Amlodipine besylate and Atorvastatin calcium

RECENT MAJOR CHANGES SECTION Warnings and Precautions, Myopathy and Rhabdomyolysis ( 5.1 ) 01/2021 Warnings and Precautions, Immune-Mediated Necrotizing Myopathy ( 5.2 ) 09/2020

1 INDICATIONS AND USAGE Amlodipine besylate and atorvastatin calcium tablets are indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. Amlodipine Amlodipine besylate and atorvastatin calcium tablets are a combination of amlodipine besylate, a calcium channel blocker, and atorvastatin calcium, a HMG CoA-reductase inhibitor, indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. Amlodipine is indicated for the treatment of hypertension, to lower blood pressure (1.1). Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Amlodipine is indicated for the treatment of Coronary Artery Disease (1.2). Atorvastatin is indicated as an adjunct therapy to diet for prevention of cardiovascular disease (1.3) and hyperlipidemia (1.4). 1.1 Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Amlodipine may be used alone or in combination with other antihypertensive agents. 1.2 Coronary Artery Disease (CAD) Chronic Stable Angina Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents. Vasospastic Angina (Prinzmetal’s or Variant Angina) Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy or in combination with other antianginal agents. Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <4 …

2 DOSAGE AND ADMINISTRATION Amlodipine besylate and atorvastatin calcium Dosage of amlodipine besylate and atorvastatin calcium must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently. Amlodipine besylate and atorvastatin calcium may be substituted for its individually titrated components. Patients may be given the equivalent dose of amlodipine besylate and atorvastatin calcium or a dose of amlodipine besylate and atorvastatin calcium with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect. Amlodipine besylate and atorvastatin calcium may be used to provide additional therapy for patients already on one of its components. Amlodipine besylate and atorvastatin calcium may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. Amlodipine The usual initial antihypertensive oral dose of amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily. Pediatric (age > 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy. Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently. Angina: The recommended dose of amlodipine for chronic stable or vasospastic angina is 5 to 10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect. Coronary Artery Disease : The recommended dose range of amlodipine for patients with CAD is 5 to 10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies ( 14.4 ) ]. Pediatrics: The effective antihypertensive oral dose of amlodipine in pediatric patients ages 6 to 17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 ) ]. Atorvastatin (Hyperlipidemia) Hyperlipidemia and Mixed Dyslipidemia: The recommended starting dose of atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. Homozygous Familial Hypercholesterolemia: The dosage range of atorvastatin in patients with HoFH is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Concomitant Lipid-Lowering Therapy: Atorvastatin may be used with bile acid resins. Monitor for signs of myopathy in patients receiving the combination of HMG-CoA reductase inhibitors (statins) and fibrates [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7 ) ]. Patients with Renal Impairment: Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 ) ]. Use with Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors: In patients taking cyclosporine or the human i …

3 DOSAGE FORMS AND STRENGTHS Amlodipine besylate and atorvastatin calcium tablets are formulated for oral administration in the following strength combinations: Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/10 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘407’ on other side. Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/20 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘408’ on other side. Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/40 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘409’ on other side. Amlodipine besylate and atorvastatin calcium tablets 5 mg/10 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘410’ on other side. Amlodipine besylate and atorvastatin calcium tablets 5 mg/20 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘411’ on other side. Amlodipine besylate and atorvastatin calcium tablets 5 mg/40 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘412’ on other side. Amlodipine besylate and atorvastatin calcium tablets 5 mg/80 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘413’ on other side. Amlodipine besylate and atorvastatin calcium tablets 10 mg/10 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘414’ on other side. Amlodipine besylate and atorvastatin calcium tablets 10 mg/20 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘415’ on other side. Amlodipine besylate and atorvastatin calcium tablets 10 mg/40 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘416’ on other side. Amlodipine besylate and atorvastatin calcium tablets 10 mg/80 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘417’ on other side. Combinations of atorvastatin with 2.5 mg and 5 mg amlodipine are film-coated white, and combinations of atorvastatin with 10 mg amlodipine are film-coated blue. Tablets contain amlodipine besylate equivalent to amlodipine 2.5, 5, or 10 mg and atorvastatin calcium equivalent to atorvastatin 10, 20, 40, or 80 mg ( 3 ).

4 CONTRAINDICATIONS • Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels • Pregnancy [see Use in Specific Populations ( 8.1 ) ] • Lactation [see Use in Specific Populations ( 8.2 ) ] Active liver disease ( 4 ) Pregnancy ( 4 ) Lactation ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 ) ] Liver enzyme abnormalities [see Warnings and Precautions ( 5.3 ) ] Most common adverse reaction (3% greater than placebo) to amlodipine is edema ( 6.1 ). Most common adverse reactions leading to atorvastatin discontinuation were myalgia and diarrhea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, 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. Amlodipine besylate and atorvastatin calcium Amlodipine besylate and atorvastatin calcium has been evaluated for safety in 1,092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia. In general, treatment with amlodipine besylate and atorvastatin calcium was well tolerated. For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with amlodipine besylate and atorvastatin calcium, no adverse reactions peculiar to this combination have been observed. Adverse reactions are similar in terms of nature, severity, and frequency to those reported previously with amlodipine and atorvastatin. The following information is based on the clinical experience with amlodipine and atorvastatin. Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1,730) at doses up to 10 mg to placebo (N=1,250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are dizziness and edema. The incidence (%) of side effects that occurred in a dose-related manner are as follows: 2.5 mg N=275 Amlodipine 5 mg N=296 10 mg N=268 Placebo N=520 Edema 1.8 3 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0 Palpitations 0.7 1.4 4.5 0.6 Other adverse reactions that were not clearly dose related but were reported at an incidence greater than 1% in placebo-controlled clinical trials include the following: Amlodipine (%) (N=1730) Placebo (%) (N=1250) Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal Pain 1.6 0.3 Somnolence 1.4 0.6 Edema, flushing, palpitations, and somnolence appear to be more common in women than in men. The following events occurred in 0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis. Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. General: allergic reaction, asthenia, 2 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System: arthralgia, arthrosis, muscle cramps, 2 myalgia. Psychiatric: sexual dysfunction (male 2 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. Respiratory System: dyspnea, 2 epistaxis. S …

7 DRUG INTERACTIONS Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the C max : 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful. No drug interaction studies have been conducted with amlodipine besylate and atorvastatin calcium and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: Amlodipine Increased Risk of Myopathy and Rhabdomyolysis ( 2 , 5.1 , 7.3 , 12.3 ) Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir,letermovir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Consider the risk/benefit of concomitant use with atorvastatin Other Lipid-Lowering Medications: Increased risk of myopathy (7) . Rifampin should be simultaneously co-administered with atorvastatin ( 7.4 ). Oral Contraceptives: Norethindrone and ethinyl estradiol may be increased ( 7.5 ). Digoxin: Patients should be monitored appropriately ( 7.5 ). 7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology ( 12.3 ) ]. CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology ( 12.2 ) ]. 7.2 Impact of Amlodipine on Other Drugs Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology ( 12.3 ) ]. Atorvastatin 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 and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology ( 12.3 ) ]. 7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Table 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [ see Clinical Pharmacolo …

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Plasma concentrations of atorvastatin markedly increased in patients with active liver disease ( 8.6 ,12.3 ). Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with amlodipine besylate and atorvastatin calcium ( 8.3 ). 8.1 Pregnancy Risk Summary Amlodipine besylate and atorvastatin calcium tablets are contraindicated in women who are pregnant. Atorvastatin Atorvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause fetal harm when administered to a pregnant woman. Amlodipine besylate and atorvastatin calcium tablets should be discontinued as soon as pregnancy is recognized [see Contraindications ( 4 ) ]. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the MRHD of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥6 times the MRHD ( see Data ). Amlodipine The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy ( see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20 times MRHD, respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Data Human Data Atorvastatin Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in …

12.1 Mechanism of Action Amlodipine besylate and atorvastatin calcium is a combination of two drugs, a dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of amlodipine besylate and atorvastatin calcium inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine besylate and atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Amlodipine Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following: Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise. Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro . This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal’s or variant) angina. Atorvastatin Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In 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.

11 DESCRIPTION Amlodipine besylate and atorvastatin calcium tablets combine the calcium channel blocker amlodipine besylate USP with the HMG CoA-reductase inhibitor atorvastatin calcium. The amlodipine besylate USP is chemically described as 3-ethyl-5-methyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Its molecular formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S. The atorvastatin calcium is chemically described as [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1). Its molecular formula is C 66 H 68 CaF 2 N 4 O 10 . The structural formulae for amlodipine besylate USP and atorvastatin calcium are shown below. Amlodipine besylate and atorvastatin calcium contains amlodipine besylate USP, a white or almost white powder, and atorvastatin calcium, a white to off-white colored powder, free from visible extraneous matter. Amlodipine besylate USP has a molecular weight of 567.1 and atorvastatin calcium has a molecular weight of 1155.36. Amlodipine besylate USP is freely soluble in methanol, sparingly soluble in ethanol, slightly soluble in water and in 2-proponal. Atorvastatin calcium is soluble in dimethyl sulphoxide, slightly soluble in alcohol, very slightly soluble in water, in pH 7.4 phosphate buffer and in acetonitrile and practically insoluble in aqueous solutions of pH 4 and below. Amlodipine besylate and atorvastatin calcium is available as film-coated tablets containing: 2.5 mg amlodipine equivalent to 3.468 mg amlodipine besylate USP and 10 mg atorvastatin equivalent to 10.341 mg atorvastatin calcium. 2.5 mg amlodipine equivalent to 3.468 mg amlodipine besylate USP and 20 mg atorvastatin equivalent to 20.683 mg atorvastatin calcium. 2.5 mg amlodipine equivalent to 3.468 mg amlodipine besylate USP and 40 mg atorvastatin equivalent to 41.365 mg atorvastatin calcium. 5 mg amlodipine equivalent to 6.935 mg amlodipine besylate USP and 10 mg atorvastatin equivalent to 10.341 mg atorvastatin calcium. 5 mg amlodipine equivalent to 6.935 mg amlodipine besylate USP and 20 mg atorvastatin equivalent to 20.683 mg atorvastatin calcium. 5 mg amlodipine equivalent to 6.935 mg amlodipine besylate USP and 40 mg atorvastatin equivalent to 41.365 mg atorvastatin calcium. 5 mg amlodipine equivalent to 6.935 mg amlodipine besylate USP and 80 mg atorvastatin equivalent to 82.730 mg atorvastatin calcium. 10 mg amlodipine equivalent to 13.870 mg amlodipine besylate USP and 10 mg atorvastatin equivalent to 10.341 mg atorvastatin calcium. 10 mg amlodipine equivalent to 13.870 mg amlodipine besylate USP and 20 mg atorvastatin equivalent to 20.683 mg atorvastatin calcium. 10 mg amlodipine equivalent to 13.870 mg amlodipine besylate USP and 40 mg atorvastatin equivalent to 41.365 mg atorvastatin calcium. 10 mg amlodipine equivalent to 13.870 mg amlodipine besylate USP and 80 mg atorvastatin equivalent to 82.730 mg atorvastatin calcium. Each film-coated tablet also contains colloidal silicon dioxide, crospovidone, hydroxy propyl cellulose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium bicarbonate, sodium lauryl sulfate, Opadry- II White 85G18490 (Polyethylene glycol, polyvinyl alcohol, lecithin, talc and titanium dioxide), or Opadry- II Blue 85G50642 (FD&C Blue No.2, polyethylene glycol, polyvinyl alcohol, lecithin, talc and titanium dioxide).

10 OVERDOSAGE There is no information on overdosage with amlodipine besylate and atorvastatin calcium in humans. Amlodipine Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the MRHD on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. If overdose should occur with amlodipine, initiate active cardiac and respiratory monitoring. Perform frequent blood pressure measurements. Should hypotension occur,provide cardiovascular support including elevation of the extremities and administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with specific attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Atorvastatin There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

16 HOW SUPPLIED/STORAGE AND HANDLING Amlodipine besylate and atorvastatin calcium tablets contain amlodipine besylate USP and atorvastatin calcium equivalent to amlodipine and atorvastatin in the dose strengths described below. Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/10 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘407’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-323-30 Bottles of 60 NDC 43598-323-60 Bottles of 90 NDC 43598-323-90 Bottles of 500 NDC 43598-323-05 Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/20 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘408’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-320-30 Bottles of 60 NDC 43598-320-60 Bottles of 90 NDC 43598-320-90 Bottles of 500 NDC 43598-320-05 Amlodipine besylate and atorvastatin calcium tablets 2.5 mg/40 mg are white to off-white, round, film coated tablets debossed ‘R’ on one side and ‘409’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-317-30 Bottles of 60 NDC 43598-317-60 Bottles of 90 NDC 43598-317-90 Bottles of 500 NDC 43598-317-05 Amlodipine besylate and atorvastatin calcium tablets 5 mg/10 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘410’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-322-30 Bottles of 60 NDC 43598-322-60 Bottles of 90 NDC 43598-322-90 Bottles of 500 NDC 43598-322-05 Amlodipine besylate and atorvastatin calcium tablets 5 mg/20 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘411’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-319-30 Bottles of 60 NDC 43598-319-60 Bottles of 90 NDC 43598-319-90 Bottles of 500 NDC 43598-319-05 Amlodipine besylate and atorvastatin calcium tablets 5 mg/40 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘412’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-316-30 Bottles of 60 NDC 43598-316-60 Bottles of 90 NDC 43598-316-90 Bottles of 500 NDC 43598-316-05 Amlodipine besylate and atorvastatin calcium tablets 5 mg/80 mg are white to off-white, oval shaped, film coated tablets debossed ‘R’ on one side and ‘413’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-314-30 Bottles of 60 NDC 43598-314-60 Bottles of 90 NDC 43598-314-90 Bottles of 500 NDC 43598-314-05 Amlodipine besylate and atorvastatin calcium tablets 10 mg/10 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘414’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-321-30 Bottles of 60 NDC 43598-321-60 Bottles of 90 NDC 43598-321-90 Bottles of 500 NDC 43598-321-05 Amlodipine besylate and atorvastatin calcium tablets 10 mg/20 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘415’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-318-30 Bottles of 60 NDC 43598-318-60 Bottles of 90 NDC 43598-318-90 Bottles of 500 NDC 43598-318-05 Amlodipine besylate and atorvastatin calcium tablets 10 mg/40 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘416’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-315-30 Bottles of 60 NDC 43598-315-60 Bottles of 90 NDC 43598-315-90 Bottles of 500 NDC 43598-315-05 Amlodipine besylate and atorvastatin calcium tablets 10 mg/80 mg are blue, oval shaped, film coated tablets debossed ‘R’ on one side and ‘417’ on other side and are supplied in bottles of 30’s, 60’s, 90’s and 500’s. Bottles of 30 NDC 43598-313-30 Bottles of 60 NDC 43598-313-60 Bottl …