Caduet

In January 2004, the Food and Drug Administration (FDA) approved the new combination drug, Caduet for the treatment of high blood pressure and high cholesterol. Caduet contains the long-acting calcium channel blocker, amlodipine besylate (Norvasc) with the lipid-lowering statin, atorvastatin calcium (Lipitor). Caduet (Pfizer) is the first medication to treat two different cardiovascular conditions with one pill.

Heart disease, the leading cause of death worldwide, has many risk factors, but high blood pressure and high cholesterol are the two primary factors. Treatment guidelines issued by the National Cholesterol Education Program (NCEP) recommend practitioners more aggressively treat patients with both high blood pres- · sure and high cholesterol, especially in the presence of known coronary heart disease (see Table: "NCEP Treatment Guidelines"). Patients with both conditions experience an increased risk for heart attack or stroke and account for 60% of all cardiovascular events.1

The new drug offers convenience and savings: Patients only take one pill, which may help them stick to their drug regimen, and they'll only have one copayment.2

* Mechanism of Action

The amlodipine part of Caduet inhibits calcium ion influx across vascular smooth muscle cell membranes. The drug is a peripheral arterial vasodilator, which leads to a reduction in peripheral vascular resistance and blood pressure.

Atorvastatin inhibits the liver's HMG-CoA reductase and cholesterol synthesis. Additionally, atorvastatin reduces low density lipoprotein (LDL) production and enhances LDL hepatic cellular uptake and breakdown. The overall result is lower plasma cholesterol and LDL levels.

* Pharmacokinetics

The absorption of Caduet following oral administration is similar to each individual drug. Amlodipine and atorvastatin produce peak plasma levels in 6 to 12 hours and 1 to 2 hours respectively; bioavailability is 64% to 90% for amlodipine and 14% for atorvastatin.3 Food taken at the same time as Caduet administration does not alter amlodipine absorption, but may decrease the absorption of atorvastatin. However, overall LDL reduction does not appear to be affected if atorvastatin is taken with or without food.3

Both amlodipine and atorvastatin are highly bound to plasma proteins (93% and 98% respectively), and both undergo hepatic metabolism. The cytochrome P-450 3A4 enzymes metabolize atorvastatin and blood levels may be affected by coadministration of other drugs metabolized by these same isoenzymes.

Excretion is primarily through the kidney for amlodipine. Its halflife is 30 to 50 hours while atorvastatin's half-life is 14 hours (although the LDL-lowering effect lasts 20 to 30 hours) and is eliminated in bile after hepatic metabolism.3 There is no evidence that atorvastatin is involved in enterohepatic recirculation.

* Clinical Studies

Amlodipine and atorvastatin have had numerous clinical studies documenting the efficacy of each drug. Fifteen studies in adult and pediatrie patients addressed the antihypertensive effects of amlodipine. This drug was also evaluated for its effects in chronic stable angina, vasospastic angina, and congestive heart failure. Atorvastatin has been studied in multiple clinical trials addressing adult hypercholesteremia, hypertriglyceridemia, dysbetalipoproteinemia, and pediatric hypercholesterolemia.

To date, one clinical study evaluated the use of combined amlodipine and atorvastatin (Caduet) in patients with hypertension and dyslipidemia. This double-blind, placebo controlled study (N = 1,660) used various combinations of amlodipine and atorvastatin, amlodipine alone, atorvastatin alone, or placebo. All patients had concomitant hypertension and dyslipidemia, and 15% also had diabetes mellitus, 22% were smokers, and 14% had a family history of cardiovascular disease.3 Results after 8 weeks demonstrated statistically significant reductions in systolic blood pressure, diastolic blood pressure, and LDL compared to placebo. These reductions were directly related to the dose of each medication.

* Prescriber's Considerations

Caduet is indicated for the treatment of patients with hyperlipidemia and hypertension or angina. Lifestyle modifications such as diet management, exercise, and smoking cessation are important interventions practitioners should encourage in addition to pharmacologie therapy. Initially, the practitioner should evaluate whether any secondary causes exist for either the hypertension or hypercholesterolemia. Caduet does not have any specific interactions with laboratory tests. Routine liver function tests should be evaluated prior to initiating drug therapy.

Dosing for Caduet may be individualized for each drug component. The manufacturer has produced combinations with amlodipine doses of either 5 mg or 10 mg and atorvastatin of 10-, 20-, 40-, or 80 mg. Most adults are started on the 5 mg daily of amlodipine and 10 to 20 mg of daily atorvastatin. Doses of 40 mg of atorvastatin maybe started in patients requiring a large LDL reduction. Titration of the Caduet dose should follow after 1 to 2 weeks for the amlodipine component and 2 to 4 weeks for atorvastatin after appropriate monitoring of the blood pressure and cholesterol levels. Elderly patients may require a lower dose of Caduet because of decreased clearance of amlodipine and the decreased hepatic metabolism of atorvastatin.

Caduet is contraindicated in patients with active liver disease or with elevated serum transaminases. Because of the atorvastatin component of Caduet, this medication is also contraindicated in pregnant or lactating women (Pregnancy Category X). Women of childbearing age must be warned of the potential hazards of taking this medication and should discontinue it immediately if they become pregnant.

Patients should be warned of the potential for the amlodipine to exacerbate angina and the atorvastatin to lead to liver dysfunction or rhabdomyolysis. Specifically, patients should be warned to report any unexplained muscle pain, tenderness, or weakness that may be indications of atorvastatin-induced myopathy. The most common side effects of the amlodipine component are headache and edema. Atorvastatin's frequent adverse reactions typically include constipation, flatulence, dyspepsia, and abdominal pain. Overdosing of Caduet has not been evaluated; however, the amlodipine component of this drug is likely to produce significant hypotension after excessive doses.

Drug interaction studies have not been conducted with Caduet, but likely problems may be extrapolated from drug interactions known to occur with each individual drug. No specific drug interactions are identified for amlodipine. This medication has been safely administered with thiazide diuretics, beta-blockers, ACE inhibitors, longacting nitrates, sublingual nitroglycerin, digoxin, warfarin, NSAIDs, antibiotics, and oral hypoglycemie drugs.3 The interaction of atorvastatin and other drugs is usually due to the competition for the same metabolic site in the liver. The risk of myopathy is increased with concurrent use of atorvastatin and cyclosporine, fibric acid derivatives, niacin, erythromycin, and azole antifungals.3

In the treatment of hypertension and hyperlipidemia, many pharmacologie regimens may be employed. The calcium channel blockers for high blood pressure and statins for cholesterol lowering have demonstrated efficacy in moderating coronary heart disease that may be exacerbated by these conditions. Caduet offers patients the convenience of treating both of these conditions with a single pill.

REFERENCES

1. Elsevier Inc. Drug updates story: Pfizer drug approved to treat hypertension and high cholesterol. MD Consult Drug Information. Retrieved March 4, 2004, from http://home.mdconsult. com/das/news/body/1/drug/251530362/127323/ 1.html February 3,2004.

2. Reuters Limited. FDA approves Pfizer hypertension, cholesterol drug. In: Elsevier's MD Consult This Week in Medicine. Retrieved March 4,2004, from http://home.mdconsult.com/das/news/body/ 1/mnfp/251530360/127381/1.html. February 4,2004.

3. Pfizer Inc. Caduet (amlodipine besylate/atorvastatin calcium) tablets [Drug Insert] 2004. Retrieved March 4,2004, from http://www. prescribersletter. com/pletters/newdrugs.asp?section=PRL&view-f da&yr-2004#284.

4. NIH Third report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults: Executive Summary (NIH Publication No. 01-3670). National Institute of Health National Heart, Lung, and Blood Institute, May 2001.

Lynn Wimett RN, ANP, EdD

Gary Laustsen RN, PhDc, CFNP

Drug News Co-Editors

Copyright Springhouse Corporation Jun 2004
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