Amicloton

Amiloride Hydrochloride:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Amicloton (Amiloride Hydrochloride) reviews

INDICATIONS AND USAGE

Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets are indicated in those patients with hypertension or with congestive heart failure who develop hypokalemia when thiazides or other kaliuretic diuretics are used alone, or in whom maintenance of normal serum potassium levels is considered to be clinically important, e.g., digitalized patients, or patients with significant cardiac arrhythmias.

The use of potassium-conserving agents is often unnecessary in patients receiving diuretics for uncomplicated essential hypertension when such patients have a normal diet.

Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets may be used alone or as an adjunct to other antihypertensive drugs, such as methyldopa or beta blockers. Since Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide enhances the action of these agents, dosage adjustments may be necessary to avoid an excessive fall in blood pressure and other unwanted side effects.

The fixed combination drug is not indicated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked.

CONTRAINDICATIONS

Hyperkalemia

Amicloton hydrochloride and hydrochlorothiazide tablets should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter).

Antikaliuretic Therapy or Potassium Supplementation

Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide should not be given to patients receiving other potassium-conserving agents, such as spironolactone or triamterene. Potassium supplementation in the form of medication, potassium-containing salt substitutes or a potassium-rich diet should not be used with this product except in severe and/or refractory cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary.

Impaired Renal Function

Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are contraindications to the use of Amicloton hydrochloride and hydrochlorothiazide. Patients with evidence of renal function impairment (blood urea nitrogen [BUN] levels over 30 mg per 100 mL or serum creatinine levels over 1.5 mg per 100 mL) or diabetes mellitus should not receive the drug without careful, frequent and continuing monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal impairment and may result in the rapid development of hyperkalemia.

Hypersensitivity

Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets is contraindicated in patients who are hypersensitive to this product, or to other sulfonamide-derived drugs.

WARNINGS

Hyperkalemia

Like other potassium-conserving diuretic combinations, Amicloton and hydrochlorothiazide may cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter). In patients without renal impairment or diabetes mellitus, the risk of hyperkalemia with this combination product is about 1 to 2 percent. This risk is higher in patients with renal impairment or diabetes mellitus (even without recognized diabetic nephropathy). Since hyperkalemia, if uncorrected, is potentially fatal, it is essential to monitor serum potassium levels carefully in any patient receiving Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide, particularly when it is first introduced, at the time of dosage adjustments, and during any illness that could affect renal function.

The risk of hyperkalemia may be increased when potassium-conserving agents, including Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide, are administered concomitantly with an angiotensin-converting enzyme inhibitor, cylosporine or tacrolimus. Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. Monitoring of the serum potassium level is essential because mild hyperkalemia is not usually associated with an abnormal ECG.

When abnormal, the ECG in hyperkalemia is characterized primarily by tall, peaked T waves or elevations from previous tracings. There may also be lowering of the R wave and increased depth of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression.

Treatment of Hyperkalemia

If hyperkalemia occurs in patients taking Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide, the drug should be discontinued immediately. If the serum potassium level exceeds 6.5 mEq per liter, active measures should be taken to reduce it. Such measures include the intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation. If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. Patients with persistent hyperkalemia may require dialysis.

Diabetes Mellitus

In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including Amicloton HCl, even in patients without evidence of diabetic nephropathy. Therefore, Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently.

Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide should be discontinued at least three days before glucose tolerance testing.

Metabolic or Respiratory Acidosis

Antikaliuretic therapy should be instituted only with caution in severely ill patients in whom respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or poorly controlled diabetes. If Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide is given to these patients, frequent monitoring of acid-base balance is necessary. Shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels.

PRECAUTIONS

General

Electrolyte Imbalance and BUN Increases

Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Patients should be observed for clinical signs of fluid or electrolytes imbalance: i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hyponatremia and hypochloremia may occur during the use of thiazides and other diuretics. Any chloride deficit during thiazide therapy is generally mild and may be lessened by the Amicloton HCl component of this product. Hypochloremia 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.

Hypokalemia may develop during thiazide therapy, especially with brisk diuresis, when severe cirrhosis is present, during concomitant use of corticosteroids or ACTH, or after prolonged therapy. However, this usually is prevented by the Amicloton (Amiloride Hydrochloride) hydrochloride component of this combination drug product.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Amicloton (Amiloride Hydrochloride) hydrochloride, a component of this combination product, has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone.

Increases in BUN levels have been reported with Amicloton (Amiloride Hydrochloride) hydrochloride and with hydrochlorothiazide. These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, when Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide is given to such patients, careful monitoring of serum electrolyte and BUN levels is important. In patients with pre-existing severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretic therapy including Amicloton (Amiloride Hydrochloride) HCl and hydrochlorothiazide.

In patients with renal disease, diuretics may precipitate azotemia. Cumulative effects of the components of Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide may develop in patients with impaired renal function. If renal impairment becomes evident, Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide should be discontinued.

Drug Interactions

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide plus non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Since indomethacin and potassium-sparing diuretics, including this product, may each be associated with increased serum potassium levels, the potential effects on potassium kinetics and renal function should be considered when these agents are administered concurrently.

Amicloton HCl

When Amicloton (Amiloride Hydrochloride) HCl is administered concomitantly with an angiotensin-converting enzyme inhibitor, cyclosporine or tacrolimus, the risk of hyperkalemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.

Hydrochlorothiazide

When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, Barbiturates, or Narcotics

Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs

Dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive Drugs

Additive effect or potentiation.

Cholestyramine and Colestipol Resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalemia.

Pressor Amines

Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing

Possible increased responsiveness to the muscle relaxant.

Lithium

Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with this combination product.

Metabolic and Endocrine Effects

In diabetic patients, insulin requirements may be increased, decreased, or unchanged due to the hydrochlorothiazide component. Diabetes mellitus that has been latent may become manifest during administration of thiazide diuretics.

Because calcium excretion is decreased by thiazides, Amicloton and hydrochlorothiazide should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.

Other Precautions

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Carcinogenesis, Mutagenicity, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenicity or carcinogenic potential of Amicloton hydrochloride and hydrochlorothiazide.

Amicloton (Amiloride Hydrochloride) HCl

There was no evidence of a tumorigenic effect when Amicloton (Amiloride Hydrochloride) hydrochloride was administered for 92 weeks to mice at doses up to 10 mg/kg/day (25 times the maximum daily human dose). Amicloton (Amiloride Hydrochloride) hydrochloride has also been administered for 104 weeks to male and female rats at doses up to 6 and 8 mg/kg/day (15 and 20 times the maximum daily dose for humans, respectively) and showed no evidence of carcinogenicity.

Amicloton (Amiloride Hydrochloride) hydrochloride was devoid of mutagenic activity in various strains of Salmonella typhimurium with or without a mammalian liver microsomal activation system (Ames test).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Teratogenicity studies have been performed with combinations of Amicloton hydrochloride and hydrochlorothiazide in rabbits and mice at doses up to 25 times the expected maximum daily dose for humans and have revealed no evidence of harm to the fetus. No evidence of impaired fertility in rats was apparent at dosage levels up to 25 times the expected maximum human daily dose. A perinatal and postnatal study in rats showed a reduction in maternal body weight gain during and after gestation at a daily dose of 25 times the expected maximum daily dose for humans. The body weights of alive pups at birth and at weaning were also reduced at this dose level. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, and because of the data listed below with the individual components, this drug should be used during pregnancy only if clearly needed.

Amicloton (Amiloride Hydrochloride) Hydrochloride

Teratogenicity studies with Amicloton (Amiloride Hydrochloride) hydrochloride in rabbits and mice given 20 and 25 times the maximum human dose, respectively, revealed no evidence of harm to the fetus, although studies showed that the drug crossed the placenta in modest amounts. Reproduction studies in rats at 20 times the expected maximum daily dose for humans showed no evidence of impaired fertility. At approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred.

Hydrochlorothiazide

Teratogenic Effects

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women.

Nonteratogenic Effects

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing Mothers

Studies in rats have shown that Amicloton is excreted in milk in concentrations higher than those found in blood, but it is not known whether Amicloton (Amiloride Hydrochloride) HCl is excreted in human milk. However, thiazides appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, 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 pediatric patients have not been established.

Geriatric Use

Clinical studies of Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience 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 the comitant 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

Amicloton hydrochloride and hydrochlorothiazide is usually well tolerated and significant clinical adverse effects have been reported infrequently. The risk of hyperkalemia (serum potassium levels greater than 5.5 mEq per liter) with Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide is about 1 to 2 percent in patients without renal impairment or diabetes mellitus. Minor adverse reactions to Amicloton (Amiloride Hydrochloride) hydrochloride have been reported relatively frequently (about 20%) but the relationship of many of the reports to Amicloton (Amiloride Hydrochloride) HCl is uncertain and the overall frequency was similar to hydrochlorothiazide treated groups. Nausea/anorexia, abdominal pain, flatulence, and mild skin rash have been reported and probably are related to Amicloton (Amiloride Hydrochloride). Other adverse experiences that have been reported with Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide are generally those known to be associated with diuresis, thiazide therapy, or with the underlying disease being treated. Clinical trials have not demonstrated that combining Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide increases the risk of adverse reactions over those seen with the individual components.

The adverse reactions for Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide listed in the following table have been arranged into two groups: (1) incidence greater than one percent; and (2) incidence one percent or less. The incidence for group (1) was determined from clinical studies conducted in the United States (607 patients treated with Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide). The adverse effects listed in group (2) include reports from the same clinical studies and voluntary reports since marketing. The probability of a causal relationship exists between Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide and these adverse reactions, some of which have been reported only rarely.

Other adverse reactions that have been reported with the individual components and within each category are listed in order of decreasing severity:

Amicloton (Amiloride Hydrochloride)

Body as a Whole: Painful extremities, neck/shoulder ache, fatigability.

Cardiovascular: Palpitation.

Digestive: Activation of probable pre-existing peptic ulcer, abnormal liver function, jaundice, dyspepsia, heartburn.

Hematologic: Aplastic anemia, neutropenia.

Integumentary: Alopecia, itching, dry mouth.

Nervous System/Psychiatric: Encephalopathy, tremors, decreased libido.

Respiratory: Shortness of breath, cough.

Special Senses: Increased intraocular pressure, tinnitus.

Urogenital: Bladder spasms, polyuria, urinary frequency.

Hydrochlorothiazide

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, purpura.

Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, hyperuricemia.

Nervous System/Psychiatric: Restlessness.

Special Senses: Transient blurred vision, xanthopsia.

Urogenital: Interstitial nephritis.

OVERDOSAGE

No data are available in regard to overdosage in humans. The oral LD₅₀ of the combination drug is 189 and 422 mg/kg for female mice and female rats, respectively.

It is not known whether the drug is dialyzable.

No specific information is available on the treatment of overdosage with Amicloton and hydrochlorothiazide and no specific antidote is available. Treatment is symptomatic and supportive. Therapy with Amicloton (Amiloride Hydrochloride) and hydrochlorothiazide should be discontinued and the patient observed closely. Suggested measures include the induction of emesis and/or gastric lavage.

Amicloton (Amiloride Hydrochloride) Hydrochloride

No data are available in regard to overdosage in humans.

The oral LD₅₀ of Amicloton (Amiloride Hydrochloride) hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain.

The most common signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. If hyperkalemia occurs, active measures should be taken to reduce the serum potassium levels.

Hydrochlorothiazide

The oral LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

DOSAGE AND ADMINISTRATION

Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets should be administered with food.

The usual starting dosage is 1 tablet a day. The dosage may be increased to 2 tablets a day, if necessary. More than 2 tablets of Amicloton (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide daily usually are not needed and there is no controlled experience with such doses.

Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. Patients usually do not require doses of hydrochlorothiazide in excess of 50 mg daily when combined with other antihypertensive agents. The daily dose is usually given as a single dose but may be given in divided doses. Once an initial diuresis has been achieved, dosage adjustment may be necessary. Maintenance therapy may be on an intermittent basis.

HOW SUPPLIED

Amicloton (Amiloride Hydrochloride) Hydrochloride and Hydrochlorothiazide Tablets USP are available as:

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. A 3/2016

NDC 0555-0483-02

Amicloton (Amiloride Hydrochloride)

Hydrochloride and

Hydrochlorothiazide

Tablets USP

5 mg/50 mg

Rx only

100 TABLETS

TEVA

Chlorthalidone:

• Indications and usage:
• Contraindications:
• Warnings:
• Precautions:
• Information for patients
• Laboratory tests
• Drug interactions
• Drug/laboratory test interactions
• Carcinogenesis, mutagenesis, impairment of fertility
• Pregnancy
• Nursing mothers
• Pediatric use
• Adverse reactions:
• Overdosage
• Dosage and administration:
• How supplied:
• Animal pharmacology:
• Amicloton (Chlorthalidone) reviews

INDICATIONS AND USAGE:

Diuretics such as Amicloton 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.

Amicloton (Chlorthalidone) is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Amicloton (Chlorthalidone) has 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. Amicloton (Chlorthalidone) is 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.

CONTRAINDICATIONS:

Anuria.

Known hypersensitivity to Amicloton (Chlorthalidone) or other sulfonamide-derived drugs.

WARNINGS:

Amicloton (Chlorthalidone) should be used with caution in severe renal disease. In patients with renal disease, Amicloton (Chlorthalidone) or related drugs may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Amicloton (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 Amicloton (Chlorthalidone). However, systemic lupus erythematosus has not been reported following Amicloton (Chlorthalidone) administration.

PRECAUTIONS:

General

Hypokalemia may develop with Amicloton (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 Amicloton (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 Amicloton (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 Amicloton (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.

Drug Interactions

Amicloton (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 Amicloton (Chlorthalidone) administration.

Amicloton (Chlorthalidone) and related drugs may increase the responsiveness to tubocurarine.

Amicloton (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

Amicloton (Chlorthalidone) and related drugs may decrease serum PBI levels without signs of thyroid disturbance.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No information available.

Pregnancy

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 Amicloton. 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 Amicloton (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 Amicloton (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 has not been established.

ADVERSE REACTIONS:

To report SUSPECTED ADVERSE REACTIONS, please call RiconPharma LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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, Amicloton (Chlorthalidone) dosage should be reduced or therapy withdrawn.

OVERDOSAGE

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.

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 Amicloton (Chlorthalidone) 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 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 to 100 mg daily, or 100 mg on alternate days. Some patients may require 150 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.

HOW SUPPLIED:

Amicloton (Chlorthalidone) Tablets, USP are available containing 25 mg or 50 mg of Amicloton (Chlorthalidone), USP.

The 25 mg tablets are green colored, biconvex, round shaped tablets debossed with ‘010’ on one side, and plain on the other side. They are available as follows:

NDC 51125-010-06

Bottles of 100 tablets

NDC 51125-010-09

Bottles of 1000 tablets

The 50 mg tablets are green colored, capsule shaped tablets debossed with ‘011’ on one side, and a break-line on the other side. They are available as follows:

NDC 51125-011-06

Bottles of 100 tablets

NDC 51125-011-09

Bottles of 1000 tablets

Store at 20ºC to 25º C (68º to 77º F).

Protect from light.

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

ANIMAL

Pharmacology:

Biochemical studies in animals have suggested reasons for the prolonged effect of Amicloton (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 for:

RiconPharma LLC.

Denville, NJ, 07834

Made in U.S.A

PC143 Revised: 03/17