Furosemide

1 INDICATIONS AND USAGE FUROSEMIDE INJECTION is a loop diuretic indicated for: • The treatment of edema associated with heart failure, cirrhosis of the liver, and renal disease ( 1.1 ) • Acute pulmonary edema as adjunctive therapy ( 1.2 ) 1.1 Edema Furosemide Injection is indicated in adults and pediatric patients for the treatment of edema associated with heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. 1.2 Acute Pulmonary Edema Furosemide Injection is indicated as adjunctive therapy in acute pulmonary edema.

2 DOSAGE AND ADMINISTRATION Edema : • Initial dose is 20 mg to 40 mg once given intramuscularly or intravenously. The intravenous dose should be administered slowly over 1 minute to 2 minutes ( 2.2 ) • If needed, a second dose may be administered 2 hours after the first dose ( 2.2 ) Acute Pulmonary Edema : • Initial dose is 40 mg injected slowly intravenously over 1 minute to 2 minutes ( 2.2 ) • If needed, a second dose is 80 mg injected intravenously slowly in 1 minute to 2 minutes ( 2.2 ) Pediatric Dosage : • The initial dose in pediatric patients is 1 mg/kg body weight once given slowly intramuscularly or intravenously. If needed, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended ( 2.3 ) 2.1 General Considerations Inspect Furosemide Injection visually for particulate matter and discoloration before administration. 2.2 Recommended Dosage for Adults Edema Individualize therapy according to patient response. The usual initial dose of furosemide is 20 mg to 40 mg given as a single-dose, injected intramuscularly or intravenously. Give the intravenous dose slowly (over 1 minute to 2 minutes). If needed, administer another dose in the same manner 2 hours later or increase the dose. The dose may be raised by 20 mg and administered not sooner than 2 hours after the previous dose until the desired diuretic effect has been obtained. Administer this individually determined single-dose once or twice daily. If the physician elects to use high-dose parenteral therapy, add the furosemide to either 0.9% Sodium Chloride Injection USP, Lactated Ringer's Injection USP, or Dextrose Injection 5%, USP, after pH has been adjusted to above 5.5, and administer as a controlled intravenous infusion at a rate not greater than 4 mg/min. Furosemide Injection is a buffered alkaline solution with a pH of about 9 and the drug may precipitate at pH values below 7. Care must be taken to ensure that the pH of the prepared infusion solution is in the weakly alkaline to neutral range. Acid solutions, including other parenteral medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same infusion because they may cause precipitation of the furosemide. Acute Pulmonary Edema The usual initial dose of furosemide is 40 mg injected slowly intravenously (over 1 minute to 2 minutes). If a satisfactory response does not occur within 1 hour, increase the dose to 80 mg injected slowly intravenously (over 1 minute to 2 minutes). 2.3 Recommended Dosage for Pediatric Patients The usual initial dose of Furosemide Injection (intravenously or intramuscularly) in pediatric patients is 1 mg/kg body weight administered slowly (over 1 minute to 2 minutes). If the diuretic response to the initial dose is not satisfactory, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended. The maximum dose for premature infants should not exceed 1 mg/kg/day [see Use in Specific Populations (8.4) ] .

5 WARNINGS AND PRECAUTIONS • Fluid, Electrolyte, and Metabolic Abnormalities : Monitor serum electrolytes, CO 2 , BUN, creatinine, glucose, and uric acid ( 5.1 ) • Worsening Renal Function : Monitor for dehydration and azotemia. ( 5.2 ) • Ototoxicity: Avoid rapid injection and higher than recommended doses. ( 5.3 , 7.1 ) • Acute Urinary Retention : Monitor patients with symptoms of urinary retention. ( 5.4 ) 5.1 Fluid, Electrolyte, and Metabolic Abnormalities Furosemide may cause fluid, electrolyte, and metabolic abnormalities such as hypovolemia, hypokalemia, azotemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypocalcemia, hyperglycemia, or hyperuricemia, particularly in patients receiving higher doses, patients with inadequate oral electrolyte intake, and in elderly patients. Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients. Serum electrolytes, CO 2 , BUN, creatinine, glucose, and uric acid should be monitored frequently during furosemide therapy. In patients with hepatic cirrhosis and ascites, sudden alterations of fluid and electrolyte balance may precipitate hepatic encephalopathy and coma. Treatment in such patients is best initiated in the hospital with small doses and careful monitoring of the patient's clinical status and electrolyte balance. 5.2 Worsening Renal Function Furosemide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, furosemide should be discontinued [see Clinical Pharmacology (12.3) ] . Furosemide use in the first year of life, especially in patients born pre-term, may precipitate nephrocalcinosis/nephrolithiasis. Therefore renal function must be monitored and renal ultrasonography performed in this age group [see Use in Specific Populations (8.4) ] . 5.3 Ototoxicity 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 Drug Interactions (7.1) ] . Hearing loss in neonates, including premature neonates has been associated with the use of Furosemide Injection [see Use in Specific Populations (8.4) ]. 5.4 Acute Urinary Retention In patients with severe symptoms of urinary retention (because of bladder emptying disorders, prostatic hyperplasia, urethral narrowing), the administration of furosemide can cause acute urinary retention related to increased production and retention of urine. Thus, these patients require careful monitoring, especially during the initial stages of treatment.

4 CONTRAINDICATIONS • Furosemide Injection is contraindicated in patients with anuria. • Furosemide Injection is contraindicated in patients with a history of hypersensitivity to furosemide. • Anuria ( 4 ) • Hypersensitivity to furosemide ( 4 )

7 DRUG INTERACTIONS • Aminoglycoside antibiotics : Increased potential ototoxicity of the antibiotics. Avoid combination ( 7.1 ) • Ethacrynic acid : Risk of ototoxicity. Avoid combination ( 7.1 ) • Salicylates : Risk of salicylate toxicity ( 7.1 ) • Cisplatin and nephrotoxic drugs : Risk of ototoxicity and nephrotoxicity ( 7.1 ) • Lithium : Risk of lithium toxicity ( 7.1 ) • Renin-angiotensin inhibitors : Increased risk of hypotension and renal failure.( 7.1 ) • Adrenergic blocking drugs : Risk of potentiation ( 7.1 ) • Drugs undergoing renal tubular secretion : Risk of toxicity potentiation ( 7.1 ) 7.1 Effects of Furosemide on Other Drugs Drug/Substance Class or Name Drug Interaction Effect Recommendations Aminoglycoside antibiotics Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function [see Warnings and Precautions (5.3) ]. Avoid combination except in life-threatening situations. Ethacrynic acid Possibility of ototoxicity [see Warnings and Precautions (5.3) ]. Avoid concomitant use with ethacrynic acid. Salicylates May experience salicylate toxicity at lower doses because of competitive renal excretory sites. Monitor for symptoms of salicylate toxicity. Cisplatin There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly [see Warnings and Precautions (5.3) ]. Cisplatin and nephrotoxic drugs Nephrotoxicity Administer furosemide at lower doses and with postitive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function. Paralytic agents Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine. Monitor for skeletal muscle effect. Lithium Furosemide reduces lithium's renal clearance and add a high-risk of lithium toxicity. Avoid concomitant use with lithium. Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers May lead to severe hypotension and deterioration in renal function, including renal failure. Monitor for changes in blood pressure and renal function and interrupt or reduce the dosage of furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers if needed. Antihypertensive drugs Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs. Monitor for changes in blood pressure and adjust the dose of other antihypertensive drugs if needed. Adrenergic blocking drugs or peripheral adrenergic blocking drugs Potentiation occurs. Monitor for changes in blood pressure and adjust the dose of adrenergic blocking drugs if needed. Norepinephrine Furosemide may decrease arterial responsiveness (vasoconstricting effect) to norepinephrine. Monitor blood pressure (or mean arterial pressure). Chloral hydrate 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. Concomitant use with chloral hydrate is not recommended. Methotrexate and other drugs undergoing renal tubular secretion Furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of furosemide may result in elevated serum levels of these drugs and may potentiate their toxicity. Monitor serum levels of drugs undergoing renal tubular secretion and adjust the dose if needed. Cephalosporin Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment. Monitor for changes in renal function. Cyclosporine Increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion. Monitor serum urate levels. Thyroid hormones High-doses (> 80 mg) of furosemide may inhibit the binding of thyroid hormones to carrier proteins and result in transient incre…

8.1 Pregnancy Risk Summary Available data from published observational studies, case reports, and postmarketing reports, from decades of use, have not demonstrated a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes with furosemide use during pregnancy. Untreated congestive heart failure and cirrhosis of the liver can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations ) . In animal reproduction studies, furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits when administered orally during organogenesis at 4 times a human i.v. dose of 80 mg based on body surface area (BSA) and oral bioavailability corrections, presumably secondary to volume depletion (see Data ) . The estimated background risk for major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with congestive heart failure are at increased risk for pre-term birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death and/or stillbirth. Closely monitor pregnant patients for destabilization of their heart failure. Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, pre-term delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly. Data Animal Data 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 (approximately 4 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections). In another study, a dose of 50 mg/kg (approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections) 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 an oral 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 of treated dams as compared with the incidence of fetuses from the control group.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Fluid, Electrolyte, and Metabolic Abnormalities [see Warnings and Precautions (5.1) ] • Ototoxicity [see Warnings and Precautions (5.3) ] The following adverse reactions associated with the use of furosemide were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized below by organ system and listed by decreasing severity. Gastrointestinal System Reactions: pancreatitis, jaundice (intrahepatic cholestatic jaundice), increased liver enzymes, anorexia, oral and gastric irritation, cramping, diarrhea, constipation, nausea, vomiting. Systemic Hypersensitivity Reactions: severe anaphylactic or anaphylactoid reactions (e.g., with shock), systemic vasculitis, interstitial nephritis, necrotizing angiitis. Central Nervous System Reactions: tinnitus and hearing loss, paresthesias, vertigo, dizziness, headache, blurred vision, xanthopsia. Hematologic Reactions: aplastic anemia, thrombocytopenia, agranulocytosis, hemolytic anemia, leukopenia, anemia, eosinophilia. Dermatologic-Hypersensitivity Reactions: toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, exfoliative dermatitis, bullous pemphigoid, purpura, photosensitivity, rash. Cardiovascular Reactions: orthostatic hypotension, increase in cholesterol and triglyceride serum levels. Other Reactions: glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever. Most common adverse reactions are related to fluid and electrolyte imbalance ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.