Amiloride hydrochloride/Hydrochlorothiazide

Description

Amiloride hydrochloride and hydrochlorothiazide tablets, USP, are formulated to combine the potassium-conserving properties of amiloride hydrochloride with the natriuretic effects of hydrochlorothiazide. Amiloride hydrochloride, USP, is chemically designated as N-amidino-3,5-diamino-6-chloropyrazine-carboxamide monohydrochloride dihydrate, with a structural formula of C₆H₈ClN₇O•HCl•2H₂O and a molecular weight of 302.12. Hydrochlorothiazide, USP, is chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a structural formula of C₇H₈ClN₃O₄S₂ and a molecular weight of 297.74.

The tablets appear as a white or practically white crystalline powder, which is slightly soluble in water and freely soluble in sodium hydroxide solution. Each tablet for oral administration contains 5 mg of amiloride hydrochloride, USP (calculated on an anhydrous basis), and 50 mg of hydrochlorothiazide, USP. Inactive ingredients include croscarmellose sodium, D&C yellow no. 10 (aluminum lake), lactose monohydrate, magnesium oxide, magnesium stearate, and microcrystalline cellulose.

Uses and Indications

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

The use of potassium-conserving agents, such as amiloride hydrochloride, is generally unnecessary in patients with uncomplicated essential hypertension who maintain a normal diet while receiving diuretics. Amiloride hydrochloride and hydrochlorothiazide tablets may be administered as monotherapy or in conjunction with other antihypertensive agents, including methyldopa or beta blockers.

It is important to note that this fixed combination is not recommended for initial therapy of edema or hypertension, except in patients for whom the risk of developing hypokalemia is unacceptable.

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 clinically indicated, 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 supporting such higher doses.

When hydrochlorothiazide is used as a monotherapy, 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 hydrochlorothiazide doses greater than 50 mg daily.

The daily dose is usually administered as a single dose, although it may be divided into multiple doses if necessary. Following the achievement of initial diuresis, dosage adjustments may be warranted based on the patient's response. Maintenance therapy can be conducted on an intermittent basis, as clinically appropriate.

Contraindications

Amiloride hydrochloride and hydrochlorothiazide tablets are contraindicated in the following conditions:

• Patients with elevated serum potassium levels (greater than 5.5 mEq per liter) due to the risk of hyperkalemia.

• Individuals receiving other potassium-conserving agents, such as spironolactone or triamterene, as this may lead to increased potassium retention.

• Patients with anuria, acute or chronic renal insufficiency, or evidence of diabetic nephropathy, as these conditions may exacerbate renal function impairment.

• Individuals 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, or those with diabetes mellitus, should not receive this medication without careful monitoring of serum electrolytes, creatinine, and BUN levels.

• Patients with hypersensitivity to amiloride hydrochloride, hydrochlorothiazide, or other sulfonamide-derived drugs, due to the risk of allergic reactions.

Potassium supplementation, including medications, potassium-containing salt substitutes, or a potassium-rich diet, is contraindicated with this product except in severe and/or refractory cases of hypokalemia.

Warnings and Precautions

Amiloride and hydrochlorothiazide are associated with the risk of hyperkalemia, defined as serum potassium levels exceeding 5.5 mEq per liter. The incidence of hyperkalemia is approximately 1 to 2 percent in patients without renal impairment or diabetes mellitus; however, this risk is significantly elevated in individuals with renal impairment or diabetes mellitus. Hyperkalemia can be life-threatening if left uncorrected. Therefore, it is imperative that serum potassium levels are monitored closely, particularly during the initial administration of the medication, during dosage adjustments, and in the presence of any illness that may impact renal function.

The risk of hyperkalemia may be further exacerbated when potassium-sparing agents are used concurrently with angiotensin-converting enzyme inhibitors, cyclosporine, or tacrolimus. Clinicians should be vigilant for warning signs and symptoms of hyperkalemia, which may include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and electrocardiogram (ECG) abnormalities. It is essential to monitor serum potassium levels, as mild hyperkalemia may not present with ECG changes.

In diabetic patients, the use of potassium-conserving diuretics, including amiloride hydrochloride, has been linked to hyperkalemia, even in the absence of diabetic nephropathy. Consequently, the use of amiloride and hydrochlorothiazide should be approached with caution in this population. If these medications are deemed necessary, frequent monitoring of serum electrolytes and renal function is required. Additionally, it is recommended that amiloride and hydrochlorothiazide be discontinued at least three days prior to glucose tolerance testing.

Caution is advised when administering antikaliuretic therapy to 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, close monitoring of acid-base balance is essential.

For patients receiving amiloride and hydrochlorothiazide, serum potassium levels must be monitored diligently, especially during the initiation of therapy, at the time of dosage adjustments, and during any illness that could affect renal function. In diabetic patients, regular monitoring of serum electrolytes and renal function is also critical.

In the event of hyperkalemia, the administration of amiloride and hydrochlorothiazide should be discontinued immediately. If serum potassium levels exceed 6.5 mEq per liter, prompt intervention is necessary to reduce potassium levels.

Healthcare professionals should be alert to the warning signs and symptoms of hyperkalemia, which include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. Immediate medical attention should be sought if these symptoms arise.

Side Effects

Patients receiving amiloride hydrochloride and hydrochlorothiazide may experience a range of adverse reactions. The following sections outline these reactions based on their incidence and seriousness.

Common adverse reactions, occurring in more than 1% of patients, include:

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

• Cardiovascular: Arrhythmia.

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

• Metabolic: Elevated serum potassium levels (greater than 5.5 mEq per liter).

• Musculoskeletal: Leg ache.

• Nervous: Dizziness.

• Respiratory: Dyspnea.

• Skin: Rash and pruritus.

Less common adverse reactions, occurring in 1% or fewer patients, include:

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

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

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

• Metabolic: Gout, dehydration, and symptomatic hyponatremia.

• Musculoskeletal: Muscle cramps/spasm and joint pain.

• Nervous: Paresthesia/numbness, stupor, and vertigo.

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

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

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

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

A significant warning associated with this medication is the risk of hyperkalemia, particularly in patients with renal impairment or diabetes mellitus. The incidence of hyperkalemia in patients without these conditions is approximately 1 to 2 percent. It is crucial to monitor serum potassium levels closely, especially when initiating treatment, adjusting dosages, or during any illness that may affect renal function, as uncorrected hyperkalemia can be potentially fatal.

Postmarketing experience has indicated an increased risk of non-melanoma skin cancer associated with hydrochlorothiazide. A study conducted in the Sentinel System revealed that the increased risk was predominantly for squamous cell carcinoma (SCC), particularly in white patients receiving large cumulative doses. The overall risk for SCC was approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of 50,000 mg or more, the risk increased to approximately 1 additional case for every 6,700 patients per year.

Drug Interactions

The concomitant use of certain medications with amiloride and hydrochlorothiazide may lead to significant drug interactions that require careful monitoring and potential dosage adjustments.

Pharmacodynamic Interactions

• Non-Steroidal Anti-Inflammatory Agents (NSAIDs): The administration of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Patients receiving amiloride and hydrochlorothiazide alongside NSAIDs should be closely monitored to ensure the desired diuretic effect is achieved. Additionally, both indomethacin and potassium-sparing diuretics can elevate serum potassium levels, necessitating consideration of their combined effects on potassium kinetics and renal function.

• Angiotensin-Converting Enzyme Inhibitors, Cyclosporine, and Tacrolimus: The concurrent use of amiloride HCl with these agents may increase the risk of hyperkalemia. If these medications are indicated due to hypokalemia, they should be administered with caution and serum potassium levels should be frequently monitored.

• Corticosteroids and ACTH: The use of corticosteroids and ACTH may lead to intensified electrolyte depletion, particularly hypokalemia, when used with diuretics.

• Alcohol, Barbiturates, and Narcotics: These substances may potentiate orthostatic hypotension when used in conjunction with thiazide diuretics.

• Antihypertensive Agents: There may be an additive effect or potentiation of antihypertensive effects when thiazide diuretics are used with other antihypertensive drugs.

• Skeletal Muscle Relaxants: There is a potential for increased responsiveness to nondepolarizing skeletal muscle relaxants, such as tubocurarine.

Pharmacokinetic Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications, including oral agents and insulin, may be necessary when used concurrently with thiazide diuretics.

• Anionic Exchange Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of anionic exchange resins. Single doses of cholestyramine and colestipol can reduce hydrochlorothiazide absorption by up to 85% and 43%, respectively.

• Lithium: Diuretics can reduce the renal clearance of lithium, increasing the risk of lithium toxicity. Caution is advised, and the package insert for lithium preparations should be consulted prior to co-administration with diuretics.

Monitoring Recommendations

Patients receiving amiloride and hydrochlorothiazide in combination with the aforementioned agents should undergo regular monitoring of serum potassium levels and blood pressure to mitigate the risk of adverse effects and ensure therapeutic efficacy.

Packaging & NDC

The table below lists all NDC Code configurations of Amiloride Hydrochloride and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider the potential risks and benefits before prescribing this medication to pediatric patients.

Geriatric Use

Clinical studies of amiloride hydrochloride and hydrochlorothiazide tablets did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experiences have not identified significant differences in responses between elderly patients and their younger counterparts.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

This medication is substantially excreted by the kidneys, which raises the risk of toxic reactions, particularly in patients with impaired renal function. Given that elderly patients are more prone to renal impairment, careful consideration should be given to dose selection. Monitoring of renal function may be beneficial in this population (refer to CONTRAINDICATIONS, Impaired Renal Function).

Pregnancy

There is no specific information available regarding the use of this medication during pregnancy. Currently, there are no identified safety concerns, dosage modifications, or special precautions related to the use of this medication in pregnant patients. Healthcare professionals should consider the lack of data when prescribing this medication to women of childbearing potential and weigh the potential benefits against any unknown risks to fetal outcomes.

Lactation

Studies in rats have demonstrated that amiloride is excreted in milk at concentrations higher than those found in blood; however, it is not known whether amiloride HCl is excreted in human milk. Thiazides have been shown to appear in breast milk.

Due to the potential for serious adverse reactions in breastfed infants, healthcare professionals should consider the importance of the drug to the lactating mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment or diabetes mellitus are at an increased risk of hyperkalemia when receiving amiloride hydrochloride and hydrochlorothiazide. In individuals without renal impairment or diabetes, the risk of hyperkalemia is approximately 1 to 2 percent; however, this risk escalates in those with reduced kidney function or diabetes, even in the absence of recognized diabetic nephropathy.

It is crucial to monitor serum potassium levels closely in all patients taking amiloride hydrochloride and hydrochlorothiazide, particularly during the initial treatment phase, at the time of dosage adjustments, and during any illness that may impact renal function. The risk of hyperkalemia may further increase when these potassium-conserving agents are used concurrently with angiotensin-converting enzyme inhibitors, cyclosporine, or tacrolimus.

Monitoring serum potassium levels is essential, as mild hyperkalemia typically does not present with abnormal electrocardiogram (ECG) findings. In diabetic patients, hyperkalemia has been observed with all potassium-conserving diuretics, including amiloride hydrochloride, even in those without evidence of diabetic nephropathy. Therefore, the use of amiloride and hydrochlorothiazide in diabetic patients should be approached with caution, and if prescribed, frequent monitoring of serum electrolytes and renal function is warranted.

Antikaliuretic therapy should be initiated with caution in severely ill patients, particularly those at risk for respiratory or metabolic acidosis, such as individuals with cardiopulmonary disease or poorly controlled diabetes. In these cases, if amiloride and hydrochlorothiazide are administered, frequent monitoring of acid-base balance is necessary.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this drug. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the prescribing information.

Overdosage

In cases of overdosage, there is currently no available data regarding the effects in humans. The oral LD50 values for the combination drug have been established at 189 mg/kg for female mice and 422 mg/kg for female rats, indicating potential toxicity levels in these animal models.

The dialyzability of the drug remains undetermined, which may complicate management strategies in the event of an overdose. There is no specific information or established treatment protocols for overdosage involving amiloride and hydrochlorothiazide, nor is there a specific antidote available for this combination.

Management of overdosage should be primarily symptomatic and supportive. It is recommended that therapy with amiloride and hydrochlorothiazide be discontinued immediately. Patients should be monitored closely for any adverse effects. Suggested interventions may include the induction of emesis and/or gastric lavage to mitigate the effects of the overdose. Healthcare professionals should remain vigilant and provide appropriate supportive care as needed.

Nonclinical Toxicology

Teratogenicity studies involving 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, reproduction studies in rats at similar dosage levels indicated no evidence of impaired fertility. However, a perinatal and postnatal study in rats demonstrated a reduction in maternal body weight gain during and after gestation at this dose, along with decreased body weights of live pups at birth and weaning. It is important to note that there are no adequate and well-controlled studies in pregnant women, and due to the limitations of animal reproduction studies in predicting human responses, this drug should be used during pregnancy only if clearly needed.

Teratogenicity studies with amiloride hydrochloride in rabbits and mice, administered at 20 and 25 times the maximum human dose respectively, also showed no evidence of fetal harm, although the drug was found to cross the placenta in modest amounts. Studies involving 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. It is noted that thiazides can cross the placental barrier and appear in cord blood, which may pose a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions observed in adults.

Long-term studies in animals have not been conducted to evaluate the effects of amiloride hydrochloride and hydrochlorothiazide on fertility, mutagenicity, or carcinogenic potential. However, there was no evidence of tumorigenic effects when amiloride hydrochloride was administered to mice for 92 weeks at doses up to 10 mg/kg/day, which is 25 times the maximum daily human dose. Similarly, amiloride hydrochloride was administered to male and female rats for 104 weeks at doses up to 6 and 8 mg/kg/day, respectively, with no evidence of carcinogenicity observed.

Amiloride hydrochloride was also found to be devoid of mutagenic activity in various strains of Salmonella typhimurium, both with and without a mammalian liver microsomal activation system (Ames test). Two-year feeding studies conducted under 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 the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in vivo in assays using mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. Furthermore, hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

Postmarketing experience with hydrochlorothiazide indicates an association with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted within the Sentinel System suggest that this increased risk is more pronounced in white patients who are administered large cumulative doses of the medication.

The overall population exhibits an approximate risk increase of 1 additional case of SCC per 16,000 patients per year. In contrast, white patients receiving a cumulative dose of 50,000 mg or more demonstrate a significantly higher risk, estimated at 1 additional case of SCC for every 6,700 patients per year.

Healthcare professionals and patients are encouraged to report any suspected adverse reactions to Teva at 1-888-838-2872, or to the FDA at 1-800-FDA-1088 or through the website http://www.fda.gov/medwatch.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to protect their skin from sun exposure and to undergo regular skin cancer screenings. It is important for patients to be monitored for clinical signs of fluid or electrolyte imbalance, including conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia.

Patients should be made aware of warning signs or symptoms indicative of fluid and electrolyte imbalance, regardless of the underlying cause. These symptoms include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

In the event that hyperkalemia occurs in patients taking amiloride and hydrochlorothiazide, the healthcare provider should advise immediate discontinuation of the medication. If potassium supplementation is necessary, careful monitoring of serum potassium levels is essential. It should be noted that hyperkalemia has been reported in diabetic patients using all potassium-conserving diuretics, including amiloride HCl, even in those without evidence of diabetic nephropathy.

Healthcare providers should recommend that amiloride and hydrochlorothiazide be discontinued at least three days prior to glucose tolerance testing. Caution should be exercised when instituting antikaliuretic therapy in severely ill patients who may be at risk for respiratory or metabolic acidosis.

Patients should be advised to report any signs of hyperkalemia, which may include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. It is also important to inform patients that thiazides can cross the placental barrier and may appear in cord blood, posing risks such as fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions.

A decision regarding whether to discontinue nursing or the medication should be made based on the importance of the drug to the mother. Safety and effectiveness in pediatric patients have not been established, and therefore, healthcare providers should exercise caution when prescribing to this population.

In general, dose selection for elderly patients should be approached with caution, typically starting at the lower end of the dosing range to account for the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of comorbid conditions or other drug therapies. Finally, patients should be advised to keep this and all medications out of the reach of children.

Storage and Handling

This product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP), equipped with a child-resistant closure as required. It is essential to store the product at a temperature range of 20º to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is crucial to keep this medication, along with all other medications, out of the reach of children to ensure safety.

Additional Clinical Information

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study within the Sentinel System indicate that this risk is notably higher in white patients who have received large cumulative doses of the medication. Specifically, the overall population shows an increased risk of approximately one additional case of SCC per 16,000 patients per year, while white patients with a cumulative dose of 50,000 mg or more face an increased risk of about one additional case per 6,700 patients per year.

Clinicians and patients are encouraged to report any suspected adverse reactions to Teva at 1-888-838-2872 or to the FDA at 1-800-FDA-1088 or via the FDA's MedWatch website at http://www.fda.gov/medwatch.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amiloride Hydrochloride and Hydrochlorothiazide as submitted by Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)