Amiloride hydrochloride/Hydrochlorothiazide

Uses and Indications

Amiloride hydrochloride and hydrochlorothiazide tablets are indicated for the treatment of hypertension or congestive heart failure in patients who develop hypokalemia when thiazides or other kaliuretic diuretics are used alone. This combination is particularly suitable for patients in whom the maintenance of normal serum potassium levels is clinically important, such as those who are digitalized or have significant cardiac arrhythmias.

The use of potassium-conserving agents is generally unnecessary in patients receiving diuretics for uncomplicated essential hypertension, provided these patients maintain a normal diet. Amiloride hydrochloride and hydrochlorothiazide tablets may be administered alone or as an adjunct to other antihypertensive medications, including methyldopa or beta blockers.

Limitations of use include that this fixed combination drug is not indicated for the initial therapy of edema or hypertension, except in individuals for whom the risk of developing hypokalemia cannot be tolerated.

Dosage and Administration

Amiloride hydrochloride and hydrochlorothiazide tablets should be administered with food to enhance absorption and minimize gastrointestinal discomfort. The usual starting dosage is 1 tablet per day. If necessary, the dosage may be increased to a maximum of 2 tablets per day; however, doses exceeding 2 tablets daily are generally not required, and there is no controlled experience with such higher doses.

When hydrochlorothiazide is used alone, it can be administered at doses ranging from 12.5 mg to 50 mg per day. In combination with other antihypertensive agents, patients typically do not require doses of hydrochlorothiazide exceeding 50 mg daily.

The daily dose is usually given as a single administration but may also be divided into multiple doses if clinically indicated. Following the achievement of initial diuresis, dosage adjustments may be necessary to optimize therapeutic outcomes. Maintenance therapy may be conducted on an intermittent basis, depending on the patient's response and clinical judgment.

Contraindications

Amiloride hydrochloride and hydrochlorothiazide tablets are contraindicated in patients with elevated serum potassium levels (greater than 5.5 mEq per liter) due to the risk of hyperkalemia. The use of this medication is also contraindicated in individuals receiving other potassium-conserving agents, such as spironolactone or triamterene.

Potassium supplementation, including medications, potassium-containing salt substitutes, or a potassium-rich diet, is contraindicated except in cases of severe and/or refractory hypokalemia. Additionally, the presence of anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy contraindicates the use of this product.

Patients with renal function impairment, indicated by blood urea nitrogen (BUN) levels over 30 mg per 100 mL or serum creatinine levels over 1.5 mg per 100 mL, as well as those with diabetes mellitus, should not receive this medication without careful, frequent, and ongoing monitoring of serum electrolytes, creatinine, and BUN levels.

Lastly, amiloride hydrochloride and hydrochlorothiazide tablets are contraindicated in individuals who are hypersensitive to this product or to other sulfonamide-derived drugs.

Warnings and Precautions

Amiloride and hydrochlorothiazide may cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter). The risk of hyperkalemia is approximately 1 to 2 percent in patients without renal impairment or diabetes mellitus, and is significantly higher in those with renal impairment or diabetes mellitus. If uncorrected, hyperkalemia can be potentially fatal; therefore, serum potassium levels must be monitored carefully, particularly when the medication is first introduced, during dosage adjustments, and during any illness that could affect renal function.

Serious Warnings

The risk of hyperkalemia may be increased when potassium-conserving agents are administered alongside an angiotensin-converting enzyme inhibitor, cyclosporine, 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 serum potassium levels is essential, as mild hyperkalemia is not typically associated with abnormal ECG findings.

General Precautions

In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including amiloride hydrochloride, even in those without evidence of diabetic nephropathy. Therefore, the use of amiloride and hydrochlorothiazide should be avoided if possible in diabetic patients. If these medications are used, frequent monitoring of serum electrolytes and renal function is necessary.

Amiloride and hydrochlorothiazide should be discontinued at least three days prior to glucose tolerance testing. Caution is advised when instituting antikaliuretic therapy in severely ill patients who may experience respiratory or metabolic acidosis, such as those with cardiopulmonary disease or poorly controlled diabetes. If administered to these patients, frequent monitoring of acid-base balance is required.

Laboratory Tests

Serum potassium levels must be monitored closely in any patient receiving amiloride hydrochloride and hydrochlorothiazide, especially when the drug is first introduced, during dosage adjustments, and during any illness that could affect renal function. In diabetic patients, serum electrolytes and renal function should be monitored frequently.

Emergency Instructions

If hyperkalemia occurs in patients taking amiloride and hydrochlorothiazide, the medication should be discontinued immediately. If the serum potassium level exceeds 6.5 mEq per liter, active measures must be taken to reduce it.

Symptoms to Report

Patients should be advised to stop taking the medication and contact their doctor if they experience warning signs or symptoms of hyperkalemia, which include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities.

Side Effects

Patients receiving amiloride hydrochloride and hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by incidence and seriousness.

Common Adverse Reactions (Incidence > 1%)

• Body as a Whole: Headache, weakness, fatigue/tiredness

• Cardiovascular: Arrhythmia

• Digestive: Nausea/anorexia, diarrhea, gastrointestinal pain, abdominal pain

• Metabolic: Elevated serum potassium levels (> 5.5 mEq per liter)

• Musculoskeletal: Leg ache

• Nervous: Dizziness

• Respiratory: Dyspnea

• Skin: Rash, pruritus

Less Common Adverse Reactions (Incidence ≤ 1%)

• Body as a Whole: Malaise, chest pain, back pain, syncope

• Cardiovascular: Tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris

• Digestive: Constipation, gastrointestinal bleeding, gastrointestinal disturbance, appetite changes, abdominal fullness, hiccups, thirst, vomiting, anorexia, flatulence

• Metabolic: Gout, dehydration, symptomatic hyponatremia

• Musculoskeletal: Muscle cramps/spasm, joint pain

• Nervous: Paresthesia/numbness, stupor, vertigo

• Psychiatric: Insomnia, nervousness, depression, sleepiness, mental confusion

• Skin: Flushing, diaphoresis, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), alopecia

• Special Senses: Bad taste, visual disturbance, nasal congestion

• Urogenital: Impotence, nocturia, dysuria, incontinence, renal dysfunction (including renal failure), gynecomastia

Serious Warnings

• Hyperkalemia: Amiloride and hydrochlorothiazide may cause hyperkalemia, with serum potassium levels exceeding 5.5 mEq per liter. The risk of hyperkalemia is approximately 1 to 2 percent in patients without renal impairment or diabetes mellitus, but this risk increases in those with renal impairment or diabetes. Hyperkalemia can be potentially fatal if uncorrected, necessitating careful monitoring of serum potassium levels, especially during initial treatment, dosage adjustments, and any illness affecting renal function.

Postmarketing Experience

• Non-melanoma Skin Cancer: Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). In a study from the Sentinel System, the overall risk for SCC was approximately 1 additional case per 16,000 patients per year. For white patients receiving cumulative doses of ≥ 50,000 mg, the risk increased to approximately 1 additional SCC case for every 6,700 patients per year.

Drug Interactions

The concomitant use of amiloride hydrochloride and hydrochlorothiazide with non-steroidal anti-inflammatory agents (NSAIDs) may diminish the diuretic, natriuretic, and antihypertensive effects of these diuretics. Patients receiving this combination should be closely monitored to ensure the desired diuretic effect is achieved. Additionally, both indomethacin and potassium-sparing diuretics, including this combination, can lead to increased serum potassium levels; thus, the potential impact on potassium kinetics and renal function must be considered.

When amiloride hydrochloride is used alongside angiotensin-converting enzyme (ACE) inhibitors, cyclosporine, or tacrolimus, there is an increased risk of hyperkalemia. Caution is advised, and frequent monitoring of serum potassium levels is recommended if these agents are used together due to the potential for hypokalemia.

The following interactions are noted with thiazide diuretics, including hydrochlorothiazide:

• Pharmacodynamic Interactions: The risk of orthostatic hypotension may be potentiated by alcohol, barbiturates, or narcotics. There may also be an additive effect with other antihypertensive medications. Corticosteroids and adrenocorticotropic hormone (ACTH) can lead to intensified electrolyte depletion, particularly hypokalemia. Furthermore, there may be a decreased response to pressor amines, such as norepinephrine, although this does not preclude their use. Conversely, there may be an increased responsiveness to nondepolarizing skeletal muscle relaxants, such as tubocurarine.

• Pharmacokinetic Interactions: The absorption of hydrochlorothiazide can be significantly impaired by anionic exchange resins, with cholestyramine and colestipol reducing its gastrointestinal absorption by up to 85% and 43%, respectively. Additionally, diuretics can reduce the renal clearance of lithium, increasing the risk of lithium toxicity; therefore, caution is warranted when considering the use of lithium preparations in conjunction with this combination product.

• Antidiabetic Medications: Dosage adjustments may be necessary for antidiabetic drugs, including both oral agents and insulin, when used concurrently with this combination.

Overall, careful monitoring and consideration of these interactions are essential when prescribing amiloride hydrochloride and hydrochlorothiazide with other medications.

Pediatric Use

Safety and effectiveness of Amiloride Hydrochloride and Hydrochlorothiazide in pediatric patients have not been established.

Geriatric Use

Clinical studies of amiloride hydrochloride and hydrochlorothiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger individuals.

In general, dose selection for geriatric patients should be approached with caution, typically starting at the lower end of the dosing range. This consideration reflects the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of comorbidities or concurrent drug therapies in this population.

Given that this medication is substantially excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function. Therefore, it is advisable to monitor renal function closely in elderly patients, as they are more prone to renal impairment.

Pregnancy

There is no specific information available regarding the use of Amiloride Hydrochloride and Hydrochlorothiazide during pregnancy. The provided data does not indicate any safety concerns, dosage modifications, or special precautions for pregnant patients. As such, healthcare professionals should exercise clinical judgment when considering the use of this medication in pregnant patients, taking into account the absence of documented risks or fetal impacts.

Lactation

Studies in animal models indicate that amiloride is excreted in milk at concentrations higher than those found in blood; however, it is not established whether amiloride hydrochloride is excreted in human milk. Thiazides, on the other hand, are known to appear in breast milk. Due to the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the lactating mother against the risks to the nursing infant.

Renal Impairment

In patients with renal impairment, the use of amiloride hydrochloride and hydrochlorothiazide requires careful consideration and monitoring due to an increased risk of hyperkalemia. The risk of hyperkalemia is notably higher in this population, particularly in those with diabetes mellitus, even in the absence of recognized diabetic nephropathy.

It is essential to monitor serum potassium levels closely when initiating treatment with amiloride hydrochloride and hydrochlorothiazide, during dosage adjustments, and throughout any illness that may impact renal function. This monitoring is critical as mild hyperkalemia may not present with abnormal electrocardiogram (ECG) findings.

In diabetic patients, the potential for hyperkalemia is significant with all potassium-conserving diuretics, including amiloride hydrochloride. Therefore, the use of this combination should be approached with caution, and if prescribed, frequent monitoring of serum electrolytes and renal function is imperative.

Additionally, antikaliuretic therapy should be administered cautiously in severely ill patients, particularly those at risk for respiratory or metabolic acidosis, such as individuals with cardiopulmonary disease or poorly controlled diabetes. In such cases, regular monitoring of acid-base balance is necessary to ensure patient safety.

Hepatic Impairment

Patients with hepatic impairment have no specific dosage adjustments, special monitoring requirements, or precautions outlined in the drug insert for Amiloride Hydrochloride and Hydrochlorothiazide. Therefore, the prescribing physician should exercise clinical judgment when considering the use of this medication in such patients.

Overdosage

In cases of overdosage with Amiloride Hydrochloride and Hydrochlorothiazide, no specific data are available regarding human overdose incidents. The oral LD50 for the combination drug has been established at 189 mg/kg for female mice and 422 mg/kg for female rats, indicating potential toxicity levels in these animal models.

Management of an overdose should be symptomatic and supportive, as there is no specific antidote available. It is recommended that therapy with Amiloride and Hydrochlorothiazide be discontinued immediately. Patients should be closely monitored for any adverse effects. Suggested interventions may include the induction of emesis and/or gastric lavage to mitigate absorption of the drug.

Additionally, it remains uncertain whether the drug is dialyzable, which may influence the management approach in severe cases. Continuous observation and supportive care are essential in the event of an overdose.

Nonclinical Toxicology

Teratogenic Effects

Teratogenicity studies conducted with combinations of amiloride hydrochloride and hydrochlorothiazide in rabbits and mice at doses up to 25 times the expected maximum daily dose for humans revealed no evidence of harm to the fetus. Additionally, studies involving amiloride hydrochloride in rabbits and mice at doses of 20 and 25 times the maximum human dose, respectively, also indicated no teratogenic effects, although the drug was shown to cross the placenta in modest amounts. Hydrochlorothiazide administered orally to pregnant mice and rats during major organogenesis at doses up to 3000 and 1000 mg/kg, respectively, provided no evidence of fetal harm. However, there is a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions in adults.

Impairment of Fertility

Reproduction studies in rats at doses up to 25 times the expected maximum daily dose for humans showed no evidence of impaired fertility. Similarly, studies involving hydrochlorothiazide indicated no adverse effects on the fertility of mice and rats of either sex when exposed to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation. A perinatal and postnatal study in rats indicated 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, with a corresponding reduction in the body weights of live pups at birth and weaning.

Carcinogenesis and Mutagenesis

Long-term studies in animals have not been performed to evaluate the effects of amiloride hydrochloride and hydrochlorothiazide on fertility, mutagenicity, or carcinogenic potential. However, no evidence of tumorigenic effects was observed when amiloride hydrochloride was administered to mice for 92 weeks at doses up to 10 mg/kg/day (25 times the maximum daily human dose). In a separate study, amiloride hydrochloride was administered to male and female rats for 104 weeks at doses up to 6 and 8 mg/kg/day (15 and 20 times the maximum daily dose for humans, respectively), with no evidence of carcinogenicity noted.

Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in various chromosomal aberration tests. Positive results were only obtained in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Storage and Handling

Dispensed in a tight, light-resistant container as defined in the USP, the product features a child-resistant closure as required. It should be stored at a temperature range of 20º to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines. It is essential to keep this medication, along with all other medications, out of the reach of children.