Chlorthalidone

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.

DOSAGE AND ADMINISTRATION Therapy should be initiated with the lowest possible dose. This dose should be titrated according to individual patient response to gain maximal therapeutic benefit while maintaining lowest dosage possible. A single dose given in the morning with food is recommended; divided daily doses are unnecessary. Hypertension Initiation Therapy, in most patients, should be initiated with a single daily dose of 25 mg. If the response is insufficient after a suitable trial, the dosage may be increased to a single daily dose of 50 mg. If additional control is required, the dosage of chlorthalidone tablets may be increased to 100 mg once daily or a second antihypertensive drug (step 2 therapy) may be added. Dosage above 100 mg daily usually does not increase effectiveness. Increases in serum uric acid and decreases in serum potassium are dose-related over the 25 mg/day to 100 mg/day range. Maintenance Maintenance doses may be lower than initial doses and should be adjusted according to individual patient response. Effectiveness is well sustained during continued use. Edema Initiation Adults, initially 50 mg to 100 mg daily, or 100 mg on alternate days. Some patients may require 150 mg to 200 mg at these intervals or up to 200 mg daily. Dosages above this level, however, do not usually produce a greater response. Maintenance Maintenance doses may often be lower than initial doses and should be adjusted according to individual patient response. Effectiveness is well sustained during continued use.

WARNINGS Chlorthalidone should be used with caution in severe renal disease. In patients with renal disease, chlorthalidone or related drugs may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Chlorthalidone should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. 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. PRECAUTIONS General Hypokalemia may develop with chlorthalidone as with any other diuretic, especially with brisk diuresis when severe cirrhosis is present or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity. Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather, appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient. If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen, a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy. Calcium excretion is decreased by thiazide-like drugs. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in few patients on thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen. Information for Patients Patients should inform their physician if they have: (1) had an allergic reaction to chlorthalidone or other diuretics or have asthma, (2) kidney disease, (3) liver disease, (4) gout, (5) systemic lupus erythematosus, or (6) been taking other drugs such as cortisone, digitalis, lithium carbonate, or drugs for diabetes. Patients should be cautioned to contact their physician if they experience any of the following symptoms of potassium loss: excess thirst, tiredness, drowsiness, restlessness, muscle pains or cramps, nausea, vomiting, or increased heart rate or pulse. Patients should also be cautioned that taking alcohol can increase the chance of dizziness occurring. Laboratory Tests Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving chlorthalidone should be observed for clinical signs of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.

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 ).

Drug Interactions Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Higher dosage of oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during chlorthalidone administration. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Chlorthalidone and related drugs may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Drug /Laboratory Test Interactions Chlorthalidone and related drugs may decrease serum PBI levels without signs of thyroid disturbance. Carcinogenesis, Mutagenesis, Impairment of Fertility No information is available. Pregnancy Teratogenic Effects. Pregnancy Category B Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to chlorthalidone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult. Nursing Mothers Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from chlorthalidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established. Geriatric Use Clinical studies of the 15 mg chlorthalidone tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with 15 mg chlorthalidone tablets has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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.

CLINICAL PHARMACOLOGY Chlorthalidone is an oral diuretic with prolonged action (48 hours to 72 hours) and low toxicity. The major portion of the drug is excreted unchanged by the kidneys. The diuretic effect of the drug occurs in approximately 2.6 hours and continues for up to 72 hours. The mean half-life following a 50 mg to 200 mg dose is 40 hours. In the first order of absorption, the elimination half-life is 53 hours following a 50 mg dose, and 60 hours following a 100 mg dose. Approximately 75 percent of the drug is bound to plasma proteins, 58 percent of the drug being bound to albumin. This is caused by an increased affinity of the drug to erythrocyte carbonic anhydrase. Nonrenal routes of elimination have yet to be clarified. Data are not available regarding percentage of dose as unchanged drug and metabolites, concentration of the drug in body fluids, degree of uptake by a particular organ or in the fetus, or passage across the blood-brain barrier. The drug produces copious diuresis with greatly increased excretion of sodium and chloride. At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The site of action appears to be the cortical diluting segment of the ascending limb of Henle’s loop of the nephron.