Thalitone

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION • 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.

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

5 WARNINGS AND PRECAUTIONS • Hypotension: Higher risk for patients with impaired sympathetic response, volume-depletion or salt restriction (5.1). • Renal Impairment: Patients with pre-existing kidney disease may be at higher risk. (5.2). • Monitor serum electrolytes periodically (5.3). 5.1 Hypotension THALITONE may cause symptomatic hypotension. Patients with impaired sympathetic response, volume-depletion or who are salt restricted may be at increased risk for developing hypotension. If hypotension occurs, place the patient in the supine position and, if necessary, give intravenous normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.2 Impaired Renal Function Changes in renal function including acute renal failure can be caused by diuretics. Patients with chronic kidney disease, heart failure, or volume depletion may be at particular risk of developing acute renal failure on THALITONE. Monitor renal function periodically. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on THALITONE [see Drug Interactions (7)]. 5.3 Electrolyte Abnormalities THALITONE can cause hypokalemia, hyponatremia, hypochloremic alkalosis, and hypomagnesemia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), THALITONE should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. 5.4 Metabolic Disturbances Chlorthalidone may alter glucose tolerance. Chlorthalidone may raise serum levels of cholesterol and triglycerides. Chlorthalidone may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Chlorthalidone decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving THALITONE.

7 DRUG INTERACTIONS 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).

6 ADVERSE REACTIONS 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 .

8.1 Pregnancy Risk Summary Available data over decades from observational studies and reports with chlorthalidone use in pregnant women have not identified a drug-associated risk of major birth defects or miscarriage. However, adverse fetal outcomes, including fetal or neonatal jaundice, thrombocytopenia, hypoglycemia, and electrolyte abnormalities have been reported following maternal use of thiazide diuretics ( see Clinical Considerations ). Chlorthalidone should not be used as first-line therapy to treat hypertension in pregnancy. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and stillbirth. Fetal/Neonatal Adverse Reactions Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Thiazides, like other diuretics, can cause placental hypoperfusion. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, hypoglycemia, and electrolyte abnormalities. Thiazides do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia) and should not be used as first-line therapy to treat hypertension in pregnant women. Data Animal Data Reproduction studies have been performed in the rat and the rabbit and have revealed no evidence of harm to the fetus due to chlorthalidone.The available data do not allow the calculation of comparisons between the exposure of chlorthalidone observed in animal studies to the systemic exposure that would be expected in humans.