Caduet

Contraindications, Pregnancy and Lactation ( 4 ) Removed 05/2024 Warnings and Precautions, CNS Toxicity ( 5.7 ) Removed 05/2024

1 INDICATIONS AND USAGE CADUET (amlodipine and atorvastatin) is indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. CADUET is a combination of amlodipine besylate, a calcium channel blocker, and atorvastatin calcium, a HMG-CoA-reductase inhibitor (statin), indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate ( 1 ). Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Amlodipine is indicated for the treatment of Coronary Artery Disease ( 1 ). Atorvastatin is indicated ( 1 ): • To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. • As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. • As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia. Amlodipine Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal 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, …

2 DOSAGE AND ADMINISTRATION Usual starting dose (mg daily) Maximum dose (mg daily) Amlodipine 5 Start small adults or children, fragile, or elderly patients, or patients with hepatic insufficiency on 2.5 mg once daily ( 2 ). 10 Atorvastatin 10–20 Start patients requiring large LDL-C reduction (> 45%) at 40 mg once daily ( 2 ). 80 CADUET Dosage of CADUET 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. CADUET may be substituted for its individually titrated components. Patients may be given the equivalent dose of CADUET or a dose of CADUET with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect. CADUET may be used to provide additional therapy for patients already on one of its components. CADUET may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. Important Dosage Information Take CADUET orally once daily at any time of the day, with or without food. Amlodipine The usual initial antihypertensive oral dosage 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 dosage of amlodipine for chronic stable or vasospastic angina is 5–10 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 dosage range of amlodipine for patients with CAD is 5–10 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 6–17 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) and Clinical Studies (14.1) ]. Atorvastatin Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin, and adjust the ‎dosage if ‎‎necessary.‎ ‎ Recommended Dosage in Adult Patients The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. Recommended Dosage in Pediatric Patients 10 Years of Age and Older with H e FH The recommended starting dosage of atorvastatin is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Dosage Modifications Due to Drug Interactions Concomitant use of atorvastatin with the following drugs requires dosage modification of atorvastatin [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]. Anti-Viral Medications • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg once daily. • In patients taking nelfinavir, do not exceed atorvastatin 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics • In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg once daily. For additional recommendations regarding concomitant use …

3 DOSAGE FORMS AND STRENGTHS CADUET tablets are formulated for oral administration in the following strength combinations of amlodipine / atorvastatin: 5 mg/10 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “051”. 5 mg/20 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “052”. 5 mg/40 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “054”. 5 mg/80 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “058”. 10 mg/10 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “101”. 10 mg/20 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “102”. 10 mg/40 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “104”. 10 mg/80 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “108”. Tablets contain amlodipine besylate equivalent to amlodipine 5 or 10 mg and atorvastatin calcium equivalent to atorvastatin 10, 20, 40, or 80 mg ( 3 ).

4 CONTRAINDICATIONS • Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] . • Hypersensitivity to amlodipine, atorvastatin or any excipients in ‎CADUET. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2) ] . • Acute liver failure or decompensated cirrhosis ( 4 ). • Hypersensitivity to amlodipine, atorvastatin or any excipient in CADUET ( 4 ).

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] • Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] • Hepatic Dysfunction [see Warnings and Precautions (5.3) ] • Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.6) ] Most common adverse reaction to amlodipine is edema which occurred in a dose related manner ( 6.1 ). Most common adverse reactions (incidence ≥ 5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection to atorvastatin ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 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, the 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. CADUET CADUET (amlodipine/atorvastatin) has been evaluated for safety in 1092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia. In general, treatment with CADUET was well tolerated. For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with CADUET, 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=1730) at doses up to 10 mg to placebo (N=1250), 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: Amlodipine 2.5 mg 5 mg 10 mg Placebo N=275 N=296 N=268 N=520 Edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 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 1.0% in placebo-controlled clinical trials include the following: Amlodipine (%) Placebo (%) (N=1730) (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, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System: arthralgia, arthrosis, muscle cramps, myalgia. Psychiatric: sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dre …

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 CADUET and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: • See full prescribing information for details regarding concomitant use of CADUET with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2.5 , 7.3 ). • Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin ( 7.4 ). • Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( 7.5 ). • Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.5 ). Amlodipine 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 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 Pharmacology (12.3) ]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3) ]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention: • Conc …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm ( 8.1 ). • Lactation: Breastfeeding not recommended during treatment with CADUET ( 8.2 ). 8.1 Pregnancy Risk Summary Atorvastatin Discontinue atorvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data ). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data ). Amlodipine The limited available data based on postmarketing 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 A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders–including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the grou …

12.1 Mechanism of Action CADUET is a combination of two drugs, a dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of CADUET inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of CADUET 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 CADUET (amlodipine and atorvastatin) tablets combine the calcium channel blocker amlodipine besylate with the HMG-CoA-reductase inhibitor atorvastatin calcium. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S. 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) trihydrate. Its empirical formula is (C 33 H 34 FN 2 O 5 ) 2 Ca•3H 2 O. The structural formulae for amlodipine besylate and atorvastatin calcium are shown below. Amlodipine besylate Atorvastatin calcium CADUET contains amlodipine besylate, a white to off-white crystalline powder, and atorvastatin calcium, also a white to off-white crystalline powder. Amlodipine besylate has a molecular weight of 567.1 and atorvastatin calcium has a molecular weight of 1209.42. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Atorvastatin calcium is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol. CADUET is available as film-coated tablets containing: • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 10 mg atorvastatin equivalent to 10.4 mg atorvastatin calcium. • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 20 mg atorvastatin equivalent to 20.7 mg atorvastatin calcium. • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 40 mg atorvastatin equivalent to 41.4 mg atorvastatin calcium. • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 80 mg atorvastatin equivalent to 82.9 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 10 mg atorvastatin equivalent to 10.4 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 20 mg atorvastatin equivalent to 20.7 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 40 mg atorvastatin equivalent to 41.4 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 80 mg atorvastatin equivalent to 82.9 mg atorvastatin calcium. Each film-coated tablet also contains calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate, Opadry ® II White 85F28751 (polyvinyl alcohol, titanium dioxide, PEG 3000, and talc) or Opadry ® II Blue 85F10919 (polyvinyl alcohol, titanium dioxide, PEG 3000, talc, and FD&C blue #2). Chemical Structure Chemical Structure

10 OVERDOSAGE There is no information on overdosage with CADUET 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 No specific antidotes for atorvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

16 HOW SUPPLIED/STORAGE AND HANDLING CADUET ® tablets contain amlodipine besylate and atorvastatin calcium equivalent to amlodipine and atorvastatin in the dose strengths described below. CADUET tablets are differentiated by tablet color/size and are engraved with a unique number on one side. Combinations of atorvastatin with 5 mg amlodipine are oval and film-coated white tablets and combinations of atorvastatin with 10 mg amlodipine are oval and are film-coated blue tablets. CADUET tablets are supplied for oral administration in the following strengths and package configurations: Table 16. CADUET Packaging Configurations CADUET Package Configuration Tablet Strength mg (amlodipine / atorvastatin) NDC # Engraving Side 1 / Side 2 Tablet Color Tablet Shape Bottle of 30 5/10 0069-2150-30 or 0069-6180-30 CDT 051/Pfizer White Oval Bottle of 30 5/20 0069-2170-30 or 0069-6323-30 CDT 052/Pfizer White Oval Bottle of 30 5/40 0069-2190-30 or 0069-6565-30 CDT 054/Pfizer White Oval Bottle of 30 5/80 0069-2260-30 or 0069-6747-30 CDT 058/Pfizer White Oval Bottle of 30 10/10 0069-2160-30 or 0069-7810-30 CDT 101/Pfizer Blue Oval Bottle of 30 10/20 0069-2180-30 or 0069-7232-30 CDT 102/Pfizer Blue Oval Bottle of 30 10/40 0069-2250-30 or 0069-7654-30 CDT 104/Pfizer Blue Oval Bottle of 30 10/80 0069-2270-30 or 0069-7476-30 CDT 108/Pfizer Blue Oval Store at 25°C (77°F); excursions permitted to 15°C -30°C (59°F -86°F) [see USP Controlled Room Temperature].