Furosemide

FUROSCIX is indicated for the treatment of edema in pediatric patients weighing 43 kg and above and in adult patients with chronic heart failure or chronic kidney disease (CKD), including the nephrotic syndrome. FUROSCIX is a loop diuretic indicated for the treatment of edema in pediatric patients weighing 43 kg and above and in adult patients with chronic heart failure or chronic kidney disease, including the nephrotic syndrome. ( 1 )

Injection : 80 mg/mL as a clear, colorless to slightly yellow solution in a single-dose prefilled autoinjector. 80 mg/10 mL (8 mg/mL) as a clear to slightly yellow solution in a single-dose prefilled cartridge for use only with co-packaged single-use, On-body Infusor. Injection: 80 mg/mL in a single-dose prefilled autoinjector ( 3 ) 80 mg/10 mL (8 mg/mL) in a single-dose prefilled cartridge co-packaged with a single-use On-body Infusor. ( 3 )

FUROSCIX is contraindicated in: Patients with anuria. Patients with a history of hypersensitivity to furosemide, or any component of the FUROSCIX formulation. The On-body Infusor for FUROSCIX is contraindicated in patients with a history of hypersensitivity to medical adhesives Anuria ( 4 ) Hypersensitivity to furosemide, or components of FUROSCIX formulation ( 4 ) FUROSCIX On-body Infusor: Hypersensitivity to medical adhesives ( 4 )

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 higher than recommended doses. ( 5.3 , 7.1 ) Acute Urinary Retention : Monitor patients with symptoms of urinary retention. ( 5.4 ) Incomplete Dosing : Fluid contact and certain patient movements during treatment may cause the On-body Infusor to prematurely terminate infusion. Ensure the patient or caregiver can detect and respond to alarms. ( 5.5 )

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 [see Use in Specific Populations ( 8.6 )] .

5.2 Worsening Renal Function Furosemide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, discontinue furosemide [see Clinical Pharmacology ( 12.3 )].

5.3 Ototoxicity Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported with furosemide. 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 )].

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. These patients require careful monitoring, especially during the initial stages of treatment.

5.5 Incomplete Dosing The FUROSCIX ReadyFlow should be held against the abdomen until the yellow plunger rod stops moving and fills the viewing window. This may take about 10 seconds. The On-body Infusor for FUROSCIX should not be allowed to get wet from water or any other fluids (blood or drug product). Fluid contact with the circuit board can lead to device errors and premature termination of infusion. The On-body Infusor for FUROSCIX is intended for use in a setting where the patient can limit their activity for the duration of administration. Certain patient movements may cause interruption of device adherence to skin and premature termination of infusion. The On-body Infusor for FUROSCIX should only be administered in settings where alarms can be detected and responded to in order to ensure a complete dose is administered [see Dosage and Administration ( 2.2 )] .

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 [see Use in Specific Populations ( 8.6 )] .

5.2 Worsening Renal Function Furosemide can cause dehydration and azotemia. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, discontinue furosemide [see Clinical Pharmacology ( 12.3 )].

5.3 Ototoxicity Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported with furosemide. 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 )].

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. These patients require careful monitoring, especially during the initial stages of treatment.

5.5 Incomplete Dosing The FUROSCIX ReadyFlow should be held against the abdomen until the yellow plunger rod stops moving and fills the viewing window. This may take about 10 seconds. The On-body Infusor for FUROSCIX should not be allowed to get wet from water or any other fluids (blood or drug product). Fluid contact with the circuit board can lead to device errors and premature termination of infusion. The On-body Infusor for FUROSCIX is intended for use in a setting where the patient can limit their activity for the duration of administration. Certain patient movements may cause interruption of device adherence to skin and premature termination of infusion. The On-body Infusor for FUROSCIX should only be administered in settings where alarms can be detected and responded to in order to ensure a complete dose is administered [see Dosage and Administration ( 2.2 )] .

The following important adverse reactions are discussed 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 trials or post-marketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably, or to 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. Administration Site and Skin Reactions : administration site erythema, bruising, edema, mass, pruritus, and pain. Other Reactions : glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever. The most common adverse reactions during treatment with FUROSCIX were administration site and skin reactions: erythema, bruising, edema and pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact MannKind Corporation at 1-877-323-8505 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ) See 17 for PATIENT COUNSELING INFORMATION .

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 )]. Administer furosemide at lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function. Cisplatin and nephrotoxic drugs Nephrotoxicity 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 increase in free thyroid hormones, followed by an overall decrease in total thyroid hormone levels. Monitor the total thyroid hormone levels.

7.2 Effect of Other Drugs on Furosemide Drug/Substance Class or Name Drug Interaction Effect Recommendations Phenytoin Phenytoin interferes directly with renal action of furosemide. Monitor diuretic effects of furosemide and adjust the dose of furosemide if needed. Methotrexate and other drugs undergoing renal tubular secretion May reduce the effect of furosemide. High-dose treatment of methotrexate and these other drugs may result in elevated serum levels of furosemide and may potentiate the toxicity of furosemide. Monitor for enhanced toxicity of furosemide. Indomethacin 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.

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 )]. Administer furosemide at lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function. Cisplatin and nephrotoxic drugs Nephrotoxicity 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. […]

8.1 Pregnancy Risk Summary Available data from published observational studies, case reports, and post marketing 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). FUROSCIX ReadyFlow contains benzyl alcohol (BA) as a preservative. Because BA is rapidly metabolized by a pregnant female, BA exposure in the fetus is unlikely. 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. Carefully monitor pregnant women with cirrhosis of the liver. 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 the 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.

8.2 Lactation Risk Summary The presence of furosemide has been reported in human breast milk. There are no data on the effects on the breastfed infant or the effects on milk production. Doses of furosemide associated with clinically significant diuresis may impair milk production. FUROSCIX ReadyFlow contains benzyl alcohol (BA) as a preservative. Because BA is rapidly metabolized by a pregnant female, BA exposure in the breastfed neonate is unlikely. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for furosemide and any potential adverse effects on the breastfed infant from furosemide or from the underlying maternal condition.

8.4 Pediatric Use Safety and efficacy of the FUROSCIX ReadyFlow for pediatric use have not been established. The On-body Infusor for FUROSCIX is approved for the treatment of edema in pediatric patients weighing at least 43 kg with chronic heart failure or chronic kidney disease, including the nephrotic syndrome. FUROSCIX has not been studied in pediatric patients. Use of FUROSCIX for this indication is supported by: 1) efficacy, safety, and pharmacokinetic data of furosemide in adult and pediatric patients; 2) pharmacokinetic and pharmacodynamic data of FUROSCIX in adults with New York Heart Association (NYHA) Functional Classification Class II and Class III heart failure [see Clinical Pharmacology ( 12.2 , 12.3 )] ; and 3) population pharmacokinetic modeling which demonstrated no significant difference in furosemide exposure following FUROSCIX administration in a simulated pediatric population weighing 43 kg and above and aged 6 to <17 years compared to adult patients with chronic heart failure [see Clinical Pharmacology ( 12.3 )]. FUROSCIX is not approved for the treatment of edema in pediatric patients weighing less than 43 kg.

8.5 Geriatric Use Controlled clinical studies did not include sufficient numbers of subjects to determine whether subjects aged 65 and over respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for the elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. FUROSCIX is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology ( 12.3 )].

8.6 Renal Impairment Significantly reduced renal function can affect the response to furosemide. The FUROSCIX ReadyFlow and the On-body Infusor will deliver only an 80 mg dose of furosemide, and patients with significantly reduced renal function may require additional diuretic therapy.

8.7 Hepatic Impairment In patients with hepatic cirrhosis and ascites, sudden alterations of fluid and electrolyte balance may precipitate hepatic encephalopathy and coma. Treat such patients in a setting where clinical status and electrolyte balance can be carefully monitored.

8.1 Pregnancy Risk Summary Available data from published observational studies, case reports, and post marketing 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). FUROSCIX ReadyFlow contains benzyl alcohol (BA) as a preservative. Because BA is rapidly metabolized by a pregnant female, BA exposure in the fetus is unlikely. 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. […]