Pharmacy & Therapeutics - February 2008 - (Page 95)

DRUG FORECAST lowering in both diastolic BP and systolic BP of 4.34 ± 1.23 mm Hg and 8.07 ± 1.90 mm Hg (P < 0.001 for both measures versus placebo), respectively. There was no significant reduction in either diastolic or systolic BP with valsartan 160 mg/ HCTZ 12.5 mg, compared with aliskiren 150 mg/valsartan 160 mg or aliskiren 300 mg/valsartan 320-mg combinations. ketoconazole (Nizoral, PriCara), may increase aliskiren plasma concentrations. Patients should be monitored for an increased incidence of adverse events such as diarrhea, dyspepsia, and hypotension. The concurrent administration of aliskiren and furosemide (Lasix, SanofiAventis) resulted in a substantial decrease in furosemide’s AUC and peak concentrations; therefore, patients taking both agents should be monitored for a decreased effect of furosemide.10 DOSING AND ADMINISTRATION The starting dose of aliskiren is 150 mg by mouth once daily. If desired BP reduction is not attained, the dose may be increased to 300 mg once daily. No additional BP-lowering effects are observed at doses higher than 300 mg daily. The antihypertensive effect of aliskiren is usually evident in two weeks. Aliskiren may be taken without regard to meals, but it is advisable to take it at the same time each day with the same meal. It is best for patients to avoid highfat meals while they are taking aliskiren. In January 2008, the FDA approved aliskeren with HCTZ (Tekturna HCT); it is available in dosage strengths of 150 mg/12.5 mg, 150 mg/25 mg, 300 mg/ 12.5 mg, and 300 mg/25 mg. ADVERSE DRUG EVENTS In clinical trials, 2.2% of patients discontinued therapy because of adverse drug events; this figure was less than the 3.5% of those receiving placebo. Angioedema of the face, extremities, lips, tongue, glottis or larynx has been reported and may occur at any time during treatment. Hypotension was rarely experienced with aliskiren alone (0.1% of patients) or with aliskiren combination therapy (in fewer than 1% of patients). Hyperkalemia, defined by a potassium level above 5.5 mEq/L, was rare with aliskiren monotherapy (0.9% with aliskiren vs. 0.9% with placebo); however, hyperkalemia occurred more frequently when aliskiren was combined with an ACE-inhibitor (5.5%). Dose-related gastrointestinal (GI) side effects were reported during clinical trials. Most of these events were mild and did not result in discontinuation of therapy. The most common GI side effect was diarrhea, in 2.3% of patients. Cough occurred slightly more often in patients receiving aliskiren (1.1%) than placebo (0.6%). In trials comparing aliskiren with an ACE-inhibitor, however, cough occurred one-third to one-half as often in the aliskiren arm. Two patients experienced a single episode of tonic–clonic seizure with a loss of consciousness, although one patient had had a history of seizures. Aliskiren was discontinued and was not re-introduced. Other adverse events occurring at rates higher than 1% included headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, and back pain. These events were experienced at the same rate or at greater rates in the placebo arms. SPECIAL POPULATIONS Aliskiren has not been studied in patients younger than 18 years of age. In patients older than 65 years of age, the AUC concentration is increased, but dose adjustments are not necessary. No dose adjustment is required in patients with mild-to-moderate renal or hepatic impairment. Aliskiren has not been evaluated in patients with more severe renal impairment (a creatinine clearance below 30 mL/minute). COST As of January 2008, the average wholesale price (AWP) for a one-month supply of aliskiren 150 mg was $69.99. The AWP for 300 mg was $87.99.17 PRECAUTIONS AND WARNINGS Aliskiren is classified as a Pregnancy Category C agent for the first trimester and as a Category D drug for the second and third trimesters. It has not been evaluated in pregnant women, but based on evidence from other drugs that influence the RAAS, aliskiren should be discontinued as soon as pregnancy is detected. Dr ugs that act on the RAAS have caused fetal and neonatal mortality and morbidity. Reports of fetal and neonatal morbidity following the use of RAAS agents in the second and third semesters include hypotension, neonatal skull hypoplasia, anuria, reversible or ir reversible renal failure, oligohydramnios, and death. The use of ACE-inhibitors in the first trimester has also been linked to birth defects. Risks and benefits should be carefully weighed for pregnant women; if no alternative treatment is available, the fetus should be closely monitored. Aliskiren is excreted in the breast milk of rats, but it has not been evaluated in humans. Women who plan to nurse should discontinue their use of the drug.10 CONCLUSION Aliskiren is suggested as a new approach to reducing BP via mediation of the RAAS pathway. The direct inhibition of renin eliminates the ACE escape phenomenon, because it inhibits angiotensin I, thereby preventing the need for ACE. Aliskiren offers another option for antihypertensive treatment, and it may be useful in patients who are unable to tolerate ACE-inhibitors. Although no data are available in terms of the drug’s potential cardiac and renal protective effects as a renin inhibitor, on the basis of evidence from other drugs affecting the RAAS, aliskiren offers promise. REFERENCES 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289(19):2560–2572. 2. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: A repor t from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115(5):e69–e171. 3. Vasan RS, Larson MG, Leip EP, et al. Assessment of frequency of progression to hypertension in nonhypertensive participants in the Framingham Heart Study: A cohort study. Lancet 2001;358:1682– 1686. 4. The European Trial on Reduction of Vol. 33 No. 2 • February 2008 • DRUG INTERACTIONS Aliskiren is metabolized by cytochrome P450 (CYP 3A4). Concurrent administration with agents that are CYP 3A4 substrates, such as atorvastatin calcium (Lipitor, Pfizer) and CYP 3A4 inhibitors such as CONTRAINDICATIONS Specific contraindications have not been determined. P&T® 95

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Pharmacy & Therapeutics - February 2008 Contents Editorial Medication Errors Prescription: Washington The Language of (Forgive Us) Change, As P&T Enters the Digital Age New Drugs/Drug News/New Medical Devices Drug Forecast Use and Outcomes of Antifibrinolytic Therapy in Patients Undergoing Cardiothoracic Surgery at 20 Academic Medical Centers in the United States Evaluation of the Management of Acute Venous Thromboembolism and Its Outcomes: One Institution's Experience American Society of Hematology, 49th Annual Meeting Pharmaceutical Approval Update

Pharmacy & Therapeutics - February 2008

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