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 percent 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 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 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 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 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 1 Weakness 1 Fatigue/tiredness Malaise Chest pain Back pain Syncope Cardiovascular Arrhythmia Tachycardia Digitalis toxicity Orthostatic hypotension Angina pectoris Digestive Nausea/anorexia 1 Diarrhea Gastrointestinal pain Abdominal pain Constipation GI bleeding GI disturbance Appetite changes Abdominal fullness Hiccups Thirst Vomiting Anorexia Flatulence Metabolic Elevated serum potassium levels (> 5.5 mEq per liter) 2 Gout Dehydration Symptomatic hyponatremia 3 Musculoskeletal Leg ache Muscle cramps/spasm Joint pain Nervous Dizziness 1 Paresthesia/numbness Stupor Vertigo Psychiatric None Insomnia Nervousness Depression Sleepiness Mental confusion Respiratory Dyspnea None Skin Rash 1 Pruritus Flushing 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 1.
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.) 2. See WARNINGS 3. See PRECAUTIONS 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 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 (see PRECAUTIONS ), hyperglycemia, glycosuria, hyperuricemia. Nervous System/Psychiatric: Restlessness. Special Senses : Transient blurred vision, xanthopsia. Urogenital: Interstitial nephritis (see WARNINGS ). Postmarketing Experience Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses.
The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
