Pronunciation (am LOW di peen & a TORE va sta tin)

Special Alerts
Caduet(amlodipine and atorvastatin combination) was approved by the Food and Drug Administration (FDA) in February, 2004. It is expected to be available at the end of the second quarter, 2004.

U.S. Brand Names Caduet

Synonyms Atorvastatin Calcium and Amlodipine Besylate

Therapeutic Category

Antilipemic Agent, HMG-CoA Reductase Inhibitor
Calcium Channel Blocker
Use For use when treatment with both agents is appropriate:
Amlodipine is used for the treatment of hypertension and angina.

Atorvastatin is used with dietary therapy for the following:Hyperlipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with primary hypercholesterolemia (elevations of 1 or more components are present in Fredrickson type IIa, IIb, III, and IV hyperlipidemias); treatment of homozygous familial hypercholesterolemia?
?Heterozygous familial hypercholesterolemia (HeFH): In adolescent patients (10-17 years of age, females >1 year postmenarche) with HeFH having LDL-C 190 mg/dL or LDL 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or with 2 or more CVD risk factors in the adolescent patient

Pregnancy Risk Factor X

Pregnancy Implications See individual agents.

Contraindications Hypersensitivity to amlodipine, atorvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding

Warnings/Precautions Amlodipine: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Use caution in severe aortic stenosis. Dosage titration should occur after 7-14 days on a given dose.

Atorvastatin: Secondary causes of hyperlipidemia should be ruled out prior to therapy. Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk is dose-related and is increased with concurrent use of lipid-lowering agents which may cause rhabdomyolysis (gemfibrozil, fibric acid derivatives, or niacin at doses 1 g/day) or during concurrent use with potent CYP3A4 inhibitors (including amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, nefazodone, grapefruit juice in large quantities, verapamil, or protease inhibitors such as indinavir, nelfinavir, or ritonavir). Assess the risk versus benefit when combining any of these drugs with atorvastatin. Discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Safety and efficacy have not been established in patients <10 years or in premenarcheal girls.

Adverse Reactions See individual agents.

Special Cardiovascular Considerations Based on the atorvastatin component:

HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors (2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (ie, the percent probability of having a CHD event in next 10 years. LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.

Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (ASCOT-LLA), patients with HTN and at least 3 other risk factors defined by the authors benefited in reducing nonfatal CV events with the use of statins; however, no significant difference in CV mortality or overall mortality was observed. These patients had a total cholesterol below 250 mg/dL before treatment.

Secondary prevention trials indicate that statin therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations.

HMG-CoA reductase inhibitors decrease levels of high-sensitivity C-reactive protein (hs-CRP). They also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus S, Spinler SA, 2002).

Myopathy: Currently marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery), drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.

Overdose/Toxicology See individual agents.

Drug Interactions

Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8/9 (weak), 2D6 (weak), 3A4 (weak)

Atorvastatin: Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)

See individual agents.

Food Interactions See individual agents.

Mechanism of Action

Amlodipine: Inhibits calcium ion from entering the slow channels or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina

Atorvastatin: Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism

Pharmacodynamics/Kinetics See individual agents.

Usual Dosage Oral: Children 10-17 years (females >1 year postmenarche) and Adults: Treatment of hypertension/angina and hyperlipidemias: Dose is individualized, given once daily and substituted for each individual component. See individual agents. Maximum dose: Amlodipine 10 mg/day, atorvastatin 80 mg/day.

Dosage adjustment in renal impairment: See individual agents.

Dosage adjustment in hepatic impairment: Use of atorvastatin is contraindicated.

Dietary Considerations May take with food if desired; may take without regard to time of day. Before initiation of therapy with atorvastatin, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy.

Administration May be administered without regard to meals.

Monitoring Parameters Blood pressure; lipid levels after 2-4 weeks, CPK, liver function tests (LFTs); It is recommended that LFTs be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose of atorvastatin, and periodically (eg, semiannually) thereafter.

Dosage Forms

Tablet: 5/10: Amlodipine 5 mg and atorvastatin 10 mg
  5/20: Amlodipine 5 mg and atorvastatin 20 mg
  5/40: Amlodipine 5 mg and atorvastatin 40 mg
  5/80: Amlodipine 5 mg and atorvastatin 80 mg
  10/10: Amlodipine 10 mg and atorvastatin 10 mg
  10/20: Amlodipine 10 mg and atorvastatin 20 mg
  10/40: Amlodipine 10 mg and atorvastatin 40 mg
  10/80: Amlodipine 10 mg and atorvastatin 80 mg