ATORLIP ASP Capsules (Atorvastatin calcium + Aspirin)

Table of Content

Composition

ATORLIP ASP10

Each capsule contains:

Atorvastatin Calcium equivalent to Atorvastatin …… 10 mg

Aspirin (as gastro-resistant tablet) ……………………75 mg

ATORLIP ASP20

Each capsule contains:

Atorvastatin Calcium equivalent to Atorvastatin …… 20 mg

Aspirin (as gastro-resistant tablet) ……………………75 mg

Dosage Form

Capsule

Description

ATORLIP ASP Capsules are a fixed-dose combination of atorvastatin and aspirin.

Pharmacology

Pharmacodynamics

Atorvastatin

Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3methylglutaryl-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.

Aspirin

Aspirin is a more potent inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo-oxygenase via acetylation.

Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet-aggregating factor thromboxane A2. Non-acetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin I2 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation.

At higher doses, aspirin is an effective anti-inflammatory agent, partially due to inhibition of inflammatory mediators via cyclo-oxygenase inhibition in peripheral tissues. In vitro studies suggest that other mediators of inflammation may also be suppressed by aspirin administration, although the precise mechanism of action has not been elucidated. It is this non-specific suppression of cyclo-oxygenase activity in peripheral tissues following large doses that leads to its primary side effect of gastric irritation.

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.

Enteric-coated aspirin products are erratically absorbed from the GI tract. Hydrolysis to salicylic acid occurs in the intestine and in the circulation. The rate of absorption from the GI tract is dependent upon the dosage form, the presence or absence of food, gastric pH (the presence or absence of GI antacids or buffering agents) and other physiologic factors.

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.

Salicylic acid is widely distributed to all tissues and fluids in the body, including the central nervous system (CNS), breast milk and fetal tissues. The highest concentrations are found in the plasma, liver, renal cortex, heart and lungs. The protein binding of salicylate is concentration-dependent, i.e., non-linear. At low concentrations (<100 mcg/mL), approximately 90% of plasma salicylate is bound to albumin while at higher concentrations (>400 mcg/mL), only about 75% is bound.

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 CYP450 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.

Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin are essentially undetectable 1 to 2 hours after dosing. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to over 20 hours.

Elimination

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.

The elimination of salicylic acid follows zero-order pharmacokinetics (i.e., the rate of drug elimination is constant in relation to plasma concentration). Renal excretion of unchanged drug depends upon urine pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalization of the urine is a key concept in the management of salicylate overdose. Following therapeutic doses, approximately 10% is found excreted in the urine as salicylic acid, 75% as salicyluric acids, and 10% and 5% as the phenolic and acyl glucuronides, respectively.

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.

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 Child-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease.

Indications

ATORLIP ASP (atorvastatin and aspirin) is indicated for the treatment of dyslipidemia associated with artherosclerotic arterial disease with risk of myocardial infarction, stroke or peripheral vascular disease.

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:
  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).

Aspirin
Vascular Indications

Aspirin is indicated to

  • reduce the combined risk of death and non-fatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli
  • reduce the risk of vascular mortality in patients with a suspected acute MI
  • reduce the combined risk of death and non-fatal MI in patients with a previous MI or unstable angina pectoris
  • reduce the combined risk of MI and sudden death in patients with chronic stable angina pectoris

Revascularization Procedures

Aspirin is indicated in patients who have undergone revascularization procedures (i.e., CABG, PTCA or carotid endarterectomy) when there is a pre-existing condition for which aspirin is already indicated.

Dosage and Administration

Patients should be placed on an appropriate lipid-lowering diet before receiving ATORLIP ASP, and should continue this diet during treatment. The recommended dosage is one or two capsules 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 10 mg once daily. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once daily.

The maximum dose of aspirin in patients with unstable angina pectoris, chronic stable angina pectoris and for prevention of recurrent acute myocardial infarction, ischemic stroke and TIA, CABG, percutaneous transluminal coronary angioplasty PTCA is 325 mg once a day.

Contraindications

  • Hypersensitivity to atorvastatin, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), salicylic acid compounds, prostaglandin synthetase inhibitors or to any of the excipients.
  • Patients with the syndrome of asthma, rhinitis and nasal polyps, as aspirin may cause severe urticaria, angioedema or bronchospasm (asthma).
  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
  • Active, or history of recurrent peptic ulcer and/or gastric /intestinal hemorrhage or other kinds of bleeding such as cerebrovascular hemorrhages
  • Hemorrhagic diathesis, coagulation disorders such as hemophilia and thrombocytopenia
  • In children or teenagers for viral infections, with or without fever, because of the risk of Reye’s syndrome with concomitant use of aspirin in certain viral illnesses
  • Methotrexate used at doses >15 mg/week
  • Severe renal impairment
  • 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 ASP 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 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 ASP should be avoided. In patients taking the HIV protease inhibitor, lopinavir plus ritonavir, caution should be used when prescribing ATORLIP ASP 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 used when the atorvastatin dose exceeds 20 mg.

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. Concomitant administration of NSAIDs and cyclosporine may increase the nephrotoxic effect of cyclosporine. The co-administration of ATORLIP ASP with cyclosporine should be avoided.

Tacrolimus: Concomitant administration of NSAIDs and tacrolimus may increase the nephrotoxic effect of tacrolimus. The renal function should be monitored in case of concomitant use of tacrolimus and ATORLIP ASP.

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 ASP. 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 postmarketing 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 ASP 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 ASP 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 ASP 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 ASP dosage should be considered in this setting.

Rifampin or other Inducers of Cytochrome (CY) P450 3A4: Concomitant administration of atorvastatin with inducers of CYP450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of ATORLIP ASP 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. Aspirin impairs the renal excretion of digoxin, resulting in increased plasma concentrations. Monitoring of plasma concentrations of digoxin is recommended when initiating and terminating treatment with ATORLIP ASP. Dose adjustment may be necessary.

Lithium: Aspirin impairs the renal excretion of lithium, resulting in increased plasma concentrations. Monitoring of plasma concentrations of lithium is recommended when initiating and terminating treatment with ATORLIP ASP. Dose adjustment may be necessary.

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 ASP.

Anticoagulant Therapy: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein-binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can also increase the anticoagulant activity of heparin, increasing bleeding risk. Concomitant therapy of ATORLIP ASP and anti-coagulants is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.

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

Angiotensin-converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway.

Antacids: The excretion of aspirin may be increased by alkaline urine, which can occur with some antacids.

Carbonic Anhydrase Inhibitors (Acetazolamide): Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. It may result in severe acidosis and increased central nervous system toxicity.

Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Beta-blockers: The hypotensive effects of beta-blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Diuretics: There is risk of acute renal failure due to decreased glomerular filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention

Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity especially in the elderly or renally impaired.

Non-steroidal Anti-inflammatory Drugs (NSAIDs): Concomitant therapy of ATORLIP ASP with other NSAIDs is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.

Oral Hypoglycemics/Insulin: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs and insulin, leading to hypoglycemia.

Systemic Corticosteroids: Use ATORLIP ASP with caution in patients on oral corticosteroids as it could increase the risk of gastrointestinal ulceration and bleeding.

Anti-platelet Agents: Concurrent administration of aspirin with drugs such as clopidogrel or dipyridamole is associated with an increased risk of GI bleeding. Concomitant therapy of ATORLIP ASP and anti-platelet agents is not recommended, unless strictly indicated, since it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.

Thrombolytic Agents: Concomitant therapy of ATORLIP ASP and thrombolytic agents is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.

Selective Serotonin Re-uptake Inhibitors (SSRIs): Concomitant therapy of ATORLIP ASP and SSRIs is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended. Concomitant use of ATORLIP ASP and SSRIs could also increase the risk of ulceration.

Deferasirox: Use ATORLIP ASP with caution in patients on deferasirox as concomitant use could increase the risk of ulceration.

Uricosuric Agents (Probenecid and Sulfinpyrazone): Salicylates antagonize the uricosuric action of uricosuric agents.

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 ASP 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 ASP, promptly interrupt therapy. If an alternate etiology is not found, do not restart ATORLIP ASP.

ATORLIP ASP 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, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and 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 ASP. ATORLIP ASP 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 ASP 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 ASP 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 ASP

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 ASP with colchicine.

ATORLIP ASP 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 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 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 versus 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 versus 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 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.

Alcohol

Patients who consume three or more alcoholic drinks every day should be counselled about the bleeding risks involved with chronic, heavy alcohol use while taking ATORLIP ASP

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 ASP therapy should be discontinued.

Diabetes Mellitus

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 ASP 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.

Coagulation Abnormalities

Even low doses of aspirin can inhibit platelet function, leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders.

GI Side Effects

GI side effects include stomach pain, heartburn, nausea, vomiting and gross GI bleeding. Although minor upper GI symptoms such as dyspepsia are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. If GI bleeding or ulceration occurs, the treatment should be withdrawn.

History of Peptic Ulcer Disease/Hemorrhagic Episodes

Patients with a history of active peptic ulcer disease or hemorrhagic episodes should avoid using ATORLIP ASP, since aspirin can cause gastric mucosal irritation and bleeding.

Sodium-retaining Disease States

Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of their high sodium content.

Surgery/Minor Procedures

Aspirin is associated with an increased risk of hemorrhage particularly during or after operative procedures (even in cases of minor procedures, e.g., tooth extraction). Use ATORLIP ASP with caution before surgery, including tooth extraction. Temporary discontinuation of treatment may be necessary.

Menorrhagia

ATORLIP ASP is not recommended during menorrhagia where it may increase menstrual bleeding.

Hypersensitivity

Aspirin may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, hay fever, nasal polyps or chronic respiratory diseases. The same applies for patients who also show allergic reaction to other substances (e.g., with skin reactions, itching or urticaria).

Serious skin reactions, including Steven-Johnsons syndrome, have rarely been reported in association with the use of aspirin. ATORLIP ASP should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Gout

Aspirin, especially in low doses, may reduce uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks. Hence, use ATORLIP ASP with caution in these patients.

Glucose 6-Phosphate Dehydrogenase Deficiency

High doses of aspirin may precipitate acute hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Hence, use ATORLIP ASP with caution in these patients.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin. Aspirin needs to be avoided in patients with severe renal failure (glomerular filtration rate <10 mL/min). Hence, ATORLIP ASP should be used with caution in patients with moderately impaired renal function while it should be avoided in those with severe renal failure.

Hepatic Impairment

Aspirin should be avoided in patients with severe hepatic insufficiency. Liver function tests should be performed regularly in patients presenting slight or moderate hepatic insufficiency. Atorvastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels. Thus, ATORLIP ASP 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. It is recommended that pregnant women should take aspirin only if clearly needed. Aspirin has the ability to alter platelet function and, therefore, there may be a risk of hemorrhage in infants whose mothers have consumed aspirin during pregnancy. The onset of labor may be delayed and the duration increased, with an increase in maternal blood loss. High doses of aspirin may result in closure of fetal arteriosus in utero and possibly persistent pulmonary hypertension in the new born. Kenicterus may be a consequence of jaundice in neonates.

ATORLIP ASP 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 ASP, 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. Salicylate is excreted in breast milk. Use of salicylates at high doses may lead to rashes, platelet abnormalities and bleeding in nursing infants. Women requiring ATORLIP ASP 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.

Aspirin is not recommended for use in adolescents/children aged under 16 years unless the expected benefits outweigh the risks. It may be a contributory factor in the causation of Reye's syndrome in some children. ATORLIP ASP should be avoided in children aged below 16 years unless expected benefits outweigh the risks.

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.

Elderly patients are particularly susceptible to the adverse effects of NSAIDs (including aspirin), especially GI bleeding and perforation, which may be fatal.

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

Undesirable Effects

Atorvastatin

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

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

Digestive System: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis

Musculoskeletal System: musculoskeletal pain, muscle fatigue, neck pain, joint swelling

Metabolic and Nutritional System: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, CPK increase, hypoglycemia, weight gain, anorexia, hyperglycemia

Nervous System: nightmare

Respiratory System: epistaxis

Skin and Appendages: urticaria

Special Senses: vision blurred, tinnitus

Urogenital System: white blood cells urine positive

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.

Aspirin

Many adverse reactions are due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature:

Body as a Whole: fever, hypothermia, thirst

Cardiovascular: dysrhythmias, hypotension, tachycardia

Central Nervous System: agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures

Fluid and Electrolyte: dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis

GI: dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye’s syndrome, pancreatitis

Hematologic: increased bleeding tendencies, prolongation of prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia, granulocytosis, aplastic anemia

Hypersensitivity: acute anaphylaxis, including shock, angioedema, allergic edema, asthma, bronchospasm, laryngeal edema, urticaria

Metabolism: hypoglycemia (in children), hyperglycemia

Musculoskeletal: rhabdomyolysis

Reproductive: menorrhagia, prolonged pregnancy and labor, stillbirths, low birth weight infants, antepartum and postpartum bleeding

Respiratory: rhinitis, dyspnea, hyperpena, pulmonary edema, tachypnea

Skin: Steven-Johnsons syndrome, Lyells syndrome, purpura, erythema nodosum, erythema multiforme

Special Senses: hearing loss, tinnitus. Patients with higher frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism.

Urogenital: interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure

Vascular: hemorrhagic vasculitis

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

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.

Aspirin

Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus, occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g.

Symptoms and Signs

In acute overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis.

Treatment

Treatment consists primarily of supporting vital functions, increasing salicylates elimination, and correcting the acid-base disturbance. Gastric emptying and/or lavage is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as slurry, is beneficial, if less than 3 hours have passed since ingestion. Charcoal adsorption should not be employed prior to emesis and lavage.

Severity of aspirin intoxication is determined by measuring the blood salicylates level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylates if renal function is normal. Infusion of glucose may be required to control hypoglycemia.

Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal impairment or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children

Incompatibility

None

Shelf-Life

2 years

Storage and Handling Instructions

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

Packaging Information

ATORLIP ASP10: Strip pack of 10 capsules

ATORLIP ASP20: Strip pack of 10 capsules

Last updated: May 2018

Last reviewed: May 2018