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DIURETICS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Diuretics promote the excretion of water and electrolytes by the kidney.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) THIAZIDE DIURETICS
    a) Bendroflumethiazide (synonym)
    b) Benzthiazide (synonym)
    c) Chlorothiazide (synonym)
    d) Chlorthalidone (synonym)
    e) Clopamide (synonym)
    f) Clorexolone (synonym)
    g) Cyclopenthiazide (synonym)
    h) Cyclothiazide (synonym)
    i) Fenquizone (synonym)
    j) Hydrochlorothiazide (synonym)
    k) Hydroflumethiazide (synonym)
    l) Indapamide (synonym)
    m) Mefruside (synonym)
    n) Methyclothiazide (synonym)
    o) Metolazone (synonym)
    p) Polythiazide (synonym)
    q) Quinethazone (synonym)
    r) Trichlormethiazide (synonym)
    s) Xipamide (synonym)
    2) LOOP DIURETICS
    a) Azosemide (synonym)
    b) Bumetanide (synonym)
    c) Ethacrynic acid (synonym)
    d) Etozolin (synonym)
    e) Furosemide (synonym)
    f) Muzolimine (synonym)
    g) Ozolinone (synonym)
    h) Piretanide (synonym)
    i) Torasemide (synonym)
    3) MERCURIAL DIURETICS
    a) Chlormerodrin (synonym)
    b) Meralluride (synonym)
    c) Mercaptomerin (synonym)
    d) Mersalyl (synonym)
    4) OSMOTIC DIURETICS
    a) Levulose (synonym)
    b) Mannitol (synonym)
    c) Urea (synonym)
    5) MISCELLANEOUS AGENTS
    a) Pamabrom (synonym)
    1.2.1) MOLECULAR FORMULA
    1) BENDROFLUMETHIAZIDE: C15H14F3N3O4S2
    2) BUMETANIDE: C17H20N2O5S
    3) CHLOROTHIAZIDE: C7H6ClN3O4S2
    4) CHLORTHALIDONE: C14H11ClN2O4S
    5) ETHACRYNIC ACID: C13H12Cl2O4
    6) FUROSEMIDE: C12H11ClN2O5S
    7) HYDROCHLOROTHIAZIDE: C7H8ClN3O4S2
    8) INDAPAMIDE: C16H16ClN3O3S
    9) MANNITOL: C6H14O6
    10) METHYCLOTHIAZIDE: C9H11Cl2N3O4S2
    11) METOLAZONE: C16H16ClN3O3S

Available Forms Sources

    A) FORMS
    1) MERCURIAL DIURETICS
    a) MERSALYL (Theo-syl-r(R)): 100 mg/mL with theophylline 50 mg/mL
    2) THIAZIDE DIURETICS
    a) BENDROFLUMETHIAZIDE (Naturetin(R)): 2.5, 5, and 10 mg tablets
    b) BENZTHIAZIDE (Aquatag(R)): 25 and 50 mg tablets
    c) CHLOROTHIAZIDE (Diuril(R)): 250 and 500 mg tablets; 250 mg/5 mL oral suspension; 500 mg/vial for injection
    d) CHLORTHALIDONE (Hygroton(R)): 25, 50, and 100 mg tablets
    e) CYCLOTHIAZIDE (Anhydron(R)): 2 mg tablets
    f) HYDROCHLOROTHIAZIDE (HydroDiuril(R)): 25, 50, and 100 mg tablets
    g) HYDROFLUMETHIAZIDE (Saluron(R)): 50 mg tablets
    h) INDAPAMIDE (Lozol(R)): 2.5 mg tablets
    i) METHYCLOTHIAZIDE (Enduron(R); Aquatensin(R)): 2.5 and 5 mg tablets
    j) METOLAZONE (Diulo(R); Zaroxolyn(R)): 2.5, 5, and 10 mg tablets
    k) POLYTHIAZIDE (Renese(R)): 1, 2, and 4 mg tablets
    l) QUINETHAZONE (Hydromox(R)): 50 mg tablets
    m) TRICHLORMETHIAZIDE (Naqua(R)): 2 and 4 mg tablets
    3) LOOP DIURETICS
    a) BUMETANIDE (Bumex(R)): 0.5, 1, and 2 mg tablets; 0.25 mg/mL injection
    b) ETHACRYNIC ACID (Edecrin(R)): 25 and 50 mg tablets; 50 mg/vial for injection
    c) FUROSEMIDE (Lasix(R)): 20, 40, and 80 mg tablets; 10 mg/mL oral solution; 10 mg/mL injection
    4) MISCELLANEOUS: PAMABROM (Fluidex with Pamabrom(R)): 50 mg capsules

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Class of drugs that are primarily used to treat hypertension and congestive heart failure. Potassium sparing diuretics and carbonic anhydrase inhibitors are covered in separate managements.
    B) PHARMACOLOGY: Work in a variety of mechanisms including inhibiting sodium and chloride reabsorption in the distal convoluted tubule (thiazides), inhibiting transport of sodium, potassium, and chloride in the thick ascending limb of the loop of henle (loop), and osmotic agents (mannitol).
    C) TOXICOLOGY: Produce hypovolemia and electrolyte deficiencies.
    D) EPIDEMIOLOGY: Rare overdose which uncommonly results in significant morbidity or death.
    E) WITH THERAPEUTIC USE
    1) Thiazides are associated with hyperglycemia and hyperlipidemia. Furosemide has been associated with ototoxicity, hyperglycemia, and hypercholesterolemia. Diuretics have a large number of drug interactions as well. Extravasation of mannitol can cause tissue injury and compartment syndrome.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild dehydration, tachycardia, dry mucous membranes, headache, muscle cramps, thirst, and brisk diuresis. Large doses of furosemide or ethacrynic acid can cause ototoxicity.
    2) SEVERE TOXICITY: Hypotension, hypochloremic metabolic alkalosis, mental status changes, and electrolyte abnormalities (i.e. hypokalemia, hypomagnesemia, hypochloremia, hypocalcemia) are the most common manifestations of severe poisoning. Rarely muscle spasms, tetany, seizures, coma, or dysrhythmias may develop secondary to severe electrolyte abnormalities. CNS depression has been reported rarely in children with acute ingestion without significant electrolyte abnormalities.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Recurrent fever has been associated with furosemide use.
    0.2.20) REPRODUCTIVE
    A) Aliskiren/amlodipine besylate/hydrochlorothiazide, aliskiren/hydrochlorothiazide, amlodipine/hydrochlorothiazide/valsartan, azilsartan medoxomil/chlorthalidone, benazepril/hydrochlorothiazide, and irbesartan/hydrochlorothiazide are classified as FDA pregnancy category D.
    B) ACE inhibitor/hydrochlorothiazide and angiotensin II antagonist/hydrochlorothiazide combination products are classified as FDA pregnancy category C for the first trimester and category D for the second and third trimesters.
    C) Bendroflumethiazide, bumetanide, chlorothiazide, furosemide, mannitol inhalation powder, metoprolol/hydrochlorothiazide, propranolol/hydrochlorothiazide, spironolactone/hydrochlorothiazide, and triamterene/hydrochlorothiazide are classified as FDA pregnancy category C.
    D) Chlorthalidone, ethacrynic acid, hydrochlorothiazide, indapamide, mannitol solution for irrigation and iv injection, metolazone, methyclothiazide, and torsemide are classified as FDA pregnancy category B.

Laboratory Monitoring

    A) Monitor vital signs and serum electrolytes.
    B) Obtain an ECG in patients with significant electrolyte abnormalities.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with minor symptoms can be managed with supportive care only. Oral hydration and oral electrolyte supplementation may be sufficient. Severe electrolyte disturbances and/or mental status changes indicate a more severe poisoning.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity is very rare. Treatment should be directed at intravenous correction of volume loss and electrolyte abnormalities.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is not indicated as toxicity is rare.
    2) HOSPITAL: Activated charcoal is rarely indicated as acute toxicity is rare.
    D) AIRWAY MANAGEMENT
    1) Diuretic poisoning should not produce symptoms mandating airway management.
    E) ANTIDOTE
    1) There is no specific antidote.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is not expected to be helpful.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent ingestion of less than a maximal daily dose can be monitored at home.
    2) OBSERVATION CRITERIA: Adults with intentional ingestions or symptomatic children should be referred to a health care facility. Patients who are asymptomatic after 6 hours can be discharged home.
    3) ADMISSION CRITERIA: Patients who have severe electrolyte abnormalities or vital sign abnormalities should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    H) PITFALLS
    1) Some preparations contain supplemental potassium; hyperkalemia may develop. Severe toxicity is rare. Aggressive treatment is rarely necessary.
    I) PHARMACOKINETICS
    1) Orally administered, furosemide has a half-life of 1.5 to 2 hours, reaches peak concentration in 1 to 2 hours, has a duration of 6 to 8 hours, is 95% protein bound, and is renally excreted. Hydrochlorothiazide has a half-life of approximately 5 to 15 hours, reaches peak concentration in 3 to 6 hours, has a duration of 6 to 12 hours, is 40% to 60% protein bound, and is renally excreted.
    J) TOXICOKINETICS
    1) Duration of action may be expected to be increased in overdose and if renal insufficiency results from hypovolemia.
    K) DIFFERENTIAL DIAGNOSIS
    1) The primary differential would be hypovolemia or hypotension from other causes.

Range Of Toxicity

    A) Toxic doses are not well established. Diuresis is expected to result at even therapeutic doses. Toxicity is most common with chronic dosing and acute toxicity is often related to other factors such as comorbid conditions and access to fluid replacement.
    B) THERAPEUTIC DOSE: Furosemide is typically dosed at 20 to 80 mg with repeat doses as necessary in adults; pediatric dose is 1 to 2 mg/kg orally. Hydrochlorothiazide is typically dosed at 12.5 to 50 mg daily in adults; pediatric dose is 1 to 3 mg/kg divided twice daily.

Clinical Effects

Summary Of Exposure

    A) USES: Class of drugs that are primarily used to treat hypertension and congestive heart failure. Potassium sparing diuretics and carbonic anhydrase inhibitors are covered in separate managements.
    B) PHARMACOLOGY: Work in a variety of mechanisms including inhibiting sodium and chloride reabsorption in the distal convoluted tubule (thiazides), inhibiting transport of sodium, potassium, and chloride in the thick ascending limb of the loop of henle (loop), and osmotic agents (mannitol).
    C) TOXICOLOGY: Produce hypovolemia and electrolyte deficiencies.
    D) EPIDEMIOLOGY: Rare overdose which uncommonly results in significant morbidity or death.
    E) WITH THERAPEUTIC USE
    1) Thiazides are associated with hyperglycemia and hyperlipidemia. Furosemide has been associated with ototoxicity, hyperglycemia, and hypercholesterolemia. Diuretics have a large number of drug interactions as well. Extravasation of mannitol can cause tissue injury and compartment syndrome.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild dehydration, tachycardia, dry mucous membranes, headache, muscle cramps, thirst, and brisk diuresis. Large doses of furosemide or ethacrynic acid can cause ototoxicity.
    2) SEVERE TOXICITY: Hypotension, hypochloremic metabolic alkalosis, mental status changes, and electrolyte abnormalities (i.e. hypokalemia, hypomagnesemia, hypochloremia, hypocalcemia) are the most common manifestations of severe poisoning. Rarely muscle spasms, tetany, seizures, coma, or dysrhythmias may develop secondary to severe electrolyte abnormalities. CNS depression has been reported rarely in children with acute ingestion without significant electrolyte abnormalities.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Recurrent fever has been associated with furosemide use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: A 5-month-old developed recurrent fever associated with furosemide use (Clegg & Riopel, 1995).

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) FUROSEMIDE/ETHACRYNIC ACID can cause ototoxicity following large oral or intravenous doses, and particularly when IV administration is too rapid in renal failure patients. Hearing loss is generally reversible, resolving within 24 hours. Most cases have occurred after chronic therapeutic ingestion(Gallagher & Jones, 1979).
    2) BUMETANIDE may cause less ototoxicity than furosemide. Tuzel (1981) reported drug-related hearing loss in 2 of 179 bumetanide-treated patients (1%) as compared to 4 of 62 furosemide-treated patients (6.4%) (Tuzel, 1981).
    a) Hearing loss was defined as a 15 decibel decrease in hearing during drug therapy.
    B) WITH POISONING/EXPOSURE
    1) One case of ototoxicity due to furosemide/ethacrynic acid overdose has been reported (Gallagher & Jones, 1979).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One case of death due to ventricular dysrhythmias after IV injection of furosemide has been reported (Dagli & Moos, 1983).
    b) STUDY (CHRONIC USE): In a retrospective analysis of 6797 patients with an ejection fraction of less than 36%, those patients receiving a diuretic were more likely to die secondary to dysrhythmias than those not taking a diuretic (RR 1.37; 95% CI 1.08 to 1.73 after controlling for covariates such as disease severity, comorbid illness, concomitant medications). Only potassium-losing diuretics were independently associated with death secondary to dysrhythmias (RR 1.33; 95% CI 1.05 to 1.69) (Cooper et al, 1999).
    B) ATRIOVENTRICULAR BLOCK
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One case with premature atrial complexes and varying degrees of atrioventricular block associated with high-dose (75 mg/day) hydrochlorothiazide therapy has been reported (Zahid et al, 1988).
    C) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Two patients suffered syncopal episodes associated with fasting and high-dose of furosemide infusion (Niezgoda et al, 1989).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Orthostatic hypotension may develop secondary to volume depletion (Wilcox, 1999; Greenberg, 2000).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Pulmonary edema has been reported in several cases after therapeutic ingestion of hydrochlorothiazide (Grace et al, 1989; Kavaru et al, 1990; Klein, 1987; Fine et al, 1995) Bernal & Patarco, 1999), and in a 19-year-old man who received 400 grams of 10% mannitol (4,000 mL) over 2.5 hours (Huff, 1990).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HYPONATREMIA
    1) WITH POISONING/EXPOSURE
    a) HYPONATREMIA-RELATED FINDINGS: Confusion, headache, hypertonia, muscle weakness, stupor, coma, or seizures may develop secondary to diuretic-induced hyponatremia (Ashral et al, 1981; (Bain et al, 1986) Zahid et al, 1988).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Intoxication resulting in coma has been reported after normal doses of mannitol (Feldman, 1971).
    b) CASE REPORT: Lethargy progressing to coma was reported in 2 children who ingested 15 grams of chlorothiazide and had no evidence of fluid/electrolyte disorder (Bass & Beisel, 1963).
    c) CASE REPORT: Lethargy was also reported in a 22-month-old child who ingested 3 grams of chlorothiazide (Rougraff, 1959).
    C) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) Weakness may develop secondary to hyponatremia or hypokalemia.
    b) CASE REPORT: A 15-year-old girl presented with dizziness, muscle weakness and hypokalemic, hypochloremic metabolic alkalosis (serum potassium 2.1 mmol/L and serum chloride 91 mmol/L) after taking her father's furosemide for several months in an attempt to lose weight. She admitted to taking 1 to 2 tablets at night every 3 to 4 days. A urine assay was positive for furosemide at a level of 7 mcg/mL (normal range up to 1 mcg/mL) (Seifert & Rasoulpour, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) BLEEDING has been reported with ethacrynic acid use.
    B) PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Pancreatitis was reported in a 29-year-old woman who chronically abused thiazide diuretics (Spratt & Pont, 1982).
    C) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) Abdominal distention, hyperperistalsis, and flatus were reported in 2 young children, who ingested a total of 15 g of chlorothiazide (Bass & Beisel, 1963).
    D) PERFORATION OF INTESTINE
    1) WITH THERAPEUTIC USE
    a) Mannitol has caused fatal colonic perforation when used orally as a purgative (Moses, 1988).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) MANNITOL has been implicated in the development of renal failure in several case reports (Gerkin & Curry, 1987; Horgan et al, 1989; Rello et al, 1989) Weaver & Domenic, 1987), as well as in a series of 8 patients receiving the drug (Dorman et al, 1990).
    b) Hydrochlorothiazide in combination with triamterene was reported to cause acute interstitial nephritis that resulted in nonoliguric renal failure. Deposition of triamterene crystals in renal tubules was the proposed mechanism. Complete recovery of renal function occurred (Farge et al, 1986).
    B) ABNORMAL URINE
    1) WITH THERAPEUTIC USE
    a) Green discoloration of the urine was reported secondary to the use of an over the counter diuretic product Diurex(R) (contains calcium sulfate, dicalcium sulfate, magnesium trisilicate, microcrystalline cellulose, magnesium stearate, potassium salicylate and stearic acid) (Joshi, 2000).
    C) KIDNEY FINDING
    1) WITH THERAPEUTIC USE
    a) PSEUDO-BARTTER'S SYNDROME, as evident by hypokalemia, elevated plasma renin activity and plasma aldosterone, normal blood pressure despite elevated plasma angiotensin II concentrations, and hyperplasia of the juxtaglomerular apparatus, developed in a 21-year-old patient following chronic abuse of furosemide. The patient ingested 40 to 160 mg/day of furosemide for 16 months (Mizuiri et al, 1987).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ALKALOSIS
    1) WITH THERAPEUTIC USE
    a) HYPOCHLOREMIC ALKALOSIS may occur following chronic therapeutic use or abuse of thiazide and loop diuretics (Morgan & Davidson, 1980; (Spratt & Pont, 1982; Brucato et al, 1993; Greenberg, 2000).
    b) CASE REPORT: A 15-year-old girl developed hypokalemic, hypochloremic metabolic alkalosis (serum potassium 2.1 mmol/L and serum chloride 91 mmol/L) after taking her father's furosemide for several months in an attempt to lose weight. She admitted to taking 1 to 2 tablets at night every 3 to 4 days. A urine assay was positive for furosemide at a level of 7 mcg/mL (normal range up to 1 mcg/mL) (Seifert & Rasoulpour, 2009).
    c) CASE REPORT: Metabolic alkalosis (pH 7.54, HCO3 31.4 mmol/L, pCO2 36.1 mmHg) was reported in a 22-year-old woman who reportedly ingested 250 mg furosemide per day for 4 months. With supportive care, she recovered without sequelae (Ruisz et al, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 24-year-old patient who ingested 15 to 20 tablets each of methyldopa and hydrochlorothiazide developed hemolytic anemia 2 days following ingestion. Antiglobulin tests demonstrated a relationship to the thiazide and not to methyldopa (PC Monograph, 1984).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 17-year-old girl, with carbosulfan poisoning, developed right forearm compartment syndrome, manifested by edema, cyanosis, tenseness, tenderness, and elevated compartment pressure, resulting from extravasation of a 20% mannitol infusion. The patient recovered without sequelae following surgical intervention (Eroglu & Uzunlar, 2004).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 24-year-old woman developed tetany, muscle spasms, carpopedal spasm, facial grimacing and polyuria. She had a history of chronic furosemide abuse (12.5 mg/day for the month prior to admission and 375 mg ingested about 18 hours prior to admission). Laboratory studies demonstrated metabolic alkalosis, hypocalcemia (ionized Ca 0.91 mmol/L), hypokalemia (2.3 mmol/L) and hypomagnesemia (0.4 mmol/L). She developed rhabdomyolysis. Tetany and muscle spasms improved slightly with potassium and calcium infusion but improved dramatically with magnesium supplementation (Brucato et al, 1993).
    b) CASE REPORT: A 22-year-old woman presented with myalgias (10-day history), vomiting and diarrhea (4-day history), and dizziness with generalized weakness (3-day history). Laboratory data revealed severe hypokalemia (1.1 mmol/L), hyponatremia, metabolic alkalosis, mild renal dysfunction , and a creatine phosphokinase concentration of 15,996 units/L (normal, less than 144 units/L). An ECG demonstrated ST abnormalities and QT interval prolongation. Approximately 12 hours post-admission, the patient revealed that she had been taking 250 mg of furosemide per day for the last 4 months to improve the shape of her muscles. With electrolyte replacement, the patient gradually recovered with normalization of lab values and resolution of her ECG abnormalities. She was discharged approximately 7 days later without sequelae (Ruisz et al, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia has been reported with thiazide use (Lowder et al, 1988).
    b) Long term diuretic use to treat hypertension has recently been associated with the development of type 2 diabetes (Verdecchia et al, 2004).
    c) CASE REPORT: Hyperglycemia (521 mg/dL; reference range 70 to 120 mg/dL) occurred in a 26-year-old bodybuilder who had ingested 2 80-mg furosemide 24 and 48 hours before a body building competition (Mayr et al, 2012).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) HYPERSENSITIVITY reactions may occur, but are considered rare.
    1) Idiosyncratic reactions including skin rash, urticaria, photosensitivity, jaundice, necrotizing vasculitis, bone marrow depression, and pulmonary edema associated with leukopenia and thrombocytopenia have been reported with hydrochlorothiazide (Prupas & Brown, 1983).
    2) Rare cases of death after IV administration to elderly, debilitated adults have been reported (Dagli & Moos, 1983; David & Hitzig, 1971; Machety, 1968).

Reproductive

    3.20.1) SUMMARY
    A) Aliskiren/amlodipine besylate/hydrochlorothiazide, aliskiren/hydrochlorothiazide, amlodipine/hydrochlorothiazide/valsartan, azilsartan medoxomil/chlorthalidone, benazepril/hydrochlorothiazide, and irbesartan/hydrochlorothiazide are classified as FDA pregnancy category D.
    B) ACE inhibitor/hydrochlorothiazide and angiotensin II antagonist/hydrochlorothiazide combination products are classified as FDA pregnancy category C for the first trimester and category D for the second and third trimesters.
    C) Bendroflumethiazide, bumetanide, chlorothiazide, furosemide, mannitol inhalation powder, metoprolol/hydrochlorothiazide, propranolol/hydrochlorothiazide, spironolactone/hydrochlorothiazide, and triamterene/hydrochlorothiazide are classified as FDA pregnancy category C.
    D) Chlorthalidone, ethacrynic acid, hydrochlorothiazide, indapamide, mannitol solution for irrigation and iv injection, metolazone, methyclothiazide, and torsemide are classified as FDA pregnancy category B.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) TORSEMIDE
    a) At the time of this review, no adequate and well-controlled studies are available to assess the teratogenic potential of this agent (Prod Info Demadex oral tablets, 2010).
    B) EMBRYO/FETAL RISK
    1) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    a) Second or third trimester use of drugs that act on the renin-angiotensin system may reduce fetal renal function and increase the risk of fetal or neonatal morbidity and death. Resulting oligohydramnios have been associated with fetal lung hypoplasia and skeletal deformations. Neonatal adverse effects due to exposure during pregnancy may include skull hypoplasia, anuria, hypotension, renal failure or death (Prod Info BENICAR HCT(R) oral tablets, 2016).
    b) In rare cases when discontinuation of the drug is not an option, in addition to apprising the mothers of the potential hazards to their fetuses, conduct serial ultrasound examinations to assess the intraamniotic environment. Depending on the week of pregnancy, fetal testing may be considered. If oligohydramnios is noted, discontinue use unless it is considered lifesaving for the mother. It should be noted that oligohydramnios may not be evident until after the fetus has experienced irreversible injury. Closely monitor infants with histories of in utero exposure to an angiotensin II receptor antagonist for hypotension, oliguria, and hyperkalemia (Prod Info BENICAR HCT(R) oral tablets, 2016).
    C) FETAL GROWTH
    1) FUROSEMIDE
    a) Furosemide may increase the birth weight of the fetus; monitoring of fetal growth is required (Prod Info LASIX(R) oral tablets, 2010).
    D) FETAL/NEONATAL EFFECTS
    1) THIAZIDES
    a) Thiazides cross the placental barrier and appear in cord blood. Fetal and neonatal morbidity and death have occurred from the use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy. The drugs reduce fetal renal function and can result in oligohydramnios, which can be associated with fetal lung hypoplasia and skeletal deformations. Fetal or neonatal injuries may include skull hypoplasia, anuria, hypotension, renal failure, and death. These conditions usually manifest only with second- or third-trimester use. Other risks include fetal or neonatal jaundice, thrombocytopenia, and other reactions that can occur in adult patients (Prod Info HYZAAR(R) 50/12.5 oral tablets, 2014; Prod Info HYZAAR(R) 100/12.5 oral tablets, 2014; Prod Info HYZAAR(R) 100/25 oral tablets, 2014).
    E) ANIMAL STUDIES
    1) TORSEMIDE
    a) RATS, RABBITS: Animal reproduction studies in rats receiving torsemide doses of up to 5 mg/kg/day (10 times the human exposure of 20 mg/day on a mg/m(2) basis) and rabbits receiving doses of 1.6 mg/kg/day (1.7 times the human exposure) reported no teratogenicity or fetotoxicity. Toxicities such as decreased averaged body weight, delayed fetal ossification, and increase in fetal resorption were reported in rats given doses 5 times larger and in rabbits given doses 4 times larger (Prod Info Demadex oral tablets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) TORSEMIDE
    a) At the time of this review, no adequate and well-controlled studies are available to assess the potential effects of torsemide exposure during pregnancy in humans (Prod Info Demadex oral tablets, 2010).
    B) PREGNANCY CATEGORY
    1) The following combination products containing a diuretic have been classified as FDA pregnancy category D:
    1) Aliskiren/hydrochlorothiazide (Prod Info TEKTURNA HCT(R) oral tablets, 2008)
    2) Aliskiren/amlodipine besylate/hydrochlorothiazide (Prod Info Amturnide oral tablets, 2012)
    3) Amlodipine/hydrochlorothiazide/valsartan (Prod Info Exforge HCT(R) oral tablets, 2009)
    4) Azilsartan medoxomil/chlorthalidone (Prod Info EDARBYCLOR oral tablets, 2011)
    5) Benazepril/hydrochlorothiazide (Prod Info LOTENSIN HCT(R) oral tablets, 2007)
    6) Irbesartan/hydrochlorothiazide (Prod Info AVALIDE(R) oral tablets, 2007)
    7) Olmesartan medoxomil/hydrochlorothiazide (Prod Info BENICAR HCT(R) oral tablets, 2016).
    2) The following combination products containing a diuretic have been classified as FDA pregnancy category C (first trimester) and FDA category D (second and third trimesters):
    1) Enalapril/hydrochlorothiazide (Prod Info VASERETIC(R) oral tablets, 2007)
    2) Fosinopril/hydrochlorothiazide (Prod Info MONOPRIL(R)-HCT 10/12.5, MONOPRIL(R)-HCT 20/12.5 oral tablets, 2008)
    3) Lisinopril/hydrochlorothiazide (Prod Info PRINZIDE(R) oral tablets, 2008)
    4) Moexipril/hydrochlorothiazide (Prod Info UNIRETIC(R) oral tablets, 2003)
    5) Olmesartan/amlodipine/hydrochlorothiazide (Prod Info TRIBENZOR(R) oral tablets, 2010)
    6) Quinapril/hydrochlorothiazide (Prod Info ACCURETIC(TM) oral tablets, 2003)
    3) The following diuretics and combination products containing a diuretic have been classified as FDA pregnancy category C:
    1) Bendroflumethiazide (Prod Info NATURETIN(R) oral tablets, 2000)
    2) Bumetanide (Prod Info bumetanide oral tablets, 2004)
    3) Chlorothiazide (Prod Info DIURIL(R) oral suspension, 2007)
    4) Furosemide (Prod Info LASIX(R) oral tablets, 2010)
    5) Mannitol inhalation powder(Prod Info ARIDOL(TM) inhalation powder, 2010)
    6) Metoprolol tartrate/hydrochlorothiazide (Prod Info Lopressor HCT(R) oral tablet, 2009)
    7) Propranolol/hydrochlorothiazide (Prod Info INDERIDE(R) oral tablets, 2011)
    8) Spironolactone/hydrochlorothiazide (Prod Info Aldactazide(R) oral tablets, 2006)
    9) Triamterene/hydrochlorothiazide (Prod Info Dyazide(R) oral capsules, 2009)
    4) The following diuretics have been classified as FDA pregnancy category B:
    1) Chlorthalidone (Prod Info THALITONE(R) oral tablets, 2004)
    2) Ethacrynic acid (Prod Info EDECRIN(R) oral tablets, 2005)
    3) Hydrochlorothiazide (Prod Info hydrochlorothiazide gelatin coated oral capsule, 2009)
    4) Indapamide (Prod Info LOZOL(R) oral tablets, 2002)
    5) Mannitol solution for irrigation and IV injection (Prod Info mannitol IV injection, urologic irrigation, 2006)
    6) Metolazone (Prod Info ZAROXOLYN(R) oral tablets, 2003)
    7) Methyclothiazide (Prod Info Enduron(R), 2000)
    8) Torsemide (Prod Info Demadex oral tablets, 2010)
    C) EMBRYO/FETAL RISK
    1) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    a) Second or third trimester use of drugs that act on the renin-angiotensin system may reduce fetal renal function and increase the risk of fetal or neonatal morbidity and death. Resulting oligohydramnios have been associated with fetal lung hypoplasia and skeletal deformations. Neonatal adverse effects due to exposure during pregnancy may include skull hypoplasia, anuria, hypotension, renal failure or death (Prod Info BENICAR HCT(R) oral tablets, 2016).
    b) In rare cases when discontinuation of the drug is not an option, in addition to apprising the mothers of the potential hazards to their fetuses, conduct serial ultrasound examinations to assess the intraamniotic environment. Depending on the week of pregnancy, fetal testing may be considered. If oligohydramnios is noted, discontinue use unless it is considered lifesaving for the mother. It should be noted that oligohydramnios may not be evident until after the fetus has experienced irreversible injury. Closely monitor infants with histories of in utero exposure to an angiotensin II receptor antagonist for hypotension, oliguria, and hyperkalemia (Prod Info BENICAR HCT(R) oral tablets, 2016).
    D) THIAZIDES
    1) Thiazides cross the placental barrier and appear in cord blood. Fetal and neonatal morbidity and death have occurred from the use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy. The drugs reduce fetal renal function and can result in oligohydramnios, which can be associated with fetal lung hypoplasia and skeletal deformations. Fetal or neonatal injuries may include skull hypoplasia, anuria, hypotension, renal failure, and death. These conditions usually manifest only with second- or third-trimester use. Other risks include fetal or neonatal jaundice, thrombocytopenia, and other reactions that can occur in adult patients (Prod Info HYZAAR(R) 50/12.5 oral tablets, 2014; Prod Info HYZAAR(R) 100/12.5 oral tablets, 2014; Prod Info HYZAAR(R) 100/25 oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) TORSEMIDE
    a) At the time of this review, it is not known whether torsemide is excreted in human breast milk (Prod Info Demadex oral tablets, 2010).
    B) BREAST MILK
    1) Thiazides appear in breast milk. Because of the potential for harm to the nursing infant, the mother should stop using the drug or stop nursing, considering the importance of the drug to the mother's health (Prod Info Amturnide oral tablets, 2012; Prod Info hydrochlorothiazide gelatin coated oral capsule, 2009).
    2) Furosemide is excreted in human milk and may inhibit lactation (Prod Info LASIX(R) oral tablets, 2010).
    3) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    a) Thiazides are known to appear in human milk and olmesartan was excreted into the milk of lactating animals at low concentrations (Prod Info BENICAR HCT(R) oral tablets, 2016).
    b) Discontinue treatment or discontinue nursing, taking into account the importance of the drug to the mother (Prod Info BENICAR HCT(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) HYDROCHLOROTHIAZIDE
    a) MICE, RATS: There was no impact on mice or rat fertility when animals were fed before conception and during gestation doses of up to 100 mg/kg and 4 mg/kg, respectively, of hydrochlorothiazide (Prod Info hydrochlorothiazide gelatin coated oral capsule, 2009).
    2) TORSEMIDE
    a) RATS: No adverse effect on fertility was seen in male or female rats given doses up to 25 mg/kg per day (equivalent to 13 times a human dose of 20 mg on a body-surface-area basis) (Prod Info Demadex oral tablets, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and serum electrolytes.
    B) Obtain an ECG in patients with significant electrolyte abnormalities.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Carefully monitor serum electrolytes, glucose levels, uric acid levels, osmolality.
    B) HEMATOLOGIC
    1) Monitor CBC in patients with evidence of GI bleeding.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.
    b) Monitor ECG in patients with significant electrolyte abnormalities.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who have severe electrolyte abnormalities or vital sign abnormalities should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent ingestion of less than a maximal daily dose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Adults with intentional ingestions or symptomatic children should be referred to a health care facility. Patients who are asymptomatic after 6 hours can be discharged home.

Monitoring

    A) Monitor vital signs and serum electrolytes.
    B) Obtain an ECG in patients with significant electrolyte abnormalities.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not indicated as toxicity is rare.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Diuretic overdoses are generally benign, with the greatest risk being dehydration. Ototoxicity rarely occurs and is generally reversible. Emesis or gastric lavage may potentiate fluid and electrolyte disturbances and are unnecessary. If the ingestion is recent and substantial and/or the patient has risk factors for ototoxicity (renal, cardiac, or liver impairment, hypoproteinemia, concomitant ototoxic drug), administer activated charcoal (in aqueous solution without cathartic).
    B) ACTIVATED CHARCOAL
    1) Administration of 8 grams of activated charcoal 5 minutes after an oral dose of furosemide 40 milligrams prevented 99.5% of absorption in healthy volunteers (Neuvonen et al, 1988).
    2) A subsequent study in a larger group of volunteers given water or charcoal demonstrated the importance of giving charcoal soon after ingestion. Efficacy diminished gradually from 15 to 45 minutes after ingestion and was no better than water alone 1 hour after ingestion (Kivisto & Neuvonen, 1990).
    3) If the ingestion is recent and substantial consider decontamination with activated charcoal (in aqueous solution without cathartic).
    4) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    5) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and serum electrolytes.
    2) Obtain an ECG in patients with significant electrolyte abnormalities.
    B) VENTRICULAR ARRHYTHMIA
    1) Primary therapy is the correction of electrolyte abnormalities, particularly hypokalemia and hypomagnesemia.
    2) SUMMARY
    a) In the setting of a diuretic overdose electrolyte abnormalities should be considered the most common reason for the development of dysrhythmias. Correction of electrolyte imbalance is the first line treatment.
    1) Dysrhythmias persisting despite correction of electrolyte imbalance may require treatment by standard advanced cardiac life support protocols.
    2) Following the correction of electrolyte abnormalities, Dysrhythmias should be treated if they are thought to be contributing to hemodynamic instability or the potential to produce hemodynamic instability.
    3) In most patients with normal electrolytes, PVCs will not require pharmacologic treatment. Pharmacological treatment of PVCs and most dysrhythmias may be accomplished by the use of lidocaine, or amiodarone.
    4) Atropine may be indicated when severe bradycardia is present. PVC's thought to represent an escape complex should NOT be pharmacologically suppressed since this could potentiate hemodynamic instability.

Enhanced Elimination

    A) HEMODIALYSIS
    1) A 65-year-old male with end-stage renal disease had a hydrochlorothiazide dialysance of 62.5 milliliters/minute (calculated). Symptoms cleared after the first dialysis (hydrochlorothiazide level 1.5 micrograms/milliliter) (Zahid et al, 1988).

Range Of Toxicity

Summary

    A) Toxic doses are not well established. Diuresis is expected to result at even therapeutic doses. Toxicity is most common with chronic dosing and acute toxicity is often related to other factors such as comorbid conditions and access to fluid replacement.
    B) THERAPEUTIC DOSE: Furosemide is typically dosed at 20 to 80 mg with repeat doses as necessary in adults; pediatric dose is 1 to 2 mg/kg orally. Hydrochlorothiazide is typically dosed at 12.5 to 50 mg daily in adults; pediatric dose is 1 to 3 mg/kg divided twice daily.

Therapeutic Dose

    7.2.1) ADULT
    A) DIURETIC CLASS
    1) OSMOTIC DIURETIC
    a) MANNITOL: The usual adult dose range is 50 to 200 g administered as an IV infusion over a 24-hour period; dose should be adjusted according to clinical response and toxicity. The rate of administration is adjusted to maintain a urine output of 30 to 50 mL/hr (Prod Info MANNITOL intravenous injection, 2009).
    2) LOOP DIURETIC
    a) BUMETANIDE
    1) ORAL: The usual daily dose is 0.5 to 2 mg orally as a single dose. If inadequate therapeutic response, a second or third daily dose may be administered at 4- to 5-hour intervals. Dosage should not exceed 10 mg/day (Prod Info bumetanide oral tablets, 2011).
    2) INJECTION: The recommended initial dose is 0.5 to 1 mg IV or IM. IV administration should be given over a period of 1 to 2 minutes. If inadequate therapeutic response, a second or third dose may be administered at 2- to 3-hour intervals. Dosage should not exceed 10 mg/day (Prod Info bumetanide intramuscular injection, intravenous injection, 2014).
    b) ETHACRYNIC ACID
    1) ORAL: The usual dose range is 50 to 200 mg daily (ie, the minimally effective dose) administered on a continuous or intermittent dosage schedule. Titration of the dose is usually in 25- to 50-mg increments in order to avoid rapid or substantial loss of fluids and electrolytes. Initial and maintenance doses of 200 mg twice daily may be necessary in patients with severe, refractory edema (Prod Info EDECRIN(R) oral tablets, 2005).
    2) INTRAVENOUS: The usual IV dose is 50 mg as a single dose. If required, a second dose may be administered. In critical situations, single doses not exceeding 100 mg have been administered (Prod Info SODIUM EDECRIN(R) IV injection, 2005).
    c) FUROSEMIDE
    1) ORAL:
    a) EDEMA: The recommended initial dose is 20 to 80 mg as a single dose. If the therapeutic response is not sufficient, the same dose may be given 6 to 8 hours later or the dose may be increased by 20 to 40 mg at intervals of at least 6 to 8 hours. If edema is clinically severe, dose may be carefully titrated up to 600 mg/day (Prod Info LASIX(R) oral tablets, 2016).
    b) HYPERTENSION: The recommended initial dose is 40 mg twice daily. The dose can then be adjusted according to individual patient response (Prod Info LASIX(R) oral tablets, 2016).
    2) INJECTION:
    a) EDEMA: The recommended initial dose is 20 to 40 mg IM or IV as a single dose administered over 1 to 2 minutes. If necessary, the same dose may be given 2 hours later. The dose may also be increased by 20 mg not sooner than 2 hours following the previous dose. After the single effective individual dose has been determined, the dose may be given once or twice daily on a routine basis in patients who are unable to take oral medications (Prod Info furosemide IV, IM injection, 2011).
    b) ACUTE PULMONARY EDEMA: The recommended initial dose is 40 mg given IV over a 1- to 2-minute period. If a satisfactory response is not achieved after 1 hour, the dose may be increased to 80 mg IV given over 1 to 2 minutes (Prod Info furosemide IV, IM injection, 2011).
    3) THIAZIDE DIURETICS
    a) CHLOROTHIAZIDE
    1) ORAL OR INJECTION:
    a) EDEMA: The usual dose is 500 to 1000 mg (10 to 20 mL) once or twice daily. In many patients, edema responds to chlorothiazide when administered as intermittent therapy (ie, on alternate days or on 3 to 5 days each week) (Prod Info chlorothiazide sodium intravenous injection, 2012; Prod Info DIURIL(R) oral suspension, 2011).
    2) ORAL:
    a) HYPERTENSION: The usual dose is 500 to 1000 mg (10 to 20 mL) per day administered as a single or divided dose. Although rare, some patients may require up to 2000 mg (40 mL) per day administered as divided doses (Prod Info DIURIL(R) oral suspension, 2011).
    b) CHLORTHALIDONE
    1) EDEMA: The recommended initial dose is 50 to 100 mg orally daily or 100 mg on alternate days. For maintenance doses, the dose may be adjusted according to individual patient response (Prod Info chlorthalidone oral tablets, 2006).
    2) HYPERTENSION: The recommended initial dose is 25 mg orally as a single daily dose. If the therapeutic response is not satisfactory, the dose may be increased up to a maximum of 100 mg once daily. For maintenance doses, the dose may be adjusted according to individual patient response (Prod Info chlorthalidone oral tablets, 2006).
    c) HYDROCHLOROTHIAZIDE
    1) EDEMA: The usual dose is 25 to 100 mg daily as a single or divided dose. In many patients, edema responds to hydrochlorothiazide when administered as intermittent therapy (ie, on alternate days or on 3 to 5 days each week) (Prod Info hydrochlorothiazide oral tablets, 2011)
    2) HYPERTENSION: The recommended initial dose is 25 mg orally once daily as a single dose. The dose may be increased up to 50 mg per day as a single or 2 divided doses, according to individual patient response. Doses exceeding 50 mg have been associated with marked serum potassium reductions. If coadministered with other antihypertensive drugs, doses of greater than 50 mg/day are generally not required (Prod Info hydrochlorothiazide oral tablets, 2011).
    d) INDAPAMIDE
    1) EDEMA (CONGESTIVE HEART FAILURE): The recommended initial dose is 2.5 mg orally as a single daily dose administered in the morning. If a satisfactory therapeutic response is not achieved after 1 week, the dose may be increased to 5 mg once daily (Prod Info indapamide oral tablets, 2012).
    2) HYPERTENSION: The recommended initial dose is 1.25 mg orally as a single daily dose administered in the morning. If a satisfactory therapeutic response is not achieved after 4 weeks, the dose may be increased to 2.5 mg once daily. If a satisfactory therapeutic response is still not achieved after 4 weeks at the 2.5-mg dose, the dose may be increased to 5 mg once daily(Prod Info indapamide oral tablets, 2012).
    e) METOLAZONE
    1) EDEMA: The recommended initial dose range is 5 to 20 mg orally once daily administered as a single dose; dose may then be adjusted based on individual response (Prod Info METOLAZONE oral tablets, 2015).
    2) HYPERTENSION: The recommended initial dose range is 2.5 to 5 mg orally once daily administered as a single dose; dose may then be adjusted based on individual response (Prod Info METOLAZONE oral tablets, 2015).
    3) NOTE: Do NOT interchange formulations bioequivalent to Zaroxolyn(R) and formulations bioequivalent to Mykrox(R) for one another (Prod Info METOLAZONE oral tablets, 2011).
    f) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    1) The recommended starting dose is olmesartan medoxomil 20 or 40 mg and hydrochlorothiazide 12.5 mg once daily. May be titrated up to olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg if necessary (Prod Info BENICAR HCT(R) oral tablets, 2016).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) BUMETANIDE
    a) INFANTS AND CHILDREN
    1) FLUID OVERLOAD OR HEART FAILURE: INTRAVENOUS AND ORAL: The usual pediatric dose is 0.01 to 0.1 mg/kg/dose IV or orally every 6 to 24 hours (van der Vorst et al, 2006; Robinson et al, 2005; Marshall et al, 1998; National High Blood Pressure Education Program Working Group, 1996). MAXIMUM DOSE: Should not exceed 1 mg/dose.
    2) HYPERTENSION: 0.02 to 0.05 mg/kg/day orally in 2 to 4 divided doses (divided every 6 to 12 hours). as adjunct therapy; reserve for children with HTN secondary to renal disease. MAXIMUM DOSE: 0.3 mg/kg/day (Robinson et al, 2005; National High Blood Pressure Education Program Working Group, 1996)
    3) Clinical experience with bumetanide in children is limited. Safety and effectiveness below the age of 18 have not been established (Prod Info bumetanide intramuscular injection, intravenous injection, 2014; Prod Info bumetanide oral tablets, 2011).
    2) CHLOROTHIAZIDE
    a) INFANTS LESS THAN 6 MONTHS OF AGE
    1) ORAL: The recommended dose is 20 to 30 mg/kg/day orally in 2 divided doses (Prod Info DIURIL(R) oral suspension, 2011; van der Vorst et al, 2006a; George & Friedman, 1986).
    b) INFANTS AND CHILDREN 6 MONTHS OF AGE AND OLDER
    1) ORAL: The recommended dose is 10 to 20 mg/kg/day orally in 2 divided doses or once daily (Prod Info DIURIL(R) oral suspension, 2011; Lowrie, 2000; Garin, 1987; Hymes & Warshaw, 1987; Witte et al, 1986; Hobbins et al, 1981). MAXIMUM DOSE: Should not exceed 2 g/day (Lowrie, 2000).
    2) INTRAVENOUS: Safety and efficacy of IV chlorothiazide in the pediatric or adolescent populations have not been established (Prod Info chlorothiazide sodium intravenous injection, 2012).
    3) CHLORTHALIDONE
    a) The safety and efficacy of chlorthalidone in the pediatric or adolescent population have not been established (Prod Info chlorthalidone oral tablets, 2006).
    4) ETHACRYNIC ACID
    a) ORAL: The initial dose is 25 mg. Careful stepwise increments of 25 mg should be made to achieve effective maintenance therapy(Prod Info EDECRIN(R) oral tablets, 2005).
    5) FUROSEMIDE
    a) INFANTS OR CHILDREN
    1) FLUID OVERLOAD: INTRAVENOUS: INITIAL DOSE: The recommended dose is 1 mg/kg/dose IV or IM administered slowly with close observation. Dose may be increased by 1 mg/kg no sooner than 2 hours after the previous dose until desired effect is obtained. MAXIMUM DOSE: Should not exceed 6 mg/kg/dose (Prod Info furosemide IV, IM injection, 2011) or 80 mg/dose (Prod Info furosemide intramuscular intravenous injection, 2008).
    2) CONTINUOUS IV INFUSION: The recommended dose is 0.1 mg/kg/hour and increase incrementally (increase by 0.1 mg/kg/hour every 2 to 12 hours) until desired urine output is obtained. MAXIMUM DOSE: Should not exceed 0.4 mg/kg/hr (van der Vorst et al, 2007; van der Vorst et al, 2001; Luciani et al, 1997; Singh et al, 1992).
    3) IV LOADING DOSE: An initial loading dose, 0.1 mg/kg (Luciani et al, 1997; Singh et al, 1992) or 1 mg/kg (van der Vorst et al, 2006a), has been used prior to the start of a continuous infusion.
    4) FLUID OVERLOAD: ORAL: The recommended dose is 1 to 2 mg/kg/dose orally 2 to 4 times per day depending on response. MAXIMUM DOSE: Should not exceed 6 mg/kg/dose (Prod Info LASIX(R) oral tablets, 2010; van der Vorst et al, 2006a; Lowrie, 2000; George & Friedman, 1986; Witte et al, 1986; McCann et al, 1985; Engle et al, 1978) or 600 mg/day (Lowrie, 2000).
    6) HYDROCHLOROTHIAZIDE
    a) INFANTS UNDER 6 MONTHS
    1) ORAL: The usual dose is 2 to 3 mg/kg/day orally in 2 divided doses or once daily (Prod Info hydrochlorothiazide oral tablets, 2011; van der Vorst et al, 2006a; Reusz et al, 1998; Voskaki et al, 1992; Stapleton et al, 1984).
    b) INFANTS OR CHILDREN
    1) ORAL: The usual dose is 1 to 2 mg/kg/day in 2 divided doses or once daily. MAXIMUM DOSE: Should not exceed 37.5 mg/day in infants up to 2 years of age or 100 mg/day in children 2 to 12 years of age (Prod Info hydrochlorothiazide oral tablets, 2011; van der Vorst et al, 2006a; Prod Info hydrochlorothiazide oral tablets, 2002). MAXIMUM DOSE: Should not exceed 200 mg/day (Lowrie, 2000; George & Friedman, 1986).
    7) INDAPAMIDE
    a) Safety and effectiveness in pediatric patients have not been established (Prod Info indapamide oral tablets, 2012).
    8) MANNITOL
    a) INTRAVENOUS: Safety and effectiveness of administration of solution from flexible containers have not been established in pediatric patients (Prod Info MANNITOL intravenous injection, 2009). However, mannitol has been administered in the pediatric population in select cases:
    b) REDUCTION OF INTRAOCULAR PRESSURE
    1) 1 to 2 g/kg/dose or 30 to 60 g/m(2) administered over 30 to 60 minutes (Prod Info MANNITOL intravenous injection, 2009).
    c) ANURIA OR OLIGURIA
    1) 0.25 to 2 g/kg/dose or 60 g/m(2) as a 15% to 20% solution over 2 to 6 hours; for persistent oliguria, no further drug should be given (Prod Info MANNITOL intravenous injection, 2009).
    d) INTRACRANIAL HYPERTENSION
    1) 1 to 2 g/kg/dose or 30 to 60 g/m(2) over a period of 30 to 60 minutes (Prod Info MANNITOL intravenous injection, 2009).
    e) ORAL INHALATION FOR BRONCHIAL CHALLENGE
    1) CHILDREN 6 YEARS OF AGE AND OLDER: One trial of oral inhalation capsules in graduated doses (0 mg, 5 mg, 10 mg, 20 mg, and 40 mg) with single use patient inhaler device until a positive response is achieved or all capsules are inhaled. Testing must be administer by a trained professional under the supervision of a physician (Prod Info ARIDOL(TM) inhalation powder, 2010).
    9) METOLAZONE
    a) Safety and effectiveness in pediatric patients have not been established in controlled, clinical trials. Metolazone data are limited in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus. The dose range was generally 0.05 mg/kg to 0.1 mg/kg administered once daily. A 1- to 2.8-kg weight loss and 150- to 300-cc increase in urine output generally occurred following doses in this range (Prod Info METOLAZONE oral tablets, 2015).
    10) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    a) Safety and efficacy in the pediatric population have not been established (Prod Info BENICAR HCT(R) oral tablets, 2016).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) ETHACRYNIC ACID: Ingestion of ethacrynic acid 2500 mg over several days in a 26-year-old man resulted in volume depletion, electrolyte imbalance, and decreased hemoglobin. A pulmonary embolism developed and the patient died (PC monograph, 1985a).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) CASE REPORTS
    a) HYDROCHLOROTHIAZIDE
    1) Ingestion of 50 mg of hydrochlorothiazide in a 3-year-old boy produced mild brief diuresis (Tech Info, 1982).
    b) CHLOROTHIAZIDE
    1) Two children, aged 2.5 and 3 years, ingested an estimated 375 mg of chlorothiazide. Both recovered uneventfully after receiving gastric lavage and potassium-containing oral fluids (PC Monograph, 1985b).
    2) Ingestion of 3000 mg of chlorothiazide produced lethargy and diuresis, but not electrolyte abnormalities, in a 2-year-old child (Rougraff, 1959).
    c) CHLORTHALIDONE
    1) Ingestion of chlorthalidone 3800 mg by a 2-year-old boy resulted in diuresis and hypokalemia (Tech Info, 1982).
    d) FUROSEMIDE
    1) A 31-year-old man developed syncope 5 hours after taking 160 mg furosemide; he recovered uneventfully after intravenous hydration (Niezgoda et al, 1989).
    2) A 25-year-old woman developed syncope, nausea, vomiting, and lightheadedness, with a serum sodium 132 and potassium 3.4, after taking furosemide 200 mg/day for 3 days in conjunction with fasting (Niezgoda et al, 1989).
    3) A 26-year-old man developed severe generalized muscle cramps, paralysis, and palpitations after ingesting 2 80-mg furosemide 24 and 48 hours before a body building competition. Laboratory analysis revealed severe hypokalemia (1.6 mmol/L; reference range 3.4 to 4.5 mmol/L), and an ECG indicated sinus tachycardia (115 bpm) and pronounced U waves associated with severe hypokalemia. Following supportive care, including potassium supplementation, the patient's condition improved after 7 hours, and he was discharged the following morning (Mayr et al, 2012).
    4) A 22-year-old woman presented with myalgias (10-day history), vomiting and diarrhea (4-day history), and dizziness with generalized weakness (3-day history). Laboratory data revealed severe hypokalemia (1.1 mmol/L), hyponatremia, metabolic alkalosis, mild renal dysfunction , and a creatine phosphokinase concentration of 15,996 units/L (normal, less than 144 units/L). An ECG demonstrated ST abnormalities and QT interval prolongation. Approximately 12 hours post-admission, the patient revealed that she had been taking 250 mg of furosemide per day for the last 4 months to improve the shape of her muscles. With electrolyte replacement, the patient gradually recovered with normalization of lab values and resolution of her ECG abnormalities. She was discharged approximately 7 days later without sequelae (Ruisz et al, 2013).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CHLOROTHIAZIDE
    1) LD50- (ORAL)MOUSE:
    a) 8.5 g/kg (PC Monograph, 1985b)
    2) LD50- (ORAL)RAT:
    a) >10 g/kg (PC Monograph, 1985b)
    B) ETHACRYNIC ACID
    1) LD50- (ORAL)MOUSE:
    a) 627 mg/kg (PC monograph, 1985a)
    C) HYDROCHLOROTHIAZIDE
    1) LD50- (ORAL)MOUSE:
    a) >10 g/kg (PC monograph, 1984)
    2) LD50- (ORAL)RAT:
    a) >10 g/kg (PC monograph, 1984)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Osmotic diuretics act by elevating the osmolarity of the glomerular filtrate, thereby hindering tubular reabsorption of water (Gilman et al, 1985).
    B) Loop diuretics inhibit sodium and chloride reabsorption, primarily in the ascending limb of the loop of Henle (Gilman et al, 1985).
    C) Thiazide diuretics inhibit tubular reabsorption of sodium and chloride by a direct action on the distal segment of the tubule (Gilman et al, 1985).

Physicochemical

Physical Characteristics

    A) ALISKIREN/HYDROCHLOROTHIAZIDE: Aliskiren hemifumarate is a white to slightly yellow crystalline powder that is highly soluble in water and soluble in phosphate buffer and n-Octanol. Hydrochlorothiazide is a white to off-white and practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; slightly soluble in water; sparingly soluble in methanol; and insoluble in ether, chloroform, and dilute mineral acids (Prod Info TEKTURNA HCT(R) oral tablets, 2010).
    B) AMLODIPINE/HYDROCHLOROTHIAZIDE/VALSARTAN: Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Hydrochlorothiazide is a white to off-white and practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; slightly soluble in water; sparingly soluble in methanol; and insoluble in ether, chloroform, and dilute mineral acids. Valsartan is a fine white to practically white powder, soluble in ethanol and methanol and slightly soluble in water (Prod Info Exforge HCT(R) oral tablets, 2009).
    C) BENAZEPRIL/HYDROCHLOROTHIAZIDE: Benazepril hydrochloride is a white to off-white crystalline powder, soluble in water (greater than 100 mg/mL), ethanol, and methanol. Hydrochlorothiazide is a white to off-white and practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; slightly soluble in water; sparingly soluble in methanol; and insoluble in ether, chloroform, and dilute mineral acids (Prod Info LOTENSIN HCT(R) oral tablets, 2007).
    D) BENDROFLUMETHIAZIDE: Bendroflumethiazide is a white crystalline powder that is soluble in alcohol and in sodium hydroxide; and insoluble in water, in hydrochloric acid, and in chloroform (Prod Info Corzide(R), 2001).
    E) BUMETANIDE: Bumetanide is a practically white powder (Prod Info BUMEX(R) oral tablets, 2009).
    F) CHLOROTHIAZIDE: Chlorothiazide is a white or practically white crystalline powder, readily soluble in dilute aqueous sodium hydroxide and slightly soluble in water; soluble in urine at about 150 mg per 100 mL at pH 7 (Prod Info DIURIL(R) oral suspension, 2007).
    G) CHLORTHALIDONE: Chlorthalidone is soluble in methanol, slightly soluble in alcohol, and practically insoluble in water, ether, and chloroform (Prod Info THALITONE(R) oral tablets, 2004).
    H) ENALAPRIL/HYDROCHLOROTHIAZIDE: Enalapril maleate is a white to off-white crystalline powder, freely soluble in methanol, soluble in ethanol, and sparingly soluble in water. Hydrochlorothiazide is a white or practically white crystalline powder, freely soluble in sodium hydroxide solution and slightly soluble in water (Prod Info VASERETIC(R) oral tablets, 2007).
    I) ETHACRYNIC ACID: Ethacrynic acid is a white or practically white crystalline powder, soluble in most organic solvents (such as alcohols, chloroform, and benzene), and very slightly soluble in water (Prod Info EDECRIN(R) oral tablets, 2005).
    J) FOSINOPRIL/HYDROCHLOROTHIAZIDE: Fosinopril sodium is a white to off-white crystalline powder, soluble (greater than 100 mg/mL) in water, in ethanol, and in methanol; slightly soluble in hexane. Hydrochlorothiazide is a white or practically white and practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide; slightly soluble in water; sparingly soluble in methanol; and insoluble in ether, chloroform, and dilute mineral acids (Prod Info MONOPRIL(R)-HCT 10/12.5, MONOPRIL(R)-HCT 20/12.5 oral tablets, 2008).
    K) FUROSEMIDE: Furosemide is a white to slightly yellow, odorless, crystalline powder, freely soluble in dilute alkali solutions, sparingly soluble in alcohol, practically insoluble in water, and insoluble in dilute acids (Prod Info furosemide oral tablets, oral solution, 2007).
    L) HYDROCHLOROTHIAZIDE: Hydrochlorothiazide is a white to off-white crystalline powder, freely soluble in sodium hydroxide solution and slightly soluble in water (Prod Info hydrochlorothiazide gelatin coated oral capsule, 2009).
    M) INDAPAMIDE: Indapamide is a white to yellow-white tetragonal crystalline powder, soluble in aqueous solutions of strong bases (Prod Info indapamide oral tablets, 2006).
    N) IRBESARTAN/HYDROCHLOROTHIAZIDE: Irbesartan is a white to off-white crystalline powder, slightly soluble in alcohol and methylene chloride and practically insoluble in water. Hydrochlorothiazide is a white or practically white crystalline powder, freely soluble in sodium hydroxide solution and slightly soluble in water (Prod Info AVALIDE(R) oral tablets, 2007).
    O) LISINOPRIL/HYDROCHLOROTHIAZIDE: Lisinopril is a white to off-white crystalline powder, soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol. Hydrochlorothiazide is a white or practically white crystalline powder, freely soluble in sodium hydroxide solution and slightly soluble in water (Prod Info PRINZIDE(R) oral tablets, 2008).
    P) MANNITOL: Mannitol is a white or almost white crystalline powder of free-flowing granules that is freely soluble in water and very slightly soluble in alcohol (Prod Info ARIDOL(TM) inhalation powder, 2010). Mannitol has an osmolar concentration of 1372 milliosmoles/L (calc) and a pH between 4.5 and 7 (5% solution) (Prod Info mannitol IV injection, urologic irrigation, 2006).
    Q) METHYCLOTHIAZIDE: Methyclothiazide is a white to practically white, basically odorless, crystalline powder that is slightly soluble in alcohol and very slightly soluble in water and chloroform (Prod Info methyclothiazide oral tablets, 2002).
    R) METOLAZONE: Metolazone is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic solvents (Prod Info metolazone oral tablets, 2006).
    S) MOEXIPRIL/HYDROCHLOROTHIAZIDE: Moexipril hydrochloride is a fine white to off-white powder, soluble at about 10% weight per volume in distilled water at room temperature. Hydrochlorothiazide is a white or practically white crystalline powder, freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide (Prod Info UNIRETIC(R) oral tablets, 2003).
    T) OLMESARTAN/AMLODIPINE/HYDROCHLOROTHIAZIDE: Olmesartan medoxomil is a white to light yellow-white powder or crystalline powder, sparingly soluble in methanol and practically insoluble in water. Amlodipine besylate is a white to off-white crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Hydrochlorothiazide is a white or practically white crystalline powder, freely soluble in sodium hydroxide solution and slightly soluble in water (Prod Info TRIBENZOR(R) oral tablets, 2010).
    U) QUINAPRIL/HYDROCHLOROTHIAZIDE: Quinapril hydrochloride is a white to off-white amorphous powder, freely soluble in aqueous solvents. Hydrochlorothiazide is a white to off-white crystalline powder, freely soluble in sodium hydroxide solution and slightly soluble in water (Prod Info ACCURETIC(TM) oral tablets, 2003).

Molecular Weight

    A) ALISKIREN/HYDROCHLOROTHIAZIDE: Aliskiren hemifumarate, 609.8 (free base, 551.8); hydrochlorothiazide 297.73 (Prod Info TEKTURNA HCT(R) oral tablets, 2010)
    B) AMLODIPINE/HYDROCHLOROTHIAZIDE/VALSARTAN: Amlodipine besylate 567.1; hydrochlorothiazide 297.73; valsartan 435.5 (Prod Info Exforge HCT(R) oral tablets, 2009)
    C) BENAZEPRIL/HYDROCHLOROTHIAZIDE: Benazepril hydrochloride 460.96; hydrochlorothiazide 297.73 (Prod Info LOTENSIN HCT(R) oral tablets, 2007)
    D) BENDROFLUMETHIAZIDE: 421.41 (Prod Info Corzide(R), 2001)
    E) BUMETANIDE: 364.41 (Prod Info BUMEX(R) oral tablets, 2009)
    F) CHLOROTHIAZIDE: 295.72 (Prod Info DIURIL(R) oral suspension, 2007)
    G) CHLORTHALIDONE: 338.76 (Prod Info THALITONE(R) oral tablets, 2004)
    H) ENALAPRIL/HYDROCHLOROTHIAZIDE: Enalapril maleate 492.53; hydrochlorothiazide 297.74 (Prod Info VASERETIC(R) oral tablets, 2007)
    I) ETHACRYNIC ACID: 303.14 (Prod Info EDECRIN(R) oral tablets, 2005)
    J) FOSINOPRIL/HYDROCHLOROTHIAZIDE: Fosinopril sodium 585.65; hydrochlorothiazide 297.73 (Prod Info MONOPRIL(R)-HCT 10/12.5, MONOPRIL(R)-HCT 20/12.5 oral tablets, 2008)
    K) FUROSEMIDE: 330.74 (Prod Info furosemide oral tablets, oral solution, 2007)
    L) HYDROCHLOROTHIAZIDE: 297.74 (Prod Info hydrochlorothiazide gelatin coated oral capsule, 2009)
    M) INDAPAMIDE: 365.84 (Prod Info indapamide oral tablets, 2006)
    N) IRBESARTAN/HYDROCHLOROTHIAZIDE: Irbesartan 428.5; hydrochlorothiazide 297.73 (Prod Info AVALIDE(R) oral tablets, 2007)
    O) LISINOPRIL/HYDROCHLOROTHIAZIDE: Lisinopril 441.52; hydrochlorothiazide 297.73 (Prod Info PRINZIDE(R) oral tablets, 2008)
    P) MANNITOL: 182.17 (Prod Info ARIDOL(TM) inhalation powder, 2010; Prod Info mannitol IV injection, urologic irrigation, 2006)
    Q) METHYCLOTHIAZIDE: 360.23 (Prod Info methyclothiazide oral tablets, 2002)
    R) METOLAZONE: 365.83 (Prod Info ZAROXOLYN(R) oral tablets, 2003)
    S) MOEXIPRIL/HYDROCHLOROTHIAZIDE: Moexipril hydrochloride 535.04; hydrochlorothiazide 297.74 (Prod Info UNIRETIC(R) oral tablets, 2003)
    T) OLMESARTAN/AMLODIPINE/HYDROCHLOROTHIAZIDE: Olmesartan medoxomil 558.6; amlodipine besylate 567.1; hydrochlorothiazide 297.73 (Prod Info TRIBENZOR(R) oral tablets, 2010)
    U) QUINAPRIL/HYDROCHLOROTHIAZIDE: Quinapril hydrochloride 474.98; hydrochlorothiazide 297.72 (Prod Info ACCURETIC(TM) oral tablets, 2003)

References

General Bibliography

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    55) Product Information: ACCURETIC(TM) oral tablets, quinapril hcl, hydrochlorothiazide oral tablets. Pfizer,Inc, New York, NY, 2003.
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    58) Product Information: Aldactazide(R) oral tablets, spironolactone and hydrochlorothiazide oral tablets. G.D. Searle LLC, New York, NY, 2006.
    59) Product Information: Amturnide oral tablets, aliskiren amlodipine hydrochlorothiazide oral tablets. Novartis Pharmaceuticals Corp. (per manufacturer), East Hanover, NJ, 2012.
    60) Product Information: BENICAR HCT(R) oral tablets, olmesartan medoxomil hydrochlorothiazide oral tablets. Daiichi Sankyo, Inc (per FDA), Parsippany, NJ, 2016.
    61) Product Information: BUMEX(R) oral tablets, bumetanide oral tablets. Validus Pharmaceuticals LLC, Parsippany, NJ, 2009.
    62) Product Information: Corzide(R), nadolol and bendroflumethiazide tablets. Monarch Pharmaceuticals, Bristol, TN, 2001.
    63) Product Information: DIURIL(R) oral suspension, chlorothiazide oral suspension. Merck & Co Inc, Whitehouse Station, NJ, 2007.
    64) Product Information: DIURIL(R) oral suspension, chlorothiazide oral suspension. Salix Pharmaceuticals, Inc. (per Manufacturer), Raleigh, NC, 2011.
    65) Product Information: Demadex oral tablets, torsemide oral tablets. Meda Pharmaceuticals, Somerset, NJ, 2010.
    66) Product Information: Dyazide(R) oral capsules, hydrochlorothiazide/triamterene oral capsules. GlaxoSmithKline, Research Triangle Park, NC, 2009.
    67) Product Information: EDARBYCLOR oral tablets, azilsartan medoxomil and chlorthalidone oral tablets. Takeda Pharmaceuticals America, Inc (Per Manufacturer), Deerfield, IL, 2011.
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    71) Product Information: HYZAAR(R) 100/12.5 oral tablets, losartan potassium hydrochlorothiazide oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    72) Product Information: HYZAAR(R) 100/25 oral tablets, losartan potassium hydrochlorothiazide oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    73) Product Information: HYZAAR(R) 50/12.5 oral tablets, losartan potassium hydrochlorothiazide oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    74) Product Information: INDERIDE(R) oral tablets, propranolol HCl and hydrochlorothiazide oral tablets. Akrimax Pharmaceuticals, LLC, Cranford, NJ, 2011.
    75) Product Information: LASIX(R) oral tablets, furosemide oral tablets. sanofi-aventis U.S. LLC (per FDA), Bridgewater, NJ, 2016.
    76) Product Information: LASIX(R) oral tablets, furosemide oral tablets. sanofi-aventis U.S. LLC, Bridgewater, NJ, 2010.
    77) Product Information: LOTENSIN HCT(R) oral tablets, benazepril hcl, hctz oral tablets. Novartis Pharmaceuticals Corporation, Suffern, NY, 2007.
    78) Product Information: LOZOL(R) oral tablets, indapamide oral tablets. Aventis Pharmaceuticals,Inc, Bridgewater, NJ, 2002.
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    90) Product Information: TRIBENZOR(R) oral tablets, olmesartan medoxomil amlodipine hydrochlorothiazide oral tablets. Daiichi Sankyo, Inc, Parsippany, NJ, 2010.
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    98) Product Information: chlorthalidone oral tablets, chlorthalidone oral tablets. Mylan Pharmaceuticals,Inc, Morgantown, WV, 2006.
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    103) Product Information: hydrochlorothiazide oral tablets, hydrochlorothiazide oral tablets. IVAX Pharmaceuticals,Inc., Miami, FL, 2002.
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