FUROSEMIDE

Each tablet for oral administration contains: Furosemide, USP . . . . . . . . . . . . . . . . 20 mg, 40 mg and 80 mg Each mL of Oral Solution for oral administration contains: Furosemide, USP . . . . . . . . . . . . . . . . 10 mg per mL or 8 mg (40 mg per 5 mL) Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro- N -furfuryl-5-sulfamoylanthranilic acid. Furosemide is a white to slightly yellow, crystalline powder. It is practically insoluble in water; freely soluble in acetone, dimethylformamide and in solutions of alkali hydroxides; soluble in methanol; sparingly soluble in alcohol; slightly soluble in ether; very slightly soluble in chloroform. The CAS Registry Number is 54-31-9. The structural formula is as follows: C 12 H 11 ClN 2 O 5 S M.W. 330.74 Furosemide Tablets, USP are available for oral administration containing 20 mg, 40 mg or 80 mg of Furosemide, USP. The tablets meet Dissolution Test 1. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, purified water, sodium lauryl sulfate, sodium starch glycolate and stearic acid. Furosemide Oral Solution, USP is also available for oral administration containing either 10 mg per mL or 40 mg per 5 mL. The oral solution contains the following inactive ingredients: D and C Yellow No. 10, FD and C Yellow No. 6, flavors, potassium carbonate 1½ hydrate, propylene glycol, purified water and sorbitol solution. The 10 mg/mL solution is orange flavored and contains prosweet liquid and saccharin sodium. The 40 mg/5 mL solution is pineapple-peach flavored and contains sweet tone. furosemide structural formula image

Edema Furosemide is 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 is 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 Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response. Adults: The usual initial dose of furosemide is 20 mg to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 mg or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (e.g., at 8 am and 2 pm). The dose of furosemide may be carefully titrated up to 600 mg/day in patients with clinically severe edematous states. Edema may be most efficiently and safely mobilized by giving furosemide on 2 to 4 consecutive days each week. When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable (See PRECAUTIONS : Laboratory Tests ). Geriatric Patients: In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range (See PRECAUTIONS : Geriatric Use ). 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. Hypertension Therapy should be individualized according to the patient’s response to gain maximal therapeutic response and to determine the minimal dose needed to maintain the therapeutic response. Adults: The usual initial dose of furosemide for hypertension is 80 mg, usually divided into 40 mg twice a day. Dosage should then be adjusted according to response. If response is not satisfactory, add other antihypertensive agents. Changes in blood pressure must be carefully monitored when furosemide is used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50% when furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of furosemide, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary. Geriatric Patients: In general, dose selection and dose adjustment for the elderly patient should be cautious, usually starting at the low end of the dosing range (See PRECAUTIONS : Geriatric Use ).

Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.

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. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function. Except in life-threatening situations, avoid this combination. Furosemide should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity. Patients receiving high doses of salicylates concomitantly with furosemide, as in rheumatic disease, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. Furosemide has a tendency to antagonize the skeletal muscle-relaxing effect of tubocurarine and may potentiate the action of succinylcholine. Lithium generally should not be given with diuretics because they reduce lithium’s renal clearance and add a high risk of lithium toxicity. Furosemide combined with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may lead to severe hypotension and deterioration in renal function, including renal failure. An interruption or reduction in the dosage of furosemide, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers may be necessary. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. Simultaneous administration of sucralfate and furosemide tablets may reduce the natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved. The intake of furosemide and sucralfate should be separated by at least two hours. In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is therefore not recommended. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of furosemide. Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperurecemia and cyclosporine impairment of renal urate excretion. High doses (>80 mg) of furosemide may inhibit the binding of thyroid hormones to carrier proteins and result in transient increase in free thyroid hormones, followed by an overall decrease in total thyroid hormone levels. One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid temporarily reduced creatinine clearance in patients with chronic renal insufficiency. There are case reports of patients who developed increased BUN, serum creatinine and serum potassium levels, and weight gain when furosemide was used in conjunction with NSAIDs. Literature reports indicate that coadministration of indomethacin may reduce the natriuretic and antihypertensive effects of furosemide in some patients by inhibiting prostaglandin synthesis. Indomethacin may also affect plasma renin levels, aldosterone excretion, and renin profile evaluation. Patients receiving both indomethacin and furosemide should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved.