HEMICLOR

1 INDICATIONS AND USAGE HEMICLOR is a thiazide-like diuretic indicated for the treatment of hypertension in adults, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.1 ). 1.1 Hypertension HEMICLOR is indicated for the treatment of hypertension in adults, 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. 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 blood 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. HEMICLOR may be used alone or in combination with other antihypertensives.

2 DOSAGE AND ADMINISTRATION The recommended starting dose is 12.5 mg or 25 mg orally once daily ( 2.1 ). Dose may be doubled after 2 to 4 weeks as needed based on individual response, up to a maximal dose of 100 mg once daily ( 2.1 ) 2.1 Recommended Dosage Therapy should be initiated with the lowest possible dose. The recommended adult initial dose of HEMICLOR is 12.5 mg or 25 mg given orally with food once daily. Double the dosage every 2 to 4 weeks as needed based on individual patient response, up to a maximum of 100 mg once daily. Dosage above 100 mg daily usually does not increase effectiveness.

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

5 WARNINGS AND PRECAUTIONS Acute Kidney Injury: Patients with pre-existing kidney disease may be at higher risk. ( 5.1 ). Electrolyte Abnormalities: Monitor serum electrolytes periodically ( 5.2 ). Metabolic Disturbances ( 5.3 ). Systemic Lupus Erythematosus ( 5.4 ). 5.1 Acute Kidney Injury Monitor kidney function periodically. Diuretics can cause hypovolemia which may precipitate acute kidney injury. Patients with chronic kidney disease, heart failure, or volume depletion may be at particular risk of developing acute renal failure on Chlorthalidone. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on chlorthalidone. 5.2 Electrolyte Abnormalities Chlorthalidone can cause hypokalemia, hyponatremia, hypochloremic alkalosis, and hypomagnesemia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Hypokalemia is dose dependent. Monitor and correct serum electrolytes prior to use and monitor periodically. 5.3 Metabolic Disturbances Chlorthalidone may increase blood sugar levels, affect diabetes control, and cause changes in the need for diabetes medication. Chlorthalidone may raise serum levels of cholesterol and triglycerides. Monitor blood sugar and lipid levels. 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. Increases in serum uric acid are dose related. Chlorthalidone decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Chlorthalidone. 5.4 Systemic Lupus Erythematosus The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics, which are structurally related to chlorthalidone. However, systemic lupus erythematosus has not been reported following chlorthalidone administration.

7 DRUG INTERACTIONS Effect of chlorthalidone on other drugs Insulin requirements in diabetic patients may be increased, decreased or unchanged. Higher dosage of oral hypoglycemic agents may be required. Chlorthalidone may increase the responsiveness to tubocurarine. Chlorthalidone may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity. Monitor serum lithium levels during concomitant use. Insulin requirements and oral hypoglycemic agent dosages may require adjustments ( 7 ). Possible increased responsiveness to tubocurarine ( 7 ). Possible decreased arterial responsiveness to norepinephrine ( 7 ). 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; Acute Kidney Injury [see Warnings and Precautions (5.1) ] Electrolyte Abnormalities [see Warnings and Precautions (5.2) ] Metabolic Disturbances [see Warnings and Precautions (5.3) ] The following adverse reactions have been observed with chlorthalidone, 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 thiazide-like diuretics are electrolyte abnormalities and metabolic disturbances ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 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 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 12.5 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. 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.