorvastatin 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 exercised when the atorvastatin dose exceeds 20 mg.

CYP2C19 Inhibitors: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged. Medicinal products that are strong or moderate CYP2C19 inhibitors include for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton Pump Inhibitors: Avoid concomitant use of ATORLIP CV with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole.

Substrates of CYP2C8: Clopidogrel has shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition by CYP2C8 by the glucuronide metabolite of clopidogrel. Due to risk of increased plasma concentrations, concomitant administration of ATORLIP CV and drugs primarily cleared by CYP2C8 metabolism (eg. Repaglinide, paclitaxel) should be undertaken with caution.

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 CV with cyclosporine should be avoided.

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 CV. Appropriate clinical monitoring of these patients is recommended.

Fusidic Acid: Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle-related events, including rhabdomyolysis, have been reported in post-marketing experience with atorvastatin and fusidic acid given concurrently. The mechanism of this interaction is not known. Patients should be closely monitored and temporary suspension of ATORLIP CV treatment may be appropriate.

Colestipol: Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) 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.

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

Rifampin or other Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg. efavirenz, rifampin, St.John’s Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of ATORLIP CV with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Digoxin: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. 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 CV.

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

Non-steroidal Anti-inflammatory Agents (NSAIDs): Co-administration of ATORLIP CV and NSAIDs increases the risk of gastrointestinal bleeding and hence should be co-administered with caution. Although aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of aspirin twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between ATORLIP CV and aspirin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and aspirin have been administered together for up to one year.

Oral Anti-coagulants: The concomitant administration of ATORLIP CV with oral anti-coagulants is not recommended since it may increase the intensity of bleeding. Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or International Normalized Ratio (INR) in patients receiving long-term warfarin therapy, at high concentrations in vitro, clopidogrel inhibits CYP2C9. Co-administration of ATORLIP CV with warfarin increases the risk of bleeding because of independent effects of clopidogrel on hemostasis.

Glycoprotein IIb/IIIa Inhibitors: ATORLIP CV should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors.

Heparin: In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs): The concomitant administration of selective serotonin re-uptake inhibitors (SSRIs) and serotonin norepinephrine re-uptake inhibitors (SNRIs) with clopidogrel may affect platelet activation. Hence concomitant administration of SSRIs and SNRIs with ATORLIP CV may increase the risk of bleeding.

Thrombolytics: The safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with aspirin.

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. Of 30 patients with persistent LFT elevations 18 continued treatment with a reduced dose of atorvastatin.

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

ATORLIP CV 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 ATORLIP CV.

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, 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 CV. ATORLIP CV 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 CV 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 ATORLIP CV 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 ATORLIP CV

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 ATORLIP CV with colchicine.

ATORLIP CV 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/ Diabetes Mellitus

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping ATORLIP CV treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

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 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.

In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding. In view of lack of data with clopidogrel, ATORLIP CV cannot be recommended during the first 7 days after acute ischemic stroke.

Central Nervous System 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 dyspnea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, ATORLIP CV therapy should be discontinued.

Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

Proton Pump Inhibitors: Avoid concomitant use of ATORLIP CV with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel.

General Risk of Bleeding

Thienopyridines, including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue ATORLIP CV five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% clopidogrel + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin.

Due to risk of bleeding and hematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment. ATORLIP CV should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions as well as medicinal products which increase the risk of bleeding. Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery.  

Patients should inform physicians and dentists that they are taking ATORLIP CV before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

Patients should be told that it may take longer than usual to stop bleeding when they take ATORLIP CV (alone or in combination with aspirin), and that they should report any unusual bleeding (site or duration) to their physician.

Discontinuation of ATORLIP CV

Avoid lapses in therapy and if ATORLIP CV must be temporarily discontinued, restart as soon as possible. Premature discontinuation of ATORLIP CV may increase the risk of cardiovascular events.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP), sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and fever.

Acquired Hemophilia

Acquired hemophilia has been reported following the use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.

Cross-Reactivity among Thienopyridines

Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) as hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin. Experience of clopidogrel is limited in patients with severe and moderate renal impairment. ATORLIP CV should be used with caution in these patients.

Hepatic Impairment

Experience of clopidogrel is limited in patients with moderate hepatic disease who may have bleeding diatheses. Atorvastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels. Thus ATORLIP CV is contraindicated in patients with active liver disease, including unexplained persistent elevations in hepatic transaminase levels.

Pregnancy

Pregnancy Category X

Atorvastatin is contraindicated in women who are or may become pregnant. Statins may cause fetal harm when administered to a pregnant woman. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy embryonal/fetal development, parturition or postnatal development. There are, however, no adequate and well-controlled studies in pregnant women.

Animal studies revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.

ATORLIP CV should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking ATORLIP CV, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus.

Lactation

It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Statins have the potential to cause serious adverse reactions in nursing infants. It is unknown whether clopidogrel is excreted in human breast milk.  Women requiring ATORLIP CV treatment should be advised not to nurse their infants.

Pediatric Use

Safety and effectiveness of atorvastatin in patients 10 to 17 years of age with heterozygous FH have been evaluated in a controlled clinical trial of 6 months' duration in adolescent boys and post-menarchal girls. Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year has been evaluated in an uncontrolled study of patients with homozygous FH, including 8 pediatric patients.

Safety and effectiveness of clopidogrel in pediatric populations have not been established.

Use of ATORLIP CV should be avoided in the pediatric population.

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, atorvastatin should be prescribed with caution in the elderly.

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.

ATORLIP CV should be prescribed with caution in the elderly. Where prolonged therapy with ATORLIP CV is required, patients should be reviewed regularly.

Undesirable Effects

Atorvastatin

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

Rhabdomyolysis, myopathy and liver enzyme abnormalities

Clinical Trial Adverse 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 (8,755 atorvastatin versus 7,311 placebo; age range 10 to 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=8755) 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=8,755), 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 included the following:

  • Body as a whole: malaise, pyrexia, asthenia, chest pain, peripheral edema, fatigue
  • Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis, constipation, vomiting
  • Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling, back pain, myositis,
  • Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, CPK increase, hypoglycemia, weight gain, anorexia, hyperglycemia, hepatitis, cholestasis,
  • Nervous system: nightmare, headache, paraesthesia, hypoesthesia, dysgeusia, amnesia
  • Respiratory system: epistaxis
  • Skin and appendages: urticaria, skin rash, pruritus, alopecia
  • Special senses: vision blurred, tinnitus
  • Urogenital system: white blood cells urine positive
  • Blood: thrombocytopenia
  • Reproductive system: gynecomastia

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT involving 10,305 participants (age range: 40 to 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 to 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 to 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 × ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in 9 (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥10 × 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 to 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 to 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 to 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 × ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 × 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% versus 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% versus 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin versus 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 versus 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%).

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 were 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).

Pediatric Patients (aged 10 to 17 years)

In a 26-week controlled study in boys and post-menarchal girls (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 was generally similar to that of placebo.

Clopidogrel

The following serious adverse reactions are discussed below and in other sections:

  • Bleeding
  • Thrombothic thrombocytopenic purpura

Clinical Studies Experience

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

Clopidogrel has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below.

Bleeding

CURE

In the CURE trial, clopidogrel use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (Table 3). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.

The overall incidence of bleeding is described in Table 3.

Table 3: CURE-Incidence of bleeding complications (% patients)

Event

Clopidogrel (+ aspirin)* (n = 6259)

Placebo (+ aspirin)* (n = 6303)

Major bleeding#

3.7@

2.7$

Life-threatening bleeding

2.2

1.8

Fatal

0.2

0.2

5g/dL hemoglobin drop

0.9

0.9

Requiring surgical intervention

0.7

0.7

Hemorrhagic strokes

0.1

0.1

Requiring ionotropes

0.5

0.5

Requiring transfusion (≥4 units)

1.2

1.0

Other major bleeding

1.6

1.0

Significantly disabling

0.4

0.3

Intraocular bleeding with significant loss of vision

0.05

0.03

Requiring 2-3 units of blood

1.3

0.9

Minor bleeding^

5.1

2.4

* Other standard therapies were used as appropriate.

# Life-threatening and other major bleeding.

@ Major bleeding event rate for clopidogrel+aspirin was dose-dependent on aspirin: <100 mg = 2.6%; 100-200 mg = 3.5%; >200 mg = 4.9%

Major bleeding event rates for clopidogrel+aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years = 5.9%.

$ Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg = 2.0%; 100-200 mg = 2.3%; >200 mg = 4.0%

Major bleeding event rates for placebo + aspirin by age were: <65 years = 2.1%, ≥65 to <75 years = 3.1%, ≥75 years = 3.6%

^ Led to interruption of study medication.

Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

COMMIT

In the COMMIT trial, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin (see Table 4)

Table 4: Incidence of bleeding events in COMMIT (% patients)

Type of bleeding

Clopidogrel (+ aspirin) (n = 22961)

Placebo (+ aspirin) (n = 22891)

p-value

Major* non-cerebral or cerebral bleeding**

0.6

0.5

0.59

Major non-cerebral

0.4

0.3

0.48

Fatal

0.2

0.2

0.9

Hemorrhagic stroke

0.2

0.2

0.91

Fatal

0.2

0.2

0.81

Other non-cerebral bleeding (non-major)

3.6

3.1

0.005

Any non-cerebral bleeding

3.9

3.4

0.004

* Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.

** The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for clopidogrel + aspirin by age were: <60 years = 0.3%, ≥60 to <70 years = 0.7%, ≥70 years = 0.8%. Event rates for placebo + aspirin by age were: <60 years = 0.4%, ≥60 to <70 years = 0.6%, ≥70 years = 0.7%.

CAPRIE (Clopidogrel vs. Aspirin)

In the CAPRIE trial, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel compared to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the clopidogrel group was epistaxis and hematoma.

CLARITY

In the CLARITY trial, there was an overall increase in bleeding in the clopidogrel plus aspirin group vs. the placebo plus aspirin group .The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

ACTIVE-A

In the ACTIVE-A trial, the rate of major bleeding was greater in the clopidogrel + aspirin group than in the placebo + aspirin group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + aspirin group; 3.5% in the placebo + aspirin group), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + aspirin treatment group compared to the placebo + aspirin group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + aspirin group and 0.7% in the placebo + aspirin group) and hemorrhagic stroke (0.8% and 0.6%, respectively) between groups.

Other Adverse Events

In CURE and CHARISMA trials, which compared clopidogrel plus aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo.

In CAPRIE trial, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel. No other differences in the rate of adverse events (other than bleeding) was reported.

Post-marketing Experience

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

  • Blood and lymphatic system disorders: Agranulocytosis, thrombocytopenia, leucopenia, eosinophilia, neutropenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A, granulocytopenia, anemia
  • Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
  • Ear and labyrinth disorders: Vertigo
  • Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea, abdominal pain, dyspepsia, gastritis, vomiting, nausea, constipation, flatulence
  • General disorders and administration site condition: Fever, hemorrhage of operative wound, bleeding at puncture site
  • Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test
  • Immune system disorders: Hypersensitivity reactions (including cross reactive drug hypersensitivity among thienopyridines), anaphylactoid reactions, serum sickness
  • Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding (hemarthrosis), myalgia, arthralgia, arthritis
  • Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache, paraesthesia, dizziness
  • Psychiatric disorders: Confusion, hallucinations
  • Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia, epistaxis, hemoptysis, pulmonary hemorrhage
  • Renal and urinary disorders: Increased creatinine levels, hematuria, glomerulonephritis
  • Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding (purpura), lichen planus, generalized pruritus, bruising
  • Reproductive systems and breast disorders: Gynecomastia
  • Vascular disorders: Vasculitis, hypotension, hematoma
  • Investigations: bleeding time prolonged, neutrophil count decreased, platelet count decreased

Overdosage

Atorvastatin

There is no specific treatment available for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Clopidogrel

Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications.

Appropriate therapy should be considered if bleeding is observed.

No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

Shelf-Life

18 Months

Storage and Handling Instructions

Store in a dry, well-ventilated place at a temperature not exceeding 300C. Protect from light and moisture.

Packaging Information

ATORLIP CV 10: Strip pack of 10 capsules

Last updated: September 2016
Last reviewed: October 2016