MAXZIDE® (triamterene and hydrochlorothiazide) combines triamterene, a potassium-conserving diuretic, with the natriuretic agent, hydrochlorothiazide.
Each MAXZIDE® tablet contains:
Triamterene, USP .................................... 75 mg
Hydrochlorothiazide, USP ........................ 50 mg
Each MAXZIDE®-25 MG tablet contains:
Triamterene, USP ................................. 37.5 mg
Hydrochlorothiazide, USP ........................ 25 mg
MAXZIDE® and MAXZIDE®-25 MG tablets for oral administration contain the following inactive ingredients: Colloidal Silicon Dioxide, Croscarmellose Sodium, Magnesium Stearate, Microcrystalline Cellulose, Powdered Cellulose, Sodium Lauryl Sulfate and D&C Yellow #10. MAXZIDE®-25 MG tablets also contain FD&C Blue #1.
Triamterene is 2,4,7-triamino-6-phenylpteridine. Triamterene is practically insoluble in water, benzene, chloroform, ether and dilute alkali hydroxides. It is soluble in formic acid and sparingly soluble in methoxyethanol. Triamterene is very slightly soluble in acetic acid, alcohol and dilute mineral acids. Its molecular weight is 253.27. Its structural formula is:
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4, benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine and dimethylformamide. It is sparingly soluble in methanol and insoluble in ether, chloroform and dilute mineral acids. Its molecular weight is 297.73. Its structural formula is:
MAXZIDE (triamterene and hydrochlorothiazide) is a diuretic, antihypertensive drug product, principally due to its hydrochlorothiazide component; the triamterene component of MAXZIDE reduces the excessive potassium loss which may occur with hydrochlorothiazide use.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It blocks the renal tubular absorption of sodium and chloride ions. This natriuresis and diuresis is accomplished by a secondary loss of potassium and bicarbonate. Onset of hydrochlorothiazide' diuretic effect occurs within two hours and the peak action takes place in four hours. Diuretic activity persists for approximately six to twelve hours.
The exact mechanism of hydrochlorothiazide' antihypertensive action is not known although it may relate to the excretion and redistribution of body sodium. Hydrochlorothiazide does not affect normal blood pressure.
Following oral administration, peak hydrochlorothiazide plasma levels are attained in approximately two hours. It is excreted rapidly and unchanged in the urine.
Well-controlled studies have demonstrated that doses of hydrochlorothiazide as low as 25 mg given once daily are effective in treating hypertension, but the dose response has not been clearly established.
Triamterene is a potassium-conserving (antikaliuretic) diuretic with relatively weak natriuretic properties. It exerts its diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium in exchange for potassium and hydrogen. With this action, triamterene increases sodium excretion and reduces the excessive loss of potassium and hydrogen associated with hydrochlorothiazide. Triamterene is not a competitive antagonist of the mineralocorticoids and its potassium-conserving effect is observed in patients with Addison' disease, ie, without aldosterone. Triamterene' onset and duration of activity is similar to hydrochlorothiazide. No predictable antihypertensive effect has been demonstrated with triamterene.
Triamterene is rapidly absorbed following oral administration. Peak plasma levels are achieved within one hour after dosing. Triamterene is primarily metabolized to the sulfate conjugate of hydroxytriamterene. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels.
The amount of triamterene added to 50 mg of hydrochlorothiazide in MAXZIDE tablets was determined from steady-state dose response evaluations in which various doses of liquid preparations of triamterene were administered to hypertensive persons who developed hypokalemia with hydrochlorothiazide (50 mg given once daily). Single daily doses of 75 mg triamterene resulted in greater increases in serum potassium than lower doses (25 mg and 50 mg), while doses greater than 75 mg of triamterene resulted in no additional levels in serum potassium levels. The amount of triamterene added to the 25 mg of hydrochlorothiazide in MAXZIDE-25 MG tablets was also determined from steady-state dose response evaluations in which various doses of liquid preparations of triamterene were administered to hypertensive persons who developed hypokalemia with hydrochlorothiazide (25 mg given once daily). Single daily doses of 37.5 mg triamterene resulted in greater increases in serum potassium than a lower dose (25 mg), while doses greater than 37.5 mg of triamterene, ie, 75 and 100 mg, resulted in no additional elevations in serum potassium levels. The dose response relationship of triamterene was also evaluated in patients rendered hypokalemic by hydrochlorothiazide given 25 mg twice daily. Triamterene given twice daily increased serum potassium levels in a dose-related fashion. However, the combination of triamterene and hydrochlorothiazide given twice daily also appeared to produce an increased frequency of elevation in serum BUN and creatinine levels. The largest increases in serum potassium, BUN and creatinine in this study were observed with 50 mg of triamterene given twice daily, the largest dose tested. Ordinarily, triamterene does not entirely compensate for the kaliuretic effect of hydrochlorothiazide and some patients may remain hypokalemic while receiving triamterene and hydrochlorothiazide. In some individuals, however, it may induce hyperkalemia (see ).
The triamterene and hydrochlorothiazide components of MAXZIDE and MAXZIDE-25 MG are well absorbed and are bioequivalent to liquid preparations of the individual components administered orally. Food does not influence the absorption of triamterene or hydrochlorothiazide from MAXZIDE or MAXZIDE-25 MG tablets. The hydrochlorothiazide components of MAXZIDE is bioequivalent to single entity hydrochlorothiazide tablet formulations.
This fixed combination drug is not indicated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked.
MAXZIDE may be used alone or in combination with other antihypertensive drugs, such as beta-blockers. Since MAXZIDE (triamterene and hydrochlorothiazide) may enhance the actions of these drugs, dosage adjustments may be necessary.
The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in absence of pregnancy. Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
MAXZIDE (triamterene and hydrochlorothiazide) should not be used in the presence of elevated serum potassium levels (greater than or equal to 5.5 mEq/liter). If hyperkalemia develops, this drug should be discontinued and a thiazide alone should be substituted.
MAXZIDE should not be given to patients receiving other potassium-conserving agents such as spironolactone, amiloride HCl or other formulations containing triamterene. Concomitant potassium supplementation in the form of medication, potassium-containing salt substitute or potassium-enriched diets should also not be used.
MAXZIDE is contraindicated in patients with anuria, acute and chronic renal insufficiency or significant renal impairment.
MAXZIDE should not be used in patients who are hypersensitive to triamterene or hydrochlorothiazide or other sulfonamide-derived drugs.
Abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) can occur with all potassium-conserving diuretic combinations, including MAXZIDE. Hyperkalemia is more likely to occur in patients with renal impairment, diabetes (even without evidence of renal impairment), or elderly or severely ill patients. Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients first receiving MAXZIDE, when dosages are changed or with any illness that may influence renal function.
If hyperkalemia is suspected, (warning signs include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock) an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.
If hyperkalemia is present, MAXZIDE (triamterene and hydrochlorothiazide) should be discontinued immediately and a thiazide alone should be substituted. If the serum potassium exceeds 6.5 mEq/liter, more vigorous therapy is required. The clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.
The development of hyperkalemia associated with potassium-sparing diuretics is accentuated in the presence of renal impairment (see CONTRAINDICATIONS). Patients with mild renal functional impairment should not receive this drug without frequent and continuing monitoring of serum electrolytes. Cumulative drug effects may be observed in patients with impaired renal function. The renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, the sulfate ester of hydroxytriamterene, have been shown to be reduced and the plasma levels increased following MAXZIDE (triamterene and hydrochlorothiazide) administration to elderly patients and patients with impaired renal function.
Hyperkalemia has been reported in diabetic patients with the use of potassium-conserving agents even in the absence of apparent renal impairment. Accordingly, MAXZIDE (triamterene and hydrochlorothiazide) should be avoided in diabetic patients. If it is employed, serum electrolytes must be frequently monitored.
Because of the potassium-sparing properties of angiotensin-converting enzyme (ACE) inhibitors, MAXZIDE should be used cautiously, if at all, with these agents (see PRECAUTIONS , Drug Interactions ).
Potassium-conserving therapy should also be avoided in severely ill patients in whom respiratory or metabolic acidosis may occur. Acidosis may be associated with rapid elevations in serum potassium levels. If MAXZIDE is employed, frequent evaluations of acid/base balance and serum electrolytes are necessary.
Electrolyte Imbalance and BUN Increases
Patients receiving MAXZIDE (triamterene and hydrochlorothiazide) should be carefully monitored for fluid or electrolyte imbalances, ie, hyponatremia, hypochloremic alkalosis, hypokalemia and hypomagnesemia. Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Serum and urine electrolyte determinations are especially important and should be frequently performed when the patient is vomiting or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Any chloride deficit during thiazide therapy is generally mild and usually does not require any specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hypokalemia may develop with thiazide therapy, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids, ACTH, amphotericin B or after prolonged thiazide therapy. However, hypokalemia of this type is usually prevented by the triamterene component of MAXZIDE (triamterene and hydrochlorothiazide).
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability).
MAXZIDE (triamterene and hydrochlorothiazide) may produce an elevated blood urea nitrogen level (BUN), creatinine level or both. This is probably not the result of renal toxicity but is secondary to a reversible reduction of the glomerular filtration rate or a depletion of the intravascular fluid volume. Elevations in BUN and creatinine levels may be more frequent in patients receiving divided dose diuretic therapy. Periodic BUN and creatinine determinations should be made especially in elderly patients, patients with suspected or confirmed hepatic disease or renal insufficiencies. If azotemia increases, MAXZIDE (triamterene and hydrochlorothiazide) should be discontinued.
MAXZIDE should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Triamterene has been reported in renal stones in association with other calculus components. MAXZIDE should be used with caution in patients with histories of renal lithiasis.
Triamterene is a weak folic acid antagonist and may contribute to the appearance of megaloblastosis in instances where folic acid stores are decreased. In such patients, periodic blood elevations are recommended.
Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.
The thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. Thiazides should be discontinued before carrying out tests for parathyroid function.
Insulin requirements in diabetic patients may be increased, decreased or unchanged. Diabetes mellitus which has been latent may become manifest during thiazide administration.
Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma.
Possible exacerbation or activation of systemic lupus erythematosus by thiazides has been reported.
Thiazides may add to or potentiate the action of other antihypertensive drugs.
The thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazides have also been shown to increase the responsiveness to tubocurarine.
Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Refer to the package insert on lithium before use of such concomitant therapy.
Acute renal failure has been reported in a few patients receiving indomethacin and formulations containing triamterene and hydrochlorothiazide. Caution is therefore advised when administering nonsteroidal anti-inflammatory agents with MAXZIDE (triamterene and hydrochlorothiazide).
Potassium-sparing agents should be used very cautiously, if at all, in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to a greatly increased risk of hyperkalemia. Serum potassium should be monitored frequently.
Triamterene and quinidine have similar fluorescence spectra; thus MAXZIDE (triamterene and hydrochlorothiazide) may interfere with the measurement of quinidine.
Studies have not been performed to evaluate the mutagenic or carcinogenic potential of MAXZIDE.
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide 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). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide 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 hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide 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 and 4 mg/kg, respectively, prior to conception and throughout gestation.
Studies have not been performed to determine the carcinogenic or mutagenic potential of triamterene. Reproductive studies have been performed in rats at doses up to 30 times the human dose and have revealed no evidence of impaired fertility.
Teratogenic Effects --Animal reproduction studies have not been conducted with MAXZIDE. It is also not known if MAXZIDE can cause fetal harm when administered to a pregnant woman.
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women.
Reproduction studies have been performed in rats at doses up to 30 times the human dose and have revealed no evidence of harm to the fetus due to triamterene. There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, MAXZIDE should be used during pregnancy only if clearly needed.
Thiazides and triamterene cross the placental barrier and appear in cord blood of animals. The use of MAXZIDE in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia following thiazides and possible other adverse reactions that have occurred in the adults.
Thiazides appear and triamterene may appear in breast milk. If use of the drug product is deemed essential the patient should stop nursing.
The safety and effectiveness of MAXZIDE (triamterene and hydrochlorothiazide) in children has not been established.
Side effects observed in association with the use of MAXZIDE, other combination products containing triamterene/hydrochlorothiazide, and products containing triamterene or hydrochlorothiazide include the following:
Gastrointestinal: jaundice (intrahepatic cholestatic jaundice), pancreatitis, nausea, appetite disturbance, taste alteration, vomiting, diarrhea, constipation, anorexia, gastric irritation, cramping.
Central Nervous System: drowsiness and fatigue, insomnia, headache, dizziness, dry mouth, depression, anxiety, vertigo, restlessness, paresthesias.
Cardiovascular: tachycardia, shortness of breath and chest pain, orthostatic hypotension (may be aggravated by alcohol, barbiturates or narcotics).
Renal: acute renal failure, acute interstitial nephritis, renal stones composed of triamterene in association with other calculus materials, urine discoloration.
Hematologic: leukopenia, agranulocytosis thrombocytopenia, aplastic anemia, hemolytic anemia and megaloblastosis.
Ophthalmic: xanthopsia, transient blurred vision.
Hypersensitivity: anaphylaxis, photosensitivity, rash, urticaria, purpura, necrotizing angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including pneumonitis.
Other: muscle cramps and weakness, decreased sexual performance and sialadenitis.
Whenever adverse reactions are moderate to severe, therapy should be reduced or withdrawn.
Altered Laboratory Findings:
Serum Electrolytes: hyperkalemia, hypokalemia, hyponatremia, hypomagnesemia, hypochloremia (see , PRECAUTIONS ).
Creatinine, Blood Urea Nitrogen: Reversible elevations in BUN and serum creatinine have been observed in hypertensive patients treated with MAXZIDE.
Glucose: hyperglycemia, glycosuria and diabetes mellitus (see PRECAUTIONS ).
Serum Uric Acid, PBI and Calcium: (see PRECAUTIONS ).
Other: Elevated liver enzymes have been reported in patients receiving MAXZIDE.
No specific data are available regarding MAXZIDE (triamterene and hydrochlorothiazide) overdosage in humans and no specific antidote is available.
Fluid and electrolyte imbalances are the most important concern. Excessive doses of the triamterene component may elicit hyperkalemia, dehydration, nausea, vomiting and weakness and possibly hypotension. Overdosing with hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, lethargy (may progress to coma) and gastrointestinal irritation. Treatment is symptomatic and supportive. Therapy with MAXZIDE (triamterene and hydrochlorothiazide) should be discontinued. Induce emesis or institute gastric lavage. Monitor serum electrolyte levels and fluid balance. Institute supportive measures as required to maintain hydration, electrolyte balance, respiratory, cardiovascular and renal function.
The usual dose of MAXZIDE-25 MG is one or two tablets daily, given as a single dose, with appropriate monitoring of serum potassium (see ). The usual dose of MAXZIDE is one tablet daily, with appropriate monitoring of serum potassium (see ). There is no experience with the use of more than one MAXZIDE tablet daily or more than two MAXZIDE-25 MG tablets daily. Clinical experience with the administration of two MAXZIDE-25 MG tablets daily in divided doses (rather than as a single dose) suggests an increased risk of electrolyte imbalance and renal dysfunction.
Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be transferred to MAXZIDE (triamterene and hydrochlorothiazide) directly. Patients receiving 25 mg hydrochlorothiazide who become hypokalemic may be transferred to MAXZIDE-25 MG (37.5 mg triamterene/25 mg hydrochlorothiazide) directly.
In patients requiring hydrochlorothiazide therapy and in whom hypokalemia cannot be risked therapy may be initiated with MAXZIDE-25 MG. If an optimal blood pressure response is not obtained with MAXZIDE-25 MG, the dose should be increased to two MAXZIDE-25 MG tablets daily as a single dose, or one MAXZIDE tablet daily. If blood pressure still is not controlled, another antihypertensive agent may be added (see PRECAUTIONS , Drug Interactions ).
Clinical studies have shown that patients taking less bioavailable formulations of triamterene and hydrochlorothiazide in daily doses of 25-50 mg hydrochlorothiazide and 50-100 mg triamterene may be safely changed to one MAXZIDE-25 MG tablet daily. All patients changed from less bioavailable formulations to MAXZIDE should be monitored clinically for serum potassium after the transfer.
MAXZIDE® (triamterene and hydrochlorothiazide) tablets are bowtie-shaped, flat-faced beveled, light yellow tablets, engraved with MAXZIDE on one side and scored on the other with B on the left and M8 on the right of the score. Each tablet contains 75 mg of triamterene, USP and 50 mg of hydrochlorothiazide, USP. They are supplied as follows:
NDC 62794-460-01--Bottle of 100 with CRC
NDC 62794-460-05--Bottle of 500
NDC 62794-460-88--Unit Dose 10 × 10s
MAXZIDE-25 MG (triamterene and hydrochlorothiazide) tablets are bowtie-shaped, flat-faced beveled, light green tablets, engraved with MAXZIDE on one side and scored on the other with B on the left and M9 on the right of the score. Each tablet contains 37.5 mg of triamterene, USP and 25 mg of hydrochlorothiazide, USP. They are supplied as follows:
NDC 62794-464-01--Bottle of 100 with CRC
NDC 62794-464-05--Bottle of 500
NDC 62794-464-88--Unit Dose 10 × 10s
Store at Controlled Room Temperature 15-30°C (59-86°F).
Protect from Light.
Dispense in a tight, light-resistant, child-resistant container.
BERTEK PHARMACEUTICALS INC.
Sugar Land, TX 77478
REVISED SEPTEMBER 1996 BKMAX:R3