Label: CHLORTHALIDONE tablet

Chlorthalidone is an oral antihypertensive/diuretic. It is a monosulfamyl diuretic that 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-1- isoindolinyl) benzenesulfonamide with the following structural formula:

Molecular Formula: C14H11ClN2O4S

Molecular weight: 338.76

Chlorthalidone, USP is practically insoluble in water, in ether and in chloroform; soluble in methanol; slightly soluble in ethanol.

Chlorthalidone tablets, USP are available containing either 25 mg or 50 mg of chlorthalidone, USP and the following inactive ingredients: colloidal silicon dioxide, D & C yellow No. 10 aluminum lake, microcrystalline cellulose, pregelatinized starch (Botanical source – maize), sodium starch glycolate Type A and stearic acid. The 50 mg tablet also contains the FD & C Blue No.1 Brilliant Blue FCF Aluminum Lake.

Chlorthalidone is an oral diuretic with prolonged action (48 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.

Diuretics such as chlorthalidone are indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension.

Chlorthalidone tablets are indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy.

Chlorthalidone tablets have also been found useful in edema due to various forms of renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis and chronic renal failure.

Usage in Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Chlorthalidone tablets are indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS, below). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy that is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but that is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and be appropriate.

Anuria

Known hypersensitivity to chlorthalidone tablets or other sulfonamide-derived drugs.

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.

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, vertigo, paresthesias, headache, xanthopsia.

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 Reactions: orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates, or narcotics.

Other Adverse Reactions: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, impotence.

Whenever adverse reactions are moderate or severe, chlorthalidone dosage should be reduced or therapy withdrawn.

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Symptoms of acute overdosage include nausea, weakness, dizziness and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

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.

Chlorthalidone Tablets USP, 25 mg, are supplied as light yellow to yellow colored mosaic appearance, round shaped tablets debossed with “AN” and “247” on one side and plain on the other side.

They are available as follows:

Bottles of 30 : NDC 65162-247-03

Bottles of 90 : NDC 65162-247-09

Chlorthalidone Tablets USP, 50 mg, are supplied as light green to green colored mosaic appearance, round shaped tablets debossed with “AN” and “250” on either side of the score on one side and plain on the other side.

They are available as follows:

Bottles of 30 : NDC 65162-250-03

Bottles of 90 : NDC 65162-250-09

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Biochemical studies in animals have suggested reasons for the prolonged effect of chlorthalidone. Absorption from the gastrointestinal tract is slow due to its low solubility. After passage to the liver, some of the drug enters the general circulation, while some is excreted in the bile, to be reabsorbed later. In the general circulation, it is distributed widely to the tissue, but is taken up in highest concentrations by the kidneys, where amounts have been found 72 hours after ingestion, long after it has disappeared from other tissues. The drug is excreted unchanged in the urine.

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad 382220, INDIA

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 12-2018-00

NDC 65162-247-03

Chlorthalidone Tablets USP, 25 mg

Rx only

30 Tablets

Amneal Pharmaceuticals LLC

NDC 65162-250-03

Chlorthalidone Tablets USP, 50 mg

Rx only

30 Tablets

Amneal Pharmaceuticals LLC