Like other potassium-conserving diuretic combinations, amiloride 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%. 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 amiloride hydrochloride and hydrochlorothiazide, particularly when it is first introduced, at the time of dosage adjustments, and during any illness that could affect renal function.
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WARNINGS Hyperkalemia Like other potassium-conserving diuretic combinations, amiloride 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%. 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 amiloride 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 amiloride hydrochloride and hydrochlorothiazide, are administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine or tacrolimus (see PRECAUTIONS: Drug Interactions ). 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 amiloride 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 amiloride hydrochloride, even in patients without evidence of diabetic nephropathy. Therefore, amiloride and hydrochlorothiazide should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently. Amiloride and hydrochlorothiazide should be discontinued at least 3 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 amiloride 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.
ADVERSE REACTIONS Amiloride 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 amiloride hydrochloride and hydrochlorothiazide is about 1% to 2% in patients without renal impairment or diabetes mellitus (see WARNINGS). Minor adverse reactions to amiloride hydrochloride have been reported relatively frequently (about 20%) but the relationship of many of the reports to amiloride hydrochloride is uncertain and the overall frequency was similar in hydrochlorothiazide treated groups. Nausea/anorexia, abdominal pain, flatulence, and mild skin rash have been reported and probably are related to amiloride. Other adverse experiences that have been reported with amiloride 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 amiloride and hydrochlorothiazide increases the risk of adverse reactions over those seen with the individual components. The adverse reactions for amiloride and hydrochlorothiazide listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence 1% or less. The incidence for group (1) was determined from clinical studies conducted in the United States (607 patients treated with amiloride 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 amiloride and hydrochlorothiazide and these adverse reactions, some of which have been reported only rarely. Incidence >1% Incidence ≤ 1% Body as a Whole Headache Reactions occurring in 3% to 8% of patients treated with amiloride hydrochloride and hydrochlorothiazide. (Those reactions occurring in less than 3% of the patients are unmarked.) Malaise Weakness Chest pain Fatigue/tiredness Back pain Syncope Cardiovascular Arrhythmia Tachycardia Digitalis toxicity Orthostatic hypotension Angina pectoris Digestive Nausea/anorexia Constipation Diarrhea GI bleeding Gastrointestinal pain GI disturbance Abdominal pain Appetite changes Abdominal fullness Hiccups Thirst Vomiting Anorexia Flatulence Metabolic Elevated serum Gout potassium levels Dehydration (> 5.5 mEq per liter) See WARNINGS. Symptomatic hyponatremia See PRECAUTIONS. Musculoskeletal Leg ache Muscle cramps/spasm Joint Pain Nervous Dizziness Paresthesia/numbness Stupor Vertigo Psychiatric None Insomnia Nervousness Depression Sleepiness Mental confusion Respiratory Dyspnea None Skin Rash Flushing Pruritus Diaphoresis Erythema multiforme including Stevens-Johnson Syndrome Exfoliative dermatitis including toxic epidermal necrolysis Alopecia Special Senses None Bad taste Visual disturbance Nasal congestion Urogenital None Impotence Nocturia Dysuria Incontinence Renal dysfunction including renal failure Gynecomastia Other adverse reactions that have been reported with the individual components and within each category are listed in order of decreasing severity: Amiloride Body as a Whole: Painful extremities, neck/shoulder ache, fatigability; Cardiovascular: Palpitation; Digestive: Activation of probable preexisting 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 (see PRECAUTIONS ), hyperglycemia, glycosuria, hyperuricemia; Nervous System/Psychiatric: Restlessness; Special Senses: Transient blurred vision, xanthopsia; Urogenital: Interstitial nephritis (see WARNINGS ).