Amiloride hydrochlorid

موضوع: Amiloride hydrochlorid الإثنين يوليو 16, 2012 7:43 pm

This monograph includes information on the following:

1) Amiloride
2) Spironolactone
3) Triamterene

VA CLASSIFICATION
Amiloride
Primary: CV704
Secondary: CV409; TN900

Spironolactone
Primary: CV704
Secondary: CV409; TN900; HS900

Triamterene
Primary: CV704
Secondary: CV409; TN900

Commonly used brand name(s): Aldactone2; Dyrenium3; Midamor1; Novospiroton2.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Diuretic—Amiloride; Spironolactone; Triamterene;

Antihypertensive—Amiloride; Spironolactone; Triamterene;

Aldosterone antagonist—Spironolactone;

Diagnostic aid (primary hyperaldosteronism)—Spironolactone;

Antihypokalemic—Amiloride; Spironolactone; Triamterene;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Edema (treatment)—Amiloride, spironolactone, and triamterene are indicated as adjuncts in the management of edematous states, especially when a potassium-sparing diuretic effect is desired. These may include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome, which often involve secondary hyperaldosteronism, as well as idiopathic edema.{01}{05}{07}{38}{43}

Hypertension (treatment adjunct)—Amiloride, spironolactone, and [triamterene]1 are indicated as adjuncts in the treatment of hypertension (for spironolactone, with or without accompanying hyperaldosteronism), especially when a potassium-sparing diuretic effect is desired. {01} {07}{43}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

Hyperaldosteronism, primary (diagnosis and treatment)—Spironolactone is indicated for diagnosis and short- or long-term management of primary hyperaldosteronism. {01}{43}

Hypokalemia (prophylaxis and treatment)—[ Amiloride]1, spironolactone, and [ triamterene]1 are indicated for prevention and treatment of hypokalemia in patients for whom other measures are inappropriate or inadequate. {01}{43}

[Congestive heart failure (treatment adjunct) ]1—Spironolactone may be used as adjunctive treatment for severe congestive heart failure to reduce morbidity and the risk of death.{44}{45}

[Polycystic ovary syndrome (treatment) ]1—Spironolactone is also used with some success in the treatment of polycystic ovary syndrome. {03} {10} {12}

[Hirsutism, female (treatment)]1—Spironolactone has been used in the treatment of female hirsutism. {22} {23} {24} {25}

1 Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
Amiloride hydrochloride: 302.12
Spironolactone: 416.57
Triamterene: 253.27

pKa—
Amiloride: 8.7
Triamterene: 6.2

Mechanism of action/Effect:

Diuretic or Antihypokalemic—Potassium-sparing diuretics interfere with sodium reabsorption in the distal convoluted tubule, thereby promoting excretion of sodium and water and retention of potassium. Amiloride and triamterene have a direct inhibiting effect on the entry of sodium into the cells, while spironolactone competitively inhibits the action of aldosterone. {01} {04}{43}

Antihypertensive—Diuretics lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases. Eventually, the extracellular fluid volume and the cardiac output return to normal with an accompanying decrease in peripheral resistance. {12} {13}

Aldosterone antagonist or Diagnostic aid (primary hyperaldosteronism)—Spironolactone is a competitive inhibitor of aldosterone; neither amiloride nor triamterene has this effect. {01} {05} {07}{43}

Hirsutism or Polycystic ovary syndrome—May be due to an antiandrogenic effect of spironolactone. {10}

Absorption:

Amiloride—Incompletely (15 to 20%) absorbed from gastrointestinal tract; rate, but not necessarily extent, of absorption is increased after 4 hours of fasting.

Spironolactone—Well absorbed following oral administration; bioavailability is greater than 90%. {03} Absorption is enhanced by concomitant intake of food. {03} {04} {08}

Triamterene—Rapidly {05} but incompletely (30 to 70%) absorbed from the gastrointestinal tract.

Protein binding:

Amiloride—Minimal.

Spironolactone and canrenone—Very high (more than 90%).

Triamterene—Moderate (67%). {05}

Biotransformation:

Amiloride—Not metabolized. {07}

Spironolactone—Hepatic; approximately 25 to 30% converted to canrenone. {18}

Triamterene—Hepatic.

Half-life:

Amiloride:

6 to 9 hours. {07}

Spironolactone:

Canrenone: 13 to 24 hours (average 19 hours) when administered once or twice daily; 9 to 16 hours (average 12.5 hours) when administered 4 times daily.

Triamterene:

Normal, 90 to 120 minutes; anuric, 10 hours. Some active metabolites have a normal half-life of up to 12 hours.

Terminal half-life: 5 to 7 hours. {28}

Onset of action:

Diuretic:

Amiloride: Single dose—Within 2 hours. {07}

Triamterene: Single dose—2 to 4 hours. {05}

Time to peak concentration:

Amiloride—3 to 4 hours. {07}

Triamterene—2 to 4 hours. {05}

Time to peak effect

Diuretic:

Amiloride: Single dose—6 to 10 hours. {07}

Spironolactone: Multiple doses—2 to 3 days. {01}

Triamterene: Multiple doses—1 day to several days.

Duration of action:

Diuretic:

Amiloride: Single dose—24 hours. {07}

Spironolactone: Multiple doses—2 to 3 days. {01}

Triamterene: Single dose—7 to 9 hours. {05}

Elimination:
Amiloride—Renal, 20 to 50% (unchanged); fecal, 40% (unchanged).
Spironolactone—Metabolites: Primary route, renal (less than 10% unchanged); secondary route, biliary/fecal. {02} {03}
Triamterene—Primary route, biliary/fecal; secondary route, renal.

Precautions to Consider

Carcinogenicity/Tumorigenicity

Amiloride

One study in mice at doses up to 25 times the maximum daily human dose and another in male and female rats at doses up to 15 and 20 times the maximum daily human dose for 104 weeks showed no evidence of carcinogenicity or tumorigenicity. {07}

Spironolactone

Breast carcinoma has been reported in men and women taking this medication, but a direct causal relationship has not yet been established. {36}{43}

Spironolactone has been found to be tumorigenic in rats, mainly in endocrine organs and the liver. {01} {36} {43}A statistically significant dose-related increase in benign adenomas of the thyroid and testes was found in male rats given spironolactone in doses up to 250 times the usual daily human dose of 2 mg per kg of body weight (mg/kg). {36}{43} In addition, a dose-related increase in proliferative liver changes was revealed in male rats. Hepatocytomegaly, hyperplastic nodules, and hepatocellular carcinoma were evident at the highest dosage level of 500 mg/kg. {36} In female rats, a statistically significant increase in malignant mammary tumors was seen at the mid-dose level. {36}{43}There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in female rats. {43}

Triamterene

Studies evaluating the carcinogenic potential of triamterene have not been done. {38}

Mutagenicity

Amiloride—In Ames tests, no evidence of mutagenicity was found. {07}

Pregnancy/Reproduction
Fertility—
Amiloride: Studies in rats given amiloride at 20 times the expected maximum human daily dose revealed no evidence of fertility impairment. {07} However, some toxicity in adult rats and rabbits and a decrease in rat pup growth and survival were seen at doses of 5 or more times the expected maximum daily human dose. {07}

Pregnancy—
Pregnant women should be advised to contact physician before taking these medications, since routine use of diuretics during normal pregnancy 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 toxemia. {05} {36} Diuretics are indicated only in the treatment of edema due to pathologic causes or as a short course of treatment in patients with severe hypervolemia. {05} {36}

Amiloride

Adequate and well-controlled studies in humans have not been done.

Amiloride crosses the placenta in modest amounts in rabbits and mice. However, teratogenicity studies in rabbits and mice given 20 and 25 times the maximum human dose, respectively, revealed no evidence of fetal harm. {07}

FDA Pregnancy Category B. {07}

Spironolactone

Spironolactone may cross the placenta. {36} However, problems in humans have not been documented. {01}

Triamterene

Adequate and well-controlled studies in humans have not been done.

Triamterene crosses the placenta and appears in the cord blood of ewes. {05} Studies in rats given triamterene in doses up to 30 times the human dose have revealed no evidence of harm to the fetus. {38}

FDA Pregnancy Category B. {05} {38}

Breast-feeding

Amiloride—It is not known whether amiloride is distributed into human breast milk. {07} However, problems in humans have not been documented. Amiloride has been shown to be distributed into rat's milk.{07}

Spironolactone—Problems in humans have not been documented. However, canrenone (an active metabolite of spironolactone) is distributed into breast milk. {01} {36}

Triamterene—It is not known whether triamterene is distributed into human breast milk. However, problems in humans have not been documented. Triamterene has been shown to be distributed into animal milk. {38}

Pediatrics

Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of potassium-sparing diuretics in children.

Geriatrics

Although appropriate studies on the relationship of age to the effects of potassium-sparing diuretics have not been performed in the geriatric population, the elderly may be at increased risk of developing hyperkalemia. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving potassium-sparing diuretics.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

For all potassium-sparing diuretics
Allopurinol or
Colchicine or
Probenecid or
Sulfinpyrazone (triamterene may raise the concentration of blood uric acid, but to a lesser extent than thiazide diuretics or ethacrynic acid or furosemide; dosage adjustment of antigout medications may be necessary to control hyperuricemia and gout {05} {35})

» Anticoagulants, coumarin- or indandione-derivative or {27}
» Heparin {16} (anticoagulant effects may be decreased when these medications are used concurrently with potassium-sparing diuretics, as a result of reduction of plasma volume leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function, resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary)

Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin {01} {05} {07} {15} (may reduce the antihypertensive effects of the potassium-sparing diuretics; indomethacin may also reduce the natriuretic and diuretic effects of potassium-sparing diuretics, possibly because of renal prostaglandin synthesis inhibition and/or sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained {01} {05})

(concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis {01})

» Angiotensin-converting enzyme (ACE) inhibitors or {01} {04} {05}
Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin or {16}
» Blood from blood bank (may contain up to 30 mEq [mmol] of potassium per liter of plasma or up to 65 mEq [mmol] per liter of whole blood when stored for more than 10 days) or {01}
» Cyclosporine or
» Diuretics, potassium-sparing, other or {01} {07}
Heparin or {16} {17}
» Low-salt milk (may contain up to 60 mEq [mmol] of potassium per liter) or {04} {05}
» Potassium-containing medications or {01} {05} {15}
» Potassium supplements or substances containing high levels of potassium or {01} {05} {15}
Salt substitutes (most contain substantial amounts of potassium) {01} {05} {15} (concurrent administration with potassium-sparing diuretics tends to promote serum potassium accumulation; hyperkalemia may result, especially in patients with renal insufficiency)

Exchange resins, sodium cycle (such as sodium polystyrene sulfonate) (whether administered orally or rectally, these medications reduce serum potassium levels by replacing potassium with sodium; fluid retention may occur in some patients because of the increased sodium intake {05})

Hypotension-producing medications, other (See Appendix II ) (antihypertensive and/or diuretic effects may be potentiated when these medications are used concurrently with potassium-sparing diuretics; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use {18})

» Lithium (concurrent use with potassium-sparing diuretics is not recommended, as they may provoke lithium toxicity by reducing renal clearance {05} {07} {15})

Sympathomimetics (may reduce the antihypertensive effects of potassium-sparing diuretics; the patient should be carefully monitored to confirm that the desired effect is being obtained {01} {20})

For spironolactone only (in addition to those listed for all potassium-sparing diuretics)
» Digoxin (spironolactone may increase the half-life of digoxin; dosage reduction or increased dosing intervals of digoxin may be necessary and careful monitoring is recommended {18} {19} {26})

For triamterene only (in addition to those listed for all potassium-sparing diuretics)
Amantadine (triamterene may reduce the renal clearance of amantadine, resulting in increased plasma concentrations and possible amantadine toxicity {13} {32})

Folic acid (triamterene may act as a folate antagonist by inhibiting dihydrofolate reductase; most significant with high doses and/or prolonged triamterene use; leucovorin calcium must be used instead of folic acid in patients receiving triamterene {33} {34})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results

For spironolactone only:
Digoxin radioimmunoassays (results may be falsely elevated {02})

Plasma cortisol concentration determination by Mattingly (fluorometric) assay {01} (concentration may be falsely increased; withdrawal of spironolactone 4 to 7 days prior to determinations, or substitution of Ertel, Peterson, or Norymberski method, is recommended)

For triamterene only:
Fluorescent measurement of quinidine (similar fluorescence spectra {05})

With physiology/laboratory test values

For amiloride, spironolactone, and triamterene
Blood urea nitrogen (BUN) concentrations (especially in patients with pre-existing renal impairment) and {01} {07}
Calcium excretion, urinary and
Creatinine concentrations, serum and
Magnesium concentrations, serum and
Plasma renin activity (PRA) and
Potassium concentrations, serum and
Uric acid concentrations, serum (may be increased)

Sodium (serum concentrations may be decreased {02} {05} {07})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hyperkalemia {01} {05} {07} (potassium-sparing diuretics may further increase serum potassium concentrations )

Risk-benefit should be considered when the following medical problems exist

For amiloride, spironolactone, and triamterene:
» Anuria or {01}
» Renal function impairment {01} {04} {05} {07} (potassium-sparing diuretics may aggravate electrolyte imbalance; risk of developing hyperkalemia is increased)

Diabetes mellitus, especially in patients with confirmed or suspected renal insufficiency or {04} {05} {07}
» Diabetic nephropathy (increased risk of hyperkalemia; potassium-sparing diuretic should be discontinued at least 3 days prior to a glucose tolerance test because of the risk of severe hyperkalemia {07})

» Hepatic function impairment (increased sensitivity to electrolyte changes {05} {07})

Hyponatremia {01}
Metabolic or respiratory acidosis, predisposition to {01} {07} (acidosis potentiates hyperkalemic effects of potassium-sparing diuretics; potassium-sparing diuretics may potentiate acidosis)

Sensitivity to the potassium-sparing diuretic prescribed
» Caution is also required in severely ill patients and those with relatively small urine volumes, who are at greater risk of developing hyperkalemia.
For spironolactone only (in addition to those listed above for all potassium-sparing diuretics):
Menstrual abnormalities or breast enlargement
For triamterene only (in addition to those listed above for all potassium-sparing diuretics):
Hyperuricemia or gout {05}
Nephrolithiasis, history of (increased risk of forming triamterene stones {05})

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

For amiloride, spironolactone, and triamterene
» Blood pressure measurements (recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)

Blood urea nitrogen (BUN) determinations and/or {05} {07}
Creatinine concentrations, serum (determinations recommended prior to initiation of therapy and at periodic intervals during therapy {05} {07})

Electrocardiograms (ECG) and
» Electrolyte concentrations, serum, especially serum potassium determinations {01} {07} (may be required at periodic intervals for patients on long-term therapy, especially if they are also taking systemic steroids, or when congestive heart failure or severe cirrhosis is present)

For triamterene only
Platelet count and
Total and differential leukocyte count (recommended prior to initiation of therapy and at periodic intervals during therapy, especially in patients with impaired hepatic function {05})

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Side/Adverse Effects
Table 1. Side/Adverse Effects*

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive: Legend:
I=Amiloride
II=Spironolactone
III =Triamterene
I
II
III

Those indicating need for medical attention
Agranulocytosis (fever or chills, cough or hoarseness, lower back or side pain, painful or difficult urination) U R R
Allergic reaction or anaphylaxis (shortness of breath, skin rash or itching) R R R
Hyperkalemia (confusion; irregular heartbeat; nervousness; numbness or tingling in hands, feet, or lips; shortness of breath or difficult breathing; unusual tiredness or weakness; weakness or heaviness of legs)
Note: Irregular heartbeat is usually the earliest clinical indication of hyperkalemia and is readily detected by electrocardiogram (ECG). M † M † M †
Megaloblastosis or overdose (burning, inflamed, or bright red tongue or cracked corners of mouth; weakness) U U R
Nephrolithiasis (severe lower back or side pain) U U R
Thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin) U U R
Those indicating need for medical attention only if they continue or are bothersome
Antiandrogenic or endocrine effect (breast tenderness in females, deepening of voice in females, enlargement of breasts in males, inability to have or keep an erection, increased hair growth in females, irregular menstrual periods, sweating)
Note: Gynecomastia occurs frequently after several months of treatment at doses of spironolactone greater than 100 mg per day and rarely may persist even after spironolactone is discontinued. U L ‡ U
Central nervous system (CNS) effect (clumsiness) U L ‡ U
CNS effect (headache) L L ‡ L
Constipation
L U U
Decreased sexual ability
L L U
Dizziness
L L L
Gastrointestinal irritation (nausea or vomiting, stomach cramps and diarrhea) L M L
Hyponatremia (drowsiness, dryness of mouth, increased thirst, lack of energy) L L L
Increased sensitivity of skin to sunlight
U U L
Muscle cramps
L U U

* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents. M = more frequent; L = less frequent; R = rare; U = unknown.
† Signs and symptoms of hyperkalemia may occur even when potassium-sparing diuretics are combined with thiazide diuretics. Hyperkalemia occurs in approximately 10% of patients when amiloride is used alone and may occur in up to 26% of patients receiving spironolactone even when combined with thiazide diuretics.
‡ Incidence related to dose and/or duration of therapy.

Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Overdose should be treated by immediate evacuation of the stomach followed by supportive, symptomatic treatment and monitoring of serum electrolyte concentrations and renal function.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diuretics, Potassium-sparing (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
» Conditions affecting use, especially:
Sensitivity to the potassium-sparing diuretic prescribed

Pregnancy—Not recommended for routine use; triamterene crosses placenta; spironolactone may cross placenta

Breast-feeding—All potassium-sparing diuretics may be distributed into breast milk

Use in the elderly—Increased risk of hyperkalemia
Other medications, especially angiotensin-converting enzyme (ACE) inhibitors, cyclosporine, digoxin, other potassium-sparing diuretics, potassium-containing medications or supplements, or lithium
Other medical problems, especially diabetic nephropathy, hyperkalemia, renal function impairment or hepatic function impairment

Proper use of this medication
Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis

Getting into habit of taking at same time each day to help increase compliance

Taking with meals or milk to reduce gastrointestinal irritation

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For use as an antihypertensive (amiloride and spironolactone only)
Possible need for control of weight and diet, especially sodium intake

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension

Precautions while using this medication
Regular visits to physician to check progress

Avoiding excessive ingestion of foods high in potassium or use of salt substitutes or other potassium supplements

To prevent dehydration, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution if any kind of surgery or emergency treatment is required

Caution if any laboratory tests required; possible interference with test results

For use as an antihypertensive (amiloride and spironolactone only)
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician

For triamterene only
Possible photosensitivity; avoiding unprotected exposure to sun; using protective clothing and sun block product; avoiding use of sunlamp, tanning bed, or tanning booth

Side/adverse effects
Signs of potential side effects, especially agranulocytosis, allergic reaction, anaphylaxis, and hyperkalemia (for all potassium-sparing diuretics); megaloblastosis, nephrolithiasis, and thrombocytopenia (for triamterene)

For spironolactone only (in addition to the above)
Possibility of enlargement of breasts in males; usually reversible within several months

General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response. The lowest effective dose should be utilized to minimize potential electrolyte imbalance. {03}

If a single daily dose is indicated, it is preferably taken on arising in order to minimize the effect of increased frequency of urination on sleep, although the diuretic effect of potassium-sparing diuretics alone is mild.

The normal adult concentration of plasma potassium is 3.5 to 5.0 mEq (mmol) per liter, with 4.5 mEq (mmol) often being used as a reference point. Potassium concentrations exceeding 6 mEq (mmol) per liter are dangerous because of possible initiation of cardiac arrhythmias. Normal potassium concentrations tend to be higher in neonates (7.7 mEq [mmol] per liter) than in adults. {05}

Plasma potassium concentrations do not necessarily indicate the true body potassium concentration. A rise in serum pH may cause a decrease in serum potassium concentration and an increase in the intracellular potassium concentration.

It is recommended that potassium-sparing diuretic therapy be withdrawn if hyperkalemia occurs. {01} If hyperkalemia is associated with ECG changes, prompt additional therapy with intravenous sodium bicarbonate, calcium gluconate, or calcium chloride; with oral or rectal sodium polystyrene sulfonate; {05} {07} or with parenteral glucose and insulin may be indicated. It is important to remember that severe hyperkalemia may occur suddenly and may not be preceded by any warning signs. {01}

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery is not necessary, but that the anesthesiologist must be aware of such therapy.

Diet/Nutrition
It is recommended that oral potassium-sparing diuretics be taken with or after meals to minimize stomach upset, and possibly also to enhance bioavailability. {05}

AMILORIDE

Summary of Differences

Pharmacology/pharmacokinetics:
Protein binding—Minimal.

Biotransformation—None; excreted unchanged.

Duration of action—Diuretic: Single dose—24 hours.

Side/adverse effects:
No reported cases of agranulocytosis. Amiloride has been reported to cause constipation and muscle cramps.

Oral Dosage Forms

AMILORIDE HYDROCHLORIDE TABLETS USP

Usual adult dose
Diuretic or
Antihypertensive
Oral, 5 to 10 mg per day as a single dose. {07}

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Usual adult prescribing limits
Up to 20 mg per day. {07}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—

5 mg (Rx) [Midamor]

Canada—

5 mg (Rx) [Midamor]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
• Take with meals or milk.
• Do not take other medicines without your doctor"s advice.

Note: Check refill frequency to determine compliance in hypertensive patients.

SPIRONOLACTONE

Summary of Differences

Indications:
Diagnosis and treatment of primary hyperaldosteronism. Treatment of polycystic ovary syndrome and female hirsutism.

Pharmacology/pharmacokinetics:
Mechanism of action/effect—Aldosterone antagonist.

Protein binding—Very high (more than 90%).

Biotransformation—Hepatic, extensive, to active metabolite (canrenone).

Duration of action—Diuretic: Multiple doses—2 to 3 days.

Precautions:
Carcinogenicity—Tumorigenic in rats and possibly associated with breast carcinoma in humans.

Drug interactions and/or related problems—Use with digoxin may increase digoxin half-life.

Laboratory value alterations—May falsely increase plasma cortisol determinations by Mattingly (fluorometric) assay. May falsely elevate digoxin radioimmunoassays.

Medical considerations/contraindications—Menstrual abnormalities or breast enlargement.

Side/adverse effects:
Endocrine or antiandrogenic effects more common at doses exceeding 100 mg per day. May cause CNS effects and causes more frequent gastrointestinal irritation.

Additional Dosing Information
See also General Dosing Information.

To reduce delay in onset of effect, a loading dose of 2 to 3 times the daily dose may be administered on the first day of therapy.

When spironolactone is added to therapy with another diuretic or antihypertensive agent, it is recommended that the dosage of the other drug (especially ganglionic blocking agents) be reduced by at least 50% and then adjusted as required. {02}

It is recommended that spironolactone be discontinued several days prior to adrenal vein catheterization for measurement of aldosterone concentrations, for the purpose of attempting lateralization in primary hyperaldosteronism, and for measurements of plasma renin activity. {01}

When high doses of spironolactone are required for treatment of edema due to hepatic cirrhosis, drug dosage may be reduced prior to completion of diuresis to avoid dehydration and precipitation of hepatic coma, although dry weight may be achieved.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

SPIRONOLACTONE TABLETS USP

Usual adult dose
Edema due to congestive heart failure, hepatic cirrhosis, or nephrotic syndrome
Initial: Oral, 25 to 200 mg a day in two to four divided doses for at least five days, when used as monotherapy for diuresis{43}.

Maintenance: Oral, adjusted to meet individual requirements{43}.

Antihypertensive
Initial: Oral, 50 to 100 mg a day as a single daily dose or in two to four divided doses for at least two weeks, followed by gradual dosage adjustment every two weeks as necessary up to 200 mg a day. {01}{43}

Maintenance: Oral, adjusted to meet individual requirements. {01}{43}

Primary hyperaldosteronism
Maintenance: Oral, 100 to 400 mg per day in two to four divided daily doses prior to surgery; smaller doses may be used for long-term maintenance in patients unsuitable for surgery. {01}{43}

[Congestive heart failure treatment adjunct ]1
Oral, 25 mg to 50 mg once daily. {44}{46}

[Polycystic ovary disease ]
Oral, 100 to 200 mg per day in two divided daily doses. {29} {30} {31}

[Hirsutism, female]
Oral, 100 mg two times a day. {22} {31}

Diagnostic aid (primary hyperaldosteronism)
Long test: Oral, 400 mg per day in two to four divided daily doses for three to four weeks. {01}{43}

Short test: Oral, 400 mg per day in two to four divided daily doses for four days. {01}{43}

Antihypokalemic
Diuretic-induced hypokalemia: Oral, 25 to 100 mg per day as a single daily dose or in two to four divided doses. {01}{43}

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Usual adult prescribing limits
Dose may be increased up to three times the initial dose or up to a maximum of 400 mg a day.

Usual pediatric dose
Edema
Ascites or
Hypertension
Initial: Oral, 1 to 3 mg per kg of body weight {04} or 30 to 90 mg per square meter of body surface a day as a single daily dose or in two to four divided doses, the dosage being readjusted after five days. {11} Dosage may be increased up to three times the initial dose. {01}

Strength(s) usually available
U.S.—

25 mg (Rx) [Aldactone][Generic] (may be scored )

50 mg (Rx) [Aldactone (scored)]

100 mg (Rx) [Aldactone (scored)]

Canada—

25 mg (Rx) [Aldactone (scored)] [Novospiroton (scored)]

100 mg (Rx) [Aldactone (scored)] [Novospiroton (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Preparation of dosage form:
For patients who cannot take oral solids—For small children or patients unable to swallow the tablets, Spironolactone Tablets USP may be crushed and dispensed as a suspension in Cherry Syrup NF. This suspension is stable in a refrigerator for 1 month.

Auxiliary labeling:
• Take with meals or milk.
• Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.

TRIAMTERENE

Summary of Differences

Pharmacology/pharmacokinetics:
Biotransformation—Hepatic.

Duration of action—Diuretic: Single dose—7 to 9 hours.

Precautions:
Drug interactions and/or related problems—Triamterene may increase blood uric acid and antagonize allopurinol, colchicine, probenecid, or sulfinpyrazone.

Laboratory value alterations—May interfere with fluorescent measurement of quinidine.

Medical considerations/contraindications—Hyperuricemia or gout; history of nephrolithiasis.

Side/adverse effects:
Nephrolithiasis; megaloblastosis; photosensitivity; thrombocytopenia. No decrease in sexual ability reported.

Additional Dosing Information
See also General Dosing Information.

Since triamterene is a weak folic acid antagonist, it may contribute to development of megaloblastosis in patients who have depleted folic acid stores (e.g., in pregnancy, hepatic cirrhosis). {05}{38}

When triamterene is combined with another diuretic, it is recommended that the initial dosage of each be reduced and then adjusted as required. {05}{38}

Oral Dosage Forms

TRIAMTERENE CAPSULES USP

Usual adult dose
Diuretic
Initial: Oral, 100 mg twice daily when used alone as monotherapy.

Maintenance: Oral, adjusted to meet individual requirements.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Usual adult prescribing limits
Up to 300 mg daily. {05}{38}

Usual pediatric dose
Diuretic
Initial: Oral, 2 to 4 mg per kg of body weight {04} {11} or 120 mg per square meter of body surface a day or on alternate days in divided doses.

Maintenance: Oral, increased to 6 mg per kg of body weight a day according to individual requirements up to a maximum of 300 mg a day in divided doses.

Strength(s) usually available
U.S.—

50 mg (Rx) [Dyrenium (lactose)]

100 mg (Rx) [Dyrenium (lactose)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
• Take with meals or milk.
• Avoid overexposure to sun or use of sunlamp.
• Do not take other medicines without your doctor's advice.

TRIAMTERENE TABLETS

Usual adult dose
Diuretic
Initial: Oral, 25 to 100 mg a day.

Maintenance: Oral, adjusted to meet individual requirements.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Usual adult prescribing limits
Up to 300 mg daily. {06}

Usual pediatric dose
Diuretic
Initial: Oral, 2 to 4 mg per kg of body weight or 120 mg per square meter of body surface a day or on alternate days in divided doses. {11}

Maintenance: Oral, increased to 6 mg per kg of body weight a day according to individual requirements up to a maximum of 300 mg a day in divided doses.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—

50 mg (Rx) [Dyrenium]

100 mg (Rx) [Dyrenium (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
• Take with meals or milk.
• Avoid overexposure to sun or use of sunlamp.
• Do not take other medicines without your doctor's advice.

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