Furosemide

DESCRIPTION Furosemide is a diuretic which is an anthranilic acid derivative. Furosemide Tablets for oral administration contain furosemide as the active ingredient and the following inactive ingredients: corn starch NF, lactose monohydrate NF, magnesium stearate NF, pregelatinized starch NF, and talc USP. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. Furosemide is available as white-off white tablets for oral administration in dosage strengths of 20, 40 and 80 mg. Furosemide is a white to off-white odorless crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids. The structural formula is as follows: Tested by USP Dissolution Test 1. This is an image of the structural formula for furosemide.

INDICATIONS AND USAGE Edema Furosemide tablets are indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. Furosemide tablets are particularly useful when an agent with greater diuretic potential is desired. Hypertension Oral furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with furosemide alone.

Edema Furosemide tablets are indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. Furosemide tablets are particularly useful when an agent with greater diuretic potential is desired.

Hypertension Oral furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with furosemide alone.

CONTRAINDICATIONS Furosemide tablets are contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.

WARNING Furosemide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required and dose and dose schedule must be adjusted to the individual patient’s needs (see DOSAGE AND ADMINISTRATION ).

WARNINGS In patients with hepatic cirrhosis and ascites, furosemide therapy is best initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is necessary during the period of diuresis. Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and metabolic alkalosis. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, furosemide should be discontinued. Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported. Reports usually indicate that furosemide ototoxicity is associated with rapid injection, severe renal impairment, the use of higher than recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs. If the physician elects to use high dose parenteral therapy, controlled intravenous infusion is advisable (for adults, an infusion rate not exceeding 4 mg furosemide per minute has been used) (see PRECAUTIONS: Drug Interactions ).

ADVERSE REACTIONS Adverse reactions are categorized below by organ system and listed by decreasing severity. Gastrointestinal System Reactions 1. hepatic encephalopathy in patients with hepatocellular insufficiency 2. pancreatitis 3. jaundice (intrahepatic cholestatic jaundice) 4. increased liver enzymes 5. anorexia 6. oral and gastric irritation 7. cramping 8. diarrhea 9. constipation 10. nausea 11. vomiting Systemic Hypersensitivity Reactions 1. severe anaphylactic or anaphylactoid reactions (e.g., with shock) 2. systemic vasculitis 3. interstitial nephritis 4. necrotizing angiitis Central Nervous System Reactions 1. tinnitus and hearing loss 2. paresthesias 3. vertigo 4. dizziness 5. headache 6. blurred vision 7. xanthopsia Hematologic Reactions 1. aplastic anemia 2. thrombocytopenia 3. agranulocytosis 4. hemolytic anemia 5. leukopenia 6. anemia 7. eosinophilia Dermatologic-Hypersensitivity Reactions 1. toxic epidermal necrolysis 2. Stevens-Johnson Syndrome 3. erythema multiforme 4. drug rash with eosinophilia and systemic symptoms 5. acute generalized exanthematous pustulosis 6. exfoliative dermatitis 7. bullous pemphigoid 8. purpura 9. photosensitivity 10. rash 11. pruritus 12. urticaria Cardiovascular Reaction 1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics. 2. Increase in cholesterol and triglyceride serum levels Other Reactions 1. hyperglycemia 2. glycosuria 3. hyperuricemia 4. muscle spasm 5. weakness 6. restlessness 7. urinary bladder spasm 8. thrombophlebitis 9. fever Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn.

Pregnancy Pregnancy Category C: Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4 and 8 times the maximal recommended human dose. There are no adequate and well-controlled studies in pregnant women. Furosemide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Treatment during pregnancy requires monitoring of fetal growth because of the potential for higher birth weights. The effects of furosemide on embryonic and fetal development and on pregnant dams were studied in mice, rats and rabbits. Furosemide caused unexplained maternal deaths and abortions in the rabbit at the lowest dose of 25 mg/kg (2 times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human dose of 600 mg/day) also caused maternal deaths and abortions when administered to rabbits between Days 12 and 17 of gestation. In a third study, none of the pregnant rabbits survived a dose of 100 mg/kg. Data from the above studies indicate fetal lethality that can precede maternal deaths. The results of the mouse study and one of the three rabbit studies also showed an increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in fetuses derived from the treated dams as compared with the incidence in fetuses from the control group.

Pediatric Use In premature infants furosemide may precipitate nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with furosemide. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving furosemide. If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus.

Pediatric Patients: The usual initial dose of oral furosemide in pediatric patients is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory after the initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy in pediatric patients, the dose should be adjusted to the minimum effective level.

OVERDOSAGE The principal signs and symptoms of overdose with furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. The acute toxicity of furosemide has been determined in mice, rats and dogs. In all three, the oral LD 50 exceeded 1000 mg/kg body weight, while the intravenous LD 50 ranged from 300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats. The concentration of furosemide in biological fluids associated with toxicity or death is not known. Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte losses. Serum electrolytes, carbon dioxide level and blood pressure should be determined frequently. Adequate drainage must be assured in patients with urinary bladder outlet obstruction (such as prostatic hypertrophy). Hemodialysis does not accelerate furosemide elimination.