Aldazide

Aldazide

Manufacturer:

Pfizer

Distributor:

Zuellig
Full Prescribing Info
Contents
Spironolactone, hydroflumethiazide.
Description
Each tablet contains 25 mg spironolactone and 25 mg hydroflumethiazide.
Aldazide Tablet contains Spironolactone and Hydroflumethiazide. Spironolactone is a diuretic agent that blocks the renal tubular actions of aldosterone. Its chemical name is (1) Pregn-4-ene-21-carboxylic acid, 7-(acetylthio)-17-hydroxy-3-oxo-, γ-lactone, (7α,17α)-;(2) 17-Hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone acetate (C24H32O4S). Its molecular weight is 416.57.
Hydroflumethiazide has diuretic and antihypertensive actions. Its chemical name is 3, 4-Dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide (C8H8F3N3O4S2).
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Spironolactone-hydroflumethiazide is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component.
The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding to receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. HCTZ promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule.
Spironolactone-hydroflumethiazide is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits.
Both spironolactone and hydroflumethiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when spironolactone and hydroflumethiazide are given concurrently.
Pharmacokinetics: No pharmacokinetic studies have been performed on spironolactone/HCTZ. Pharmacokinetic studies have been performed on the individual components of spironolactone/HCTZ.
Absorption: Studies with Spironolactone: Following oral administration of 500 mg titrated spironolactone in five healthy male volunteers (fasting state), the total radioactivity in plasma reached a peak between 25 and 40 minutes. Although the absolute bioavailability of spironolactone was not determined, the extent of absorption was estimated to be 75%, as 53% of the dose was excreted in the urine during 6 days and approximately 20% in the bile.
Administration with food resulted in higher exposure compared to fasted conditions. Following a single oral dose of 200 mg spironolactone to four healthy volunteers, the mean (±SD) AUC (0 to 24 hours) of the parent drug increased from 288±138 (empty stomach) to 493±105 ng·mL-1/hr (with food) (p<0.001).
Studies with Hydrochlorothiazide: Following single oral administration of HCTZ (25 mg, 50 mg, 100 mg and 200 mg) in 12 healthy volunteers, the extent of absorption ranged between 50% and 63%, with peak plasma concentrations occurring at approximately 2 hours in all treatment groups. Absorption of oral HCTZ was independent of dose.
Concurrent administration of HCTZ with food has resulted in significant decreases in plasma drug levels as compared to the administration of HCTZ in a fasted state. Eight healthy volunteers were administered HCTZ as three single-dose (50 mg) oral tablets with 250 mL of water (fasting), 20 mL of water (fasting) or 250 mL of water and a standard breakfast (fed). Mean peak plasma levels of 310 and 291 ng/mL were obtained in the 2 fasting treatment groups, as compared to a peak level of 241 ng/mL observed in the fed state.
Distribution: Studies with Spironolactone: Approximately 90% of spironolactone was protein bound based on equilibrium dialysis.
Studies with Hydrochlorothiazide: HCTZ is approximately 40% protein bound and accumulates in erythrocytes by an unknown mechanism. The ratio between red blood corpuscles and plasma is 3.5:1. The volume of distribution of HCTZ is approximately 3 L/kg to 4 L/kg.
Metabolism: Studies with Spironolactone: Spironolactone is metabolized by both the kidneys and liver. Following deacetylation and S-methylation, spironolactone is converted to 7-α-thiomethylspironolactone, a sulfur-containing active metabolite that is considered the major metabolite of spironolactone in serum. Approximately 25% to 30% of spironolactone is also converted to canrenone by dethioacetylation (non-sulfur-containing active metabolite).
Studies with Hydrochlorothiazide: There is no evidence that suggests metabolic degradation of HCTZ.
Excretion: Studies with Spironolactone: In one pharmacokinetic study in five healthy male volunteers receiving 500 mg of spironolactone, 47% to 57% of the dose was excreted in the urine within 6 days and the remaining amount could be detected in the feces (total recovery 90%). In another study of 5 healthy men, a single dose of spironolactone 200 mg (with radioactive tracer) was administered, and in 5 days, 31.6%±5.87% of the radioactivity was excreted in the urine mainly as metabolites and 22.7%±14.1% in the feces.
Studies with Hydrochlorothiazide: Following oral administration of four different doses (12.5 mg, 25 mg, 50 mg and 75 mg) of HCTZ to eight healthy volunteers, renal clearance ranged between 319 mL/min and 345 mL/min. HCTZ is excreted completely unchanged in the urine and appears in the urine within 1 hour of dosing. Approximately 50% to 70% was recovered in the urine 24 hours after the oral administration of 25 mg to 65 mg of HCTZ.
Special Populations: Hepatic Insufficiency: No pharmacokinetic studies have been performed with spironolactone/HCTZ in patients with hepatic insufficiency.
Renal Insufficiency: No pharmacokinetic studies have been performed with spironolactone/HCTZ in patients with renal insufficiency.
Elderly: No pharmacokinetic studies have been performed with spironolactone/HCTZ in the elderly population.
Pediatrics: No pharmacokinetic studies have been performed with spironolactone/HCTZ in the pediatric population.
Toxicology: Preclinical Safety Data: Spironolactone: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in Sprague-Dawley rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150 mg/kg/day and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, and 100 mg/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.
A dose-related (above 30 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of 1 year. In 2-year studies in the rats, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular and mammary tumors.
Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone was not mutagenic in some mammalian tests in vitro and results were inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others.
In a continuous breeding study in which female rats received dietary doses of 15 mg and 500 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 500 mg/kg/day.
When injected into female rats (100 mg/kg/day for 7 days, IP), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a 2-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity. Spironolactone (100 mg/kg/day), administered IP to female mice during a 2-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating.
Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryo-toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offsprings exposed during late pregnancy to 50 mg/kg/day and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, increased ovary and uterus weights in females, and other indications of endocrine dysfunction, which persisted into adulthood. Spironolactone has known endocrine effects in animals including progestational and anti-androgenic effects.
Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted uncovered no evidence of a carcinogenic potential of HCTZ in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). There was, however, equivocal evidence for hepatocarcinogenicity in male mice.
HCTZ was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese hamster ovary (CHO) test for chromosomal aberrations, or in in vivo 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 HCTZ from 43 mcg/mL to 1,300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.
HCTZ 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 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.
Studies in which HCTZ was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 mg/kg and 1,000 mg/kg, respectively, provided no evidence of harm to the fetus.
Indications/Uses
Spironolactone/Hydroflumethiazide is indicated for the following conditions: Essential hypertension; Congestive heart failure; Liver cirrhosis accompanied by edema and/or ascites; Nephrotic syndrome and other edematous conditions; Patients taking digitalis when other diuretics are inadequate or inappropriate to maintain electrolyte balance.
Dosage/Direction for Use
Essential Hypertension: The usual dose is 25 mg/25 mg/day to 100/100 mg/day.
Tablets may be taken daily in divided doses or as single daily dose. Treatment should be continued for at least 2 weeks to ensure an adequate response to therapy. Dose should be individually determined.
Congestive Heart Failure or Other Edematous Conditions: Adults: Initial Therapy: 100/100 mg/day.
Daily in divided doses or as a single daily dose. Treatment should be continued for at least 2 weeks to ensure adequate response to therapy. Maintenance daily dose should be individually determined.
Children: Daily dose should be that which provides 1.5 to 3.0 mg of spironolactone per kg of body weight. Dosage should be adjusted on the basis of response and tolerance.
Overdosage
Symptoms: Acute overdose may be manifested by nausea, vomiting, drowsiness, mental confusion, maculopapular or erythematous rash, dizziness or diarrhea. Electrolyte imbalance and dehydration may occur. If digitalis has been administered, hypokalemia may accentuate cardiac arrhythmias.
Treatment: There is no specific antidote. Spironolactone/thiazide use should be discontinued and potassium intake (including dietary sources) restricted.
Contraindications
Spironolactone/hydroflumethiazide is contraindicated in patients with acute renal insufficiency, significant renal compromise, anuria, Addison's disease, significant hypercalcemia, hyperkalemia, or hypersensitivity to spironolactone, thiazide diuretics, or to other sulfonamide-derived drugs. Hypersensitivity to Spironolactone/hydroflumethiazide or any of the inert ingredients including calcium sulphate dehydrate, corn starch, peppermint, magnesium stearate, povidone, hypromellose, polyethylene glycol, opaspray yellow.
Special Precautions
Concomitant use of spironolactone with other potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, non-steroidal anti-inflammatory drugs, angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin, or other drugs or conditions known to cause hyperkalemia, potassium supplements, a diet rich in potassium, or salt substitutes containing potassium, may lead to severe hyperkalemia.
Periodic estimation of serum electrolytes is recommended due to the possibility of hypokalemia or hyperkalemia, hypochloremic alkalosis, or hyponatremia and possible transient BUN elevation, especially in the elderly and/or in patients with pre-existing impaired renal or hepatic function.
Monitor serum potassium levels when using concomitantly with other drugs known to increase the risk of hypokalemia induced by thiazide diuretics.
Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.
Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even when renal function is normal. Caution should be used in treating patients with acute or severe liver impairment, since vigorous diuretic therapy may precipitate hepatic encephalopathy.
Hyponatremia may be induced, especially when spironolactone/thiazide is combined with other diuretics.
Thiazides may raise the concentration of blood uric acid. Dosage adjustment of anti-gout medications may be necessary.
In diabetic and prediabetic patients, thiazides may increase blood glucose concentrations. Dosage adjustments of insulin or hypoglycemic medications may be required.
Increases in cholesterol and triglyceride levels may be associated with thiazide therapy.
Acute myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue HCTZ as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Use In Pregnancy & Lactation
Fertility: Spironolactone: Spironolactone administered to female mice reduced fertility.
Thiazides: HCTZ administered to mice and rats did not affect fertility.
Pregnancy:
Spironolactone: Spironolactone was devoid of teratogenic effects in mice. Rabbits receiving spironolactone showed reduced conception rate, increased resorption rate, and lower number of live births. No embryotoxic effects were seen in rats administered with high dosages, but limited, dosage-related decreased plasma prolactin and decreased ventral prostate and seminal vesicle weights in males, and increased luteinizing hormone secretion and ovarian and uterine weights in females were reported in adult offspring. Feminization of the external genitalia of male fetuses was reported in another study in rats.
There are no studies in pregnant women.
Thiazides: HCTZ did not cause reproductive toxicity when administered to pregnant mice or rats. Thiazides cross the placental barrier. Thiazides may decrease placental perfusion, increase uterine inertia, and inhibit labor.
There is limited experience with thiazides during pregnancy, especially during the first trimester. Based on the pharmacological mechanism of action of thiazides, their use during the second and third trimesters may compromise placental perfusion and may cause fetal and neonatal effects like icterus, disturbances of electrolyte balance and thrombocytopenia.
Thiazides should not be used for gestational edema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion.
Thiazides should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Spironolactone/thiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: Spironolactone: Canrenone, a major (and) active) metabolite of spironolactone appears in human breast milk.
Thiazides: Thiazides are excreted in human milk in small amounts. Thiazides when given at high doses can cause intense diuresis, which can in turn inhibit milk production. The use of Spironolactone/Hydroflumethiazide (Aldazide) during breast feeding is not recommended. If Spironolactone/Hydroflumethiazide (Aldazide) is used during breast feeding, doses should be kept as low as possible.
Adverse Reactions
The following adverse events have been reported in association with spironolactone and spironolactone/thiazide therapy: See table.

Click on icon to see table/diagram/image
Drug Interactions
Concomitant use of drugs known to cause hyperkalemia with spironolactone may result in severe hyperkalemia.
Spironolactone/thiazide may have an additive effect when given concomitantly with other diuretics and antihypertensive agents. The dose of such drugs may need to be reduced when spironolactone is added to the treatment regimen.
Spironolactone and thiazides may reduce vascular responsiveness to norepinephrine. Caution should be exercised in the management of patients subjected to anesthesia while they are being treated with spironolactone/thiazide.
Cholestyramine and colestipol reduce the absorption of thiazides and may reduce their diuretic effects.
Thiazide diuretic agents reduce lithium renal clearance and increase the risk of toxicity. Lithium dose adjustment may be required.
Thiazides may increase responsiveness to skeletal muscle relaxants (e.g., tubocurarine).
Non-steroidal anti-inflammatory drugs such as aspirin, indomethacin and mefenamic acid may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins and have been shown to attenuate the diuretic effect of spironolactone.
Spironolactone enhances the metabolism of antipyrine.
Digoxin: Spironolactone has been shown to increase the half-life of digoxin.
Spironolactone can interfere with assays for plasma digoxin concentrations.
Thiazide-induced electrolyte disturbances, i.e. hypokalemia, and hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see Precautions).
Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with ammonium chloride or cholestyramine.
Co-administration of spironolactone with carbenoxolone may result in decreased efficacy of either agent.
Antidiabetic Drugs (oral hypoglycemic agents and insulin): Dosage adjustments of the antidiabetic drug may be required with thiazides.
Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycemic control, supplement potassium if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as requires (see Precautions).
Corticosteroids, Adrenocorticotropic Hormone: Intensified electrolyte depletion, particularly hypokalemia with thiazides.
Gout Medications (allopurinol, uricosurics, and xanthine oxidase inhibitors): Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid (see Precautions). The co-administration of HCTZ and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.
Storage
Store at temperature not exceeding 30°C.
ATC Classification
C03EA - Low-ceiling diuretics and potassium-sparing agents ; Used as diuretics.
Presentation/Packing
FC tab (film-coated, circular, biconvex, buff coloured, peppermint odour, engraved 'SEARLE 101' on one surface) 100's.
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