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Kerledex™
(betaxolol hydrochloride and chlorthalidone) Tablets

DESCRIPTION

Kerledex (betaxolol hydrochloride and chlorthalidone) is a combination product indicated for the treatment of hypertension. It combines the activities of betaxolol hydrochloride, a β1-selective (cardioselective) adrenergic receptor blocking agent, with chlorthalidone, a monosulfamyl diuretic.

Betaxolol hydrochloride is chemically described as 2-propanol, 1-[4-[2-(cyclopropylmethoxy) ethyl] phenoxy]-3-[(1-methylethyl)amino]-,hydrochloride,(±). It has the following chemical structure:

Betaxolol hydrochloride is a water-soluble white crystalline powder with a molecular formula of C18H29NO3 • HCl and a molecular weight of 343.9. It is freely soluble in water, ethanol, chloroform, and methanol, and has a pKa of 9.4.

Chlorthalidone, a monosulfamyl diuretic, differs chemically from thiazide diuretics in that a double-ring system is incorporated in its structure. It is 2-chloro-5-(1-hydroxy-3-oxo-1isoindolinyl)benzenesulfonamide with a molecular formula of C14H11ClN2O4S and a molecular weight of 338.76. It is practically insoluble in water, ether and chloroform; soluble in methanol; and slightly soluble in alcohol.

Kerledex is available as orally administered tablets containing 5 or 10 mg of betaxolol HCl and 12.5 mg of chlorthalidone (5/12.5; 10/12.5). Inactive ingredients include corn starch, hydroxypropyl methylcellulose, iron oxide colorant, lactose, magnesium stearate, polyethylene glycol 400, povidone, and titanium dioxide.

INDICATIONS

Kerledex is indicated in the management of hypertension.

DOSAGE AND ADMINISTRATION

Betaxolol is effective in the treatment of hypertension in once-daily doses of 5-20 mg, while chlorthalidone is effective in doses of 12.5-50 mg. In clinical trials of betaxolol/chlorthalidone combination therapy using betaxolol doses of 5-20 mg and chlorthalidone doses of 12.5-25 mg, the antihypertensive effects increased with increasing doses of either component.

The adverse effects of betaxolol are a mixture of dose-dependent phenomena (principally bradycardia) and dose-independent phenomena (eg, probably skin rash); those of chlorthalidone are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy with a combination of betaxolol and chlorthalidone will be associated with both sets of dose-independent adverse effects and to minimize these, it may be appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. On the other hand, regimens that combine low doses of betaxolol and chlorthalidone should produce minimal dose-dependent adverse effects, ie, bradycardia and decreases in serum potassium (see CLINICAL PHARMACOLOGY).

Therapy guided by clinical effect: A patient whose blood pressure is not adequately controlled with monotherapy using either betaxolol (usually 10-20 mg) or chlorthalidone may be switched to Kerledex 5/12.5 mg. Subsequent titration (14-day intervals) could add additional betaxolol, chlorthalidone, or both, using single entity products, Kerledex 5/12.5, or Kerledex 10/12.5 as appropriate.

Initial therapy: Antihypertensive therapy should be initiated with the lowest dose of Kerledex, one 5/12.5 mg tablet once daily. Subsequent titration (14-day intervals) may be carried out with Kerledex tablets up to the maximum recommended dose of 20/25 mg (two 10/12.5 mg tablets) once daily, as appropriate. Alternatively, the single entity products could be used for dose titration.

Replacement therapy: The combination may be substituted for the titrated individual components.

Cessation of therapy: If withdrawal of Kerledex therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed.

HOW SUPPLIED

Kerledex 5/12.5 (betaxolol HCl 5 mg and chlorthalidone 12.5 mg) tablets are oval, yellow, film coated, with KERLEDEX debossed on one side and 5221 on the other, supplied as:

Kerledex 10/12.5 (betaxolol HCl 10 mg and chlorthalidone 12.5 mg) tablets are capsule-shaped, yellow, film coated, with KERLEDEX debossed on one side and 5231 on the other, supplied as:

Store below 86°F (30°C) and protect from moisture. Dispense in a tight container.

Caution: Federal law prohibits dispensing without prescription.

Revised: July 2011. Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807

SIDE EFFECTS

Kerledex is usually well tolerated in properly selected patients. Discontinuation of therapy due to adverse events in U.S. controlled clinical trials was necessary in about 4% of patients receiving betaxolol in combination with chlorthalidone. The most frequent reasons for discontinuation were fatigue (1.1%) and bradycardia (0.9%). The following reasons for discontinuation of therapy were reported in 0.4% (2 patients each) of the 465 patients receiving the combination in U.S. controlled studies: myalgia, depression, insomnia, lethargy, palpitation, and elevated serum transaminase levels.

In controlled clinical trials, Kerledex has been evaluated versus placebo and/or its component monotherapies in doses of 5/12.5 mg, 5/25 mg, 10/12.5 mg, 10/25 mg, and 20/25 mg for treatment periods lasting 3 to 24 weeks. In these controlled studies, the most common adverse reactions to Kerledex were bradycardia, headache, dizziness, arthralgia, dyspepsia, and fatigue.

Kerledex adverse events with a 2% or greater frequency, and selected events with lower frequency, in these controlled studies are: