THALITONE

THALITONE (chlorthalidone USP) is an antihypertensive/diuretic supplied as 15 mg and 25 mg tablets for oral use. It is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is a racemic mixture of 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide, with the following structural formula: Chlorthalidone is practically insoluble in water, in ether and in chloroform; soluble in methanol; slightly soluble in alcohol. The inactive ingredients are colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. chlorthalidone-struc-1.jpg

THALITONE is a thiazide-like diuretic indicated: • For the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1). • as adjunctive therapy in edema associated with heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome (1.2). 1.1 Hypertension THALITONE ® is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal 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 the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with THALITONE. 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. THALITONE can be used alone or in combination with other antihypertensive agents. 1.2 Edema Chlorthalidone is indicated in adults as adjunctive therapy in edema associated with heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome.

• Initiate therapy with the lowest possible dose, then titrate according to individual patient response (2.1). • Hypertension: Recommended initial dose is 15 mg daily with food. If additional blood pressure reduction is needed, increase the dose to 25 mg (2.2). • Edema: Recommended initial dose is 50 mg to 100 mg daily or 100 mg on alternate days. Depending on response, dosage can be decreased or increased up to a maximum of 200 mg daily (2.3). 2.1 General Considerations THALITONE cannot be substituted with other formulations of chlorthalidone. Initiate therapy with the lowest possible dose, then titrate according to individual patient response. 2.2 Hypertension The initial recommended dose is 15 mg once daily with food. After 2 weeks, the dosage may be increased to a single daily dose of 25 mg if additional blood pressure reduction is needed. Doses above 25 mg are not expected to result in increased blood pressure reduction. 2.3 Edema The recommended initial dosage is 50 to 100 mg daily or 100 mg on alternate days. Depending on response, dosage can be decreased or increased up to a maximum of 200 mg daily.

THALITONE is contraindicated in patients with anuria or hypersensitivity to chlorthalidone or other sulfonamide-derived drugs. • Anuria (4). • Hypersensitivity (4).

The following adverse reactions are described in more detail elsewhere in the label; • Hypotension [see Warnings and Precautions (5.1)] • Impaired Renal Function [see Warnings and Precautions (5.2)] • Electrolyte Abnormalities [see Warnings and Precautions (5.3)] • Metabolic Disturbances [see Warnings and Precautions (5.4)] The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency. Gastrointestinal System Reactions: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis. Central Nervous System Reactions : dizziness, paresthesias, headache. Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia. Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis). Cardiovascular Reaction: Orthostatic hypotension. Other Adverse Reactions: muscle spasm, weakness, restlessness, impotence, xanthopsia. The most frequently expected adverse drug reactions among patients receiving THALITONE are hypotension, dizziness, renal dysfunction, and electrolyte abnormalities (6). To report SUSPECTED ADVERSE REACTIONS, contact Casper Pharma LLC at 1-844-5-CASPER (1-844-522-7737) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Effect of chlorthalidone on other drugs Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity. Monitor serum lithium levels during concomitant use. • Antihypertensive drugs: Chlorthalidone may add to or potentiate the action of other antihypertensive drugs (7). • Lithium: Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity (7).