FUROSCIX is indicated for the treatment of edema in adult patients with chronic heart failure or chronic kidney disease (CKD), including the nephrotic syndrome.

{ "type": "p", "children": [], "text": "FUROSCIX is indicated for the treatment of edema in adult patients with chronic heart failure or chronic kidney disease (CKD), including the nephrotic syndrome." }

The single-use, On-body Infusor with prefilled cartridge is pre-programmed to deliver 30 mg of furosemide over the first hour followed by 12.5 mg per hour for the subsequent 4 hours [see Use in Specific Populations ( 8.6) and see Clinical Pharmacology ( 12)].

FUROSCIX is not for chronic use and should be replaced with oral diuretics as soon as practical.

FUROSCIX is intended for use in a setting where the patient can limit their activity for the duration of administration. [see Warnings and Precautions ( 5.5)]

FUROSCIX is not compatible with use in an MRI setting.

Inspect FUROSCIX prefilled cartridge prior to administration. FUROSCIX is a clear to slightly yellow solution. Do not use FUROSCIX if solution is discolored or cloudy [see Description ( 11)] .

Refer to the Instructions for Use for additional information.

Load the prefilled cartridge of furosemide into the On-body Infusor and close the cartridge holder.

Peel away the adhesive liner on the On-body Infusor and apply onto a clean, dry area of the abdomen between the top of the beltline and the bottom of the ribcage that is not tender, bruised, red or indurated. The distance from the top of the beltline to the bottom of the ribcage should be at least 2 ½ inches.

Start the injection by firmly pressing and releasing the blue start button.

Do not remove until the injection is complete (signaled by the solid green status light, beeping sound, and the white plunger rod filling the cartridge window).

Rotate the site of each subcutaneous administration.

Injection: 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.

{ "type": "p", "children": [], "text": "Injection: 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." }

{ "type": "ul", "children": [ "FUROSCIX is contraindicated in patients with anuria.", "FUROSCIX is contraindicated in patients with a history of hypersensitivity to furosemide, any component of the FUROSCIX formulation, or medical adhesives." ], "text": "" }

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)] .

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)].

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)].

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.

The On-body Infusor 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 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 used in patients who can detect and respond to alarms to ensure a complete dose is administered.

The following important adverse reactions are discussed elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following important adverse reactions are discussed elsewhere in the labeling:" }

{ "type": "ul", "children": [ "Fluid, Electrolyte, and Metabolic Abnormalities \n [see Warnings and Precautions (\n 5.1)]. \n \n", "Ototoxicity \n [see Warnings and Precautions (\n 5.3)] \n \n" ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nGastrointestinal System Reactions: pancreatitis, jaundice (intrahepatic cholestatic jaundice), increased liver enzymes, anorexia, oral and gastric irritation, cramping, diarrhea, constipation, nausea, vomiting.\n " }

Systemic Hypersensitivity Reactions: severe anaphylactic or anaphylactoid reactions (e.g., with shock), systemic vasculitis, interstitial nephritis, necrotizing angiitis.

{ "type": "p", "children": [], "text": "\nSystemic Hypersensitivity Reactions: severe anaphylactic or anaphylactoid reactions (e.g., with shock), systemic vasculitis, interstitial nephritis, necrotizing angiitis.\n " }

Central Nervous System Reactions: tinnitus and hearing loss, paresthesias, vertigo, dizziness, headache, blurred vision, xanthopsia.

{ "type": "p", "children": [], "text": "\nCentral Nervous System Reactions: tinnitus and hearing loss, paresthesias, vertigo, dizziness, headache, blurred vision, xanthopsia.\n " }

Hematologic Reactions: aplastic anemia, thrombocytopenia, agranulocytosis, hemolytic anemia, leukopenia, anemia, eosinophilia.

{ "type": "p", "children": [], "text": "\nHematologic Reactions: aplastic anemia, thrombocytopenia, agranulocytosis, hemolytic anemia, leukopenia, anemia, eosinophilia.\n " }

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.

{ "type": "p", "children": [], "text": "\nDermatologic 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.\n " }

Cardiovascular Reactions: orthostatic hypotension, increase in cholesterol and triglyceride serum levels.

{ "type": "p", "children": [], "text": "\nCardiovascular Reactions: orthostatic hypotension, increase in cholesterol and triglyceride serum levels.\n " }

Administration Site and Skin Reactions: erythema, bruising, edema, infusion site pain.

{ "type": "p", "children": [], "text": "\nAdministration Site and Skin Reactions: erythema, bruising, edema, infusion site pain.\n " }

Other Reactions: glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever.

{ "type": "p", "children": [], "text": "\nOther Reactions: glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever.\n " }

<div class="scrollingtable"><table border="5" width="100%"> <tbody class="Headless"> <tr class="First"> <td><span class="Bold">Drug/Substance Class or Name</span></td><td><span class="Bold">Drug Interaction Effect</span></td><td><span class="Bold">Recommendations</span></td> </tr> <tr> <td>Aminoglycoside antibiotics</td><td>Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function <span class="Italics">[see Warnings and Precautions ( <a href="#id_link_ec6b80a0-c23c-fab0-e053-2a95a90adba5">5.3</a>)]. </span></td><td>Avoid combination except in life-threatening situations.</td> </tr> <tr> <td>Ethacrynic acid</td><td>Possibility of ototoxicity <span class="Italics"> [see Warnings and Precautions ( <a href="#id_link_ec6b80a0-c23c-fab0-e053-2a95a90adba5">5.3</a>)]. </span></td><td>Avoid concomitant use with ethacrynic acid.</td> </tr> <tr> <td>Salicylates</td><td>May experience salicylate toxicity at lower doses because of competitive renal excretory sites.</td><td>Monitor for symptoms of salicylate toxicity.</td> </tr> <tr> <td>Cisplatin</td><td>There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly <span class="Italics">[see Warnings and Precautions ( <a href="#id_link_ec6b80a0-c23c-fab0-e053-2a95a90adba5">5.3</a>)]. </span></td><td></td> </tr> <tr> <td>Cisplatin and nephrotoxic drugs</td><td>Nephrotoxicity</td><td>Administer furosemide at lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function.</td> </tr> <tr> <td>Paralytic agents</td><td>Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine.</td><td>Monitor for skeletal muscle effect.</td> </tr> <tr> <td>Lithium</td><td>Furosemide reduces lithium’s renal clearance and add a high-risk of lithium toxicity.</td><td>Avoid concomitant use with lithium.</td> </tr> <tr> <td>Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers</td><td>May lead to severe hypotension and deterioration in renal function, including renal failure.</td><td>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.</td> </tr> <tr> <td>Antihypertensive drugs</td><td>Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs.</td><td>Monitor for changes in blood pressure and adjust the dose of other antihypertensive drugs if needed.</td> </tr> <tr> <td>Adrenergic blocking drugs or peripheral adrenergic blocking drugs</td><td>Potentiation occurs.</td><td>Monitor for changes in blood pressure and adjust the dose of adrenergic blocking drugs if needed.</td> </tr> <tr> <td>Norepinephrine</td><td>Furosemide may decrease arterial responsiveness (vasoconstricting effect) to norepinephrine.</td><td>Monitor blood pressure (or mean arterial pressure).</td> </tr> <tr> <td>Chloral hydrate</td><td>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.</td><td>Concomitant use with chloral hydrate is not recommended.</td> </tr> <tr> <td>Methotrexate and other drugs undergoing renal tubular secretion</td><td>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.</td><td>Monitor serum levels of drugs undergoing renal tubular secretion and adjust the dose if needed.</td> </tr> <tr> <td>Cephalosporin</td><td>Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment.</td><td>Monitor for changes in renal function.</td> </tr> <tr> <td>Cyclosporine</td><td>Increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion.</td><td>Monitor serum urate levels.</td> </tr> <tr class="Last"> <td>Thyroid hormones</td><td>High-doses (&gt; 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.</td><td>Monitor the total thyroid hormone levels.</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table border="10" width="100%"> <tbody class="Headless"> <tr class="First"> <td><span class="Bold">Drug/Substance Class or Name</span></td><td><span class="Bold">Drug Interaction Effect</span></td><td><span class="Bold">Recommendations</span></td> </tr> <tr> <td>Phenytoin</td><td> <p class="First">Phenytoin interferes directly with renal action of furosemide.</p> </td><td>Monitor diuretic effects of furosemide and adjust the dose of furosemide if needed.</td> </tr> <tr> <td>Methotrexate and other drugs undergoing renal tubular secretion</td><td>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.</td><td>Monitor for enhanced toxicity of furosemide.</td> </tr> <tr class="Last"> <td> <p class="First">Indomethacin</p> </td><td>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.</td><td>Patients receiving both indomethacin and furosemide should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved.</td> </tr> </tbody> </table></div>

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).

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.

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. 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.

Safety and efficacy for pediatric use have not been established [see Indications and Usage (1)].

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)].

Significantly reduced renal function can affect the response to furosemide. 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.

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.

The principal signs and symptoms of overdose with FUROSCIX are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action.

{ "type": "p", "children": [], "text": "The principal signs and symptoms of overdose with FUROSCIX are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action." }

The concentration of furosemide in biological fluids associated with toxicity or death is not known.

{ "type": "p", "children": [], "text": "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).

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Hemodialysis does not accelerate furosemide elimination." }

FUROSCIX (furosemide injection 80 mg/10 mL) is a loop diuretic which is an anthranilic acid derivative.

{ "type": "p", "children": [], "text": "FUROSCIX (furosemide injection 80 mg/10 mL) is a loop diuretic which is an anthranilic acid derivative." }

Chemically, it is 4-­chloro-­N-­furfuryl-­5-­sulfamoylanthranilic acid.

{ "type": "p", "children": [], "text": "Chemically, it is 4-­chloro-­N-­furfuryl-­5-­sulfamoylanthranilic acid." }

Furosemide is a white to slightly yellow crystalline powder. It is sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids. The structural formula is as follows:

{ "type": "p", "children": [], "text": "Furosemide is a white to slightly yellow crystalline powder. It is sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids. The structural formula is as follows:" }

Molecular Formula: C 12H 11ClN 2O 5S

{ "type": "p", "children": [], "text": "Molecular Formula: C \n 12H \n 11ClN \n 2O \n 5S\n " }

Molecular Weight: 330.75 g/mol

{ "type": "p", "children": [], "text": "Molecular Weight: 330.75 g/mol" }

FUROSCIX is a single-dose prefilled cartridge co-packaged with a single-use, On-body Infusor. The single-dose prefilled cartridge contains 80 mg per 10 mL sterile, clear to slightly yellow, and non-pyrogenic furosemide solution. The pH of FUROSCIX, 7.4, differs from that of Furosemide Injection, USP.

{ "type": "p", "children": [], "text": "FUROSCIX is a single-dose prefilled cartridge co-packaged with a single-use, On-body Infusor. The single-dose prefilled cartridge contains 80 mg per 10 mL sterile, clear to slightly yellow, and non-pyrogenic furosemide solution. The pH of FUROSCIX, 7.4, differs from that of Furosemide Injection, USP." }

Each 1 mL of FUROSCIX contains the following inactive ingredients: hydrochloric acid for pH adjustment if needed, sodium chloride (5.84 mg), sodium hydroxide for pH adjustment if needed, tris HCl (7.88 mg), and water for injection (q.s.).

{ "type": "p", "children": [], "text": "Each 1 mL of FUROSCIX contains the following inactive ingredients: hydrochloric acid for pH adjustment if needed, sodium chloride (5.84 mg), sodium hydroxide for pH adjustment if needed, tris HCl (7.88 mg), and water for injection (q.s.)." }

FUROSCIX is administered via a wearable, single-use, electromechanical (battery powered, micro-processor controlled), On-body delivery system that is pre-programmed to deliver 80 mg of FUROSCIX over 5-hours using a bi-phasic delivery profile.

{ "type": "p", "children": [], "text": "FUROSCIX is administered via a wearable, single-use, electromechanical (battery powered, micro-processor controlled), On-body delivery system that is pre-programmed to deliver 80 mg of FUROSCIX over 5-hours using a bi-phasic delivery profile." }

Furosemide primarily inhibits the reabsorption of sodium and chloride in the proximal and distal tubules and in the loop of Henle. The high degree of diuresis is largely due to the unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase and aldosterone.

In patients with NYHA Class II and Class III heart failure, subcutaneous administration of FUROSCIX (30 mg furosemide over the first hour followed by 12.5 mg per hour for the subsequent 4 hours, total 80mg furosemide) produced similar diuresis and natriuresis to intravenous administration (two 40 mg bolus doses separated by 120 minutes) at 8 and 24 hour post-dose. The duration of diuretic effect with FUROSCIX is up to 8 hours after initiation of dosing.

Absorption

In patients with NYHA Class II-III congestive heart failure, subcutaneous infusion of FUROSCIX (30 mg furosemide over the first hour followed by 12.5 mg per hour for the subsequent 4 hours, 80 mg furosemide total), the bioavailability was 99.6% (90% CI: 94.8, 104.8) with a median T max of 4 hours relative to 80 mg intravenous furosemide (two 40-mg bolus doses separated by 120 minutes). The pharmacokinetic parameters of FUROSCIX are presented in Table 1 below:

Table 1: Pharmacokinetic Data of FUROSCIX Following Subcutaneous Infusion (n = 15)

<div class="scrollingtable"><table border="10" width="100%"> <tbody class="Headless"> <tr class="First"> <td><span class="Bold">Dose</span></td><td> <p class="First"> <span class="Bold">C <span class="Sub">max</span></span> </p> <span class="Bold">(ng/mL)</span></td><td><span class="Bold">AUC <span class="Sub">t</span> (ng×hr/mL) </span></td><td><span class="Bold">T <span class="Sub">1/2</span> (hr) </span></td><td> <p class="First"> <span class="Bold">AUC <span class="Sub">∞</span></span> </p> <span class="Bold">(ng×hr/mL)</span></td> </tr> <tr> <td>FUROSCIX: 30 mg subcutaneously infused over the first hour followed by 12.5 mg per hour for the subsequent 4 hours (total dose: 80 mg furosemide)</td><td> <p class="First">2040 ± 449</p> </td><td>13000 ± 4000</td><td> <p class="First">3.2 ± 0.9</p> </td><td>13100 ± 4010</td> </tr> <tr class="Last"> <td>Furosemide administered as 2 x 40 mg bolus doses intravenously, separated by 120 minutes (total dose: 80 mg furosemide)</td><td>8580 ± 2540</td><td>13000 ± 4050</td><td>2.6 ± 0.3</td><td>13200 ± 4170</td> </tr> </tbody> </table></div>

The terminal half-life of furosemide is approximately 2 hours.

The impact of subcutaneous edema at the administration site of FUROSCIX on drug absorption is unknown.

Distribution

Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 mcg per mL to 400 mcg per mL are 91% to 99% bound in healthy individuals. The unbound fraction averages 2.3% to 4.1% at therapeutic concentrations.

Furosemide binding to albumin may be reduced in elderly patients.

Metabolism

Furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man.

Elimination

Significantly more furosemide is excreted in urine following the intravenous injection than after the tablet or oral solution.

Furosemide is predominantly excreted unchanged in the urine.

The renal clearance of furosemide after intravenous administration in older healthy male subjects (60 to 70 years of age) is significantly less than in younger healthy male subjects (20 to 35 years of age).

Carcinogenesis

Furosemide was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. A small but significantly increased incidence of mammary gland carcinomas occurred in female mice at a dose approximately 8 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg per kg (slightly greater than the maximum human dose) but not at 30 mg per kg.

Mutagenesis

Furosemide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system, and questionably positive for gene mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister chromatid exchange in human cells in vitro, but other studies on chromosomal aberrations in human cells in vitro gave conflicting results. In Chinese hamster cells it induced chromosomal damage but was questionably positive for sister chromatid exchange. Studies on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of rats treated with this drug did not induce gene conversion in Saccharomyces cerevisiae.

Impairment of Fertility

Furosemide produced no impairment of fertility in male or female rats, at 100 mg per kg per day (the maximum effective diuretic dose in the rat), approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections.

FUROSCIX injection is a sterile, clear to slightly yellow, non-pyrogenic liquid supplied in a single-dose prefilled cartridge for subcutaneous infusion co-packaged with the On-body Infusor. Each single-use On-body Infusor with prefilled cartridge is designed to deliver 80 mg of FUROSCIX in 10 mL solution over 5-hours.

{ "type": "p", "children": [], "text": "FUROSCIX injection is a sterile, clear to slightly yellow, non-pyrogenic liquid supplied in a single-dose prefilled cartridge for subcutaneous infusion co-packaged with the On-body Infusor. Each single-use On-body Infusor with prefilled cartridge is designed to deliver 80 mg of FUROSCIX in 10 mL solution over 5-hours." }

<div class="scrollingtable"><table border="1" width="100%"> <tbody class="Headless"> <tr class="First Last"> <td> <p class="First">Carton containing one 80 mg/10 mL (8 mg/mL) prefilled cartridge co-packaged with one On-body Infusor</p> </td><td>NDC 71767-100-01</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" width=\"100%\">\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td>\n<p class=\"First\">Carton containing one 80 mg/10 mL (8 mg/mL) prefilled cartridge co-packaged with one On-body Infusor</p>\n</td><td>NDC 71767-100-01</td>\n</tr>\n</tbody>\n</table></div>" }

Store between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze.

{ "type": "p", "children": [], "text": "Store between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze." }

Protect FUROSCIX from light. Do not remove the cartridge from carton until it is ready for use. Do not use if the solution is discolored or cloudy. Protect the On-body Infusor from water.

{ "type": "p", "children": [], "text": "Protect FUROSCIX from light. Do not remove the cartridge from carton until it is ready for use. Do not use if the solution is discolored or cloudy. Protect the On-body Infusor from water." }

Advise the patient and/or caregiver to read the FDA-approved patient labeling [see FDA-approved Instructions for Use].

{ "type": "p", "children": [], "text": "Advise the patient and/or caregiver to read the FDA-approved patient labeling \n [see FDA-approved Instructions for Use].\n " }

Advise the patient that they should not allow the On-body Infusor to come into contact with water or other fluids. Patients should check the device for alarms to ensure a complete dose is administered [see Warnings and Precautions ( 5.5)] .

{ "type": "p", "children": [], "text": "Advise the patient that they should not allow the On-body Infusor to come into contact with water or other fluids. Patients should check the device for alarms to ensure a complete dose is administered\n [see Warnings and Precautions (\n 5.5)]\n .\n " }

Fluid, Electrolyte, and Metabolic Abnormalities

{ "type": "p", "children": [], "text": "\nFluid, Electrolyte, and Metabolic Abnormalities\n" }

Advise patients that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia [see Warnings and Precautions ( 5.1)] .

{ "type": "p", "children": [], "text": "Advise patients that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia \n [see Warnings and Precautions (\n 5.1)]\n .\n " }

Advise patients that furosemide may increase blood glucose levels and thereby affect urine glucose tests [see Warnings and Precautions ( 5.1)].

{ "type": "p", "children": [], "text": "Advise patients that furosemide may increase blood glucose levels and thereby affect urine glucose tests \n [see Warnings and Precautions (\n 5.1)].\n \n" }

Photosensitivity

{ "type": "p", "children": [], "text": "\nPhotosensitivity\n" }

The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide [see Adverse Reactions ( 6)] .

{ "type": "p", "children": [], "text": "The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide \n [see Adverse Reactions (\n 6)]\n .\n " }

Advise hypertensive patients to avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms [see Drug Interactions ( 7.1)] .

{ "type": "p", "children": [], "text": "Advise hypertensive patients to avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms \n [see Drug Interactions (\n 7.1)]\n .\n " }

For more information about FUROSCIX, go to www.FUROSCIX.com or call 1-855-SCPHARMA (1-855-727-4276)

{ "type": "p", "children": [], "text": "For more information about FUROSCIX, go to www.FUROSCIX.com or call 1-855-SCPHARMA (1-855-727-4276)" }

scPharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "scPharmaceuticals, Inc." }

FUROSCIX ® (furosemide injection 80 mg/10 mL) for subcutaneous use

{ "type": "p", "children": [], "text": "FUROSCIX\n ® (furosemide injection 80 mg/10 mL) for subcutaneous use\n " }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

scPharmaceuticals, Inc.,

{ "type": "p", "children": [], "text": "scPharmaceuticals, Inc.," }

25 Mall Road, Suite 203,

{ "type": "p", "children": [], "text": "25 Mall Road, Suite 203," }

Burlington, MA 01803

{ "type": "p", "children": [], "text": "Burlington, MA 01803" }

Patent Protected: www.scpharmaceuticals.com/patents

{ "type": "p", "children": [], "text": "Patent Protected: www.scpharmaceuticals.com/patents" }

FUROSCIX ® is a mark of scPharmaceuticals Inc.

{ "type": "p", "children": [], "text": "FUROSCIX\n ® is a mark of scPharmaceuticals Inc.\n " }

Reg-0018 Rev 02

{ "type": "p", "children": [], "text": "Reg-0018 Rev 02" }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

Model/REF # FUR-80W5

{ "type": "p", "children": [], "text": "Model/REF # FUR-80W5" }

Instructions For Use

{ "type": "p", "children": [], "text": "\nInstructions For Use\n" }

On-Body Infusor for

{ "type": "p", "children": [], "text": "\nOn-Body Infusor for\n" }

FUROSCIX® [fue roe’ six]

{ "type": "p", "children": [], "text": "\nFUROSCIX® [fue roe’ six]\n" }

(furosemide injection) for subcutaneous use

{ "type": "p", "children": [], "text": "\n(furosemide injection) for subcutaneous use\n" }

Single-Use On-Body Infusor and

{ "type": "p", "children": [], "text": "\nSingle-Use On-Body Infusor and\n" }

80 mg/10 mL (8 mg/mL) Prefilled Cartridge

{ "type": "p", "children": [], "text": "\n80 mg/10 mL (8 mg/mL) Prefilled Cartridge\n" }

This Instructions for Use contains information about how to prepare and use FUROSCIX On-Body Infusor.

{ "type": "p", "children": [], "text": "This Instructions for Use contains information about how to prepare and use FUROSCIX On-Body Infusor." }

Before Starting

{ "type": "p", "children": [], "text": "\nBefore Starting\n" }

{ "type": "ul", "children": [ "Read this Instructions for Use before using the FUROSCIX On-Body Infusor for the first time.", "You or a caregiver should receive training before using the Furoscix On-Body Infusor.", "Always wash your hands before starting.", "The FUROSCIX On-Body Infusor will deliver a fixed dose of 80 mg of furosemide over about 5 hours.", "The FUROSCIX On-Body Infusor delivers the medicine just under the skin (subcutaneously).", "When the FUROSCIX On-Body Infusor is started, a small needle sticks into the skin to deliver the medicine. The on-body Infusor signals when all the medicine has been delivered. When the on-body Infusor is removed from the skin, a needle cover will extend over the needle to protect from an accidental needle stick." ], "text": "" }

Parts of the FUROSCIX On-Body Infusor and Prefilled Cartridge

{ "type": "p", "children": [], "text": "\nParts of the FUROSCIX On-Body Infusor and Prefilled Cartridge\n" }

Important Information

{ "type": "p", "children": [], "text": "\nImportant Information\n" }

{ "type": "ul", "children": [ "The on-body Infusor and prefilled cartridge are not made with natural rubber latex.", "The infusion will last about 5 hours. During this time, you should limit your activity so that your bending movements are limited. Wearing the Infusor while riding in a car or flying in an airplane is not recommended.", "You should notice an increase in urine production in about an hour after the infusion is started and may need to make frequent bathroom visits. Be sure you have access to a bathroom for up to 8 hours after starting the infusion. If you do not notice the need to go to the bathroom, call your healthcare provider.", "The on-body Infusor can only be used with the prefilled FUROSCIX cartridge supplied in the kit.", "\nDo not use any other cartridges or medicines inside the on-body Infusor.\n ", "\nDo not apply lotions, oils, or ointments to the adhesion area of the abdomen prior to applying the on-body Infusor to the abdomen.\n ", "\nDo not use the on-body Infusor if the packaging appears to be opened, or if the on-body Infusor has been dropped or appears to be broken or damaged.\n ", "\nDo not use the on-body Infusor within 12 inches of mobile phones, tablets, computers or wireless accessories (for example: TV remote control, Bluetooth computer keyboard or mouse).\n ", "\nDo not use the on-body Infusor or prefilled cartridge after the expiration date on the carton.\n ", "\nDo not use the prefilled cartridge if the liquid is discolored or cloudy. The liquid in the prefilled cartridge should be clear to slightly yellow in color.\n ", "\nDo not use the on-body Infusor in or around an MRI machine.\n ", "\nDo not take the on-body Infusor off your skin while it is infusing, unless there is an emergency or a device error. Removing the on-body Infusor before the infusion is done will result in a partial dose. The on-body Infusor will stop infusing and it cannot be restarted. \n Do not apply a new on-body Infusor unless instructed to do so by your healthcare provider.\n ", "\nDo not reuse the on-body Infusor. The on-body Infusor is for single use only.\n ", "\nDo not let the on-body Infusor get wet from water or any other liquids. \n Do not shower, bathe, swim or do activities that may make you sweat while wearing the on-body Infusor. It contains parts that should not get wet.\n " ], "text": "" }

Call your healthcare provider or scPharmaceuticals at 1-855-SCPHARMA (1-855-727-4276) if you have any questions.

{ "type": "p", "children": [], "text": "\nCall your healthcare provider or scPharmaceuticals at 1-855-SCPHARMA (1-855-727-4276) if you have any questions.\n" }

Storage Information

{ "type": "p", "children": [], "text": "\nStorage Information\n" }

{ "type": "ul", "children": [ "The FUROSCIX On-Body Infusor and prefilled cartridge should be stored at controlled room temperature between 68°F to 77°F (20°C to 25°C) (see Figure B). Do not refrigerate or freeze.", "\nKeep the FUROSCIX prefilled cartridge in the original carton to protect from light or physical damage until you are ready to use.\n ", "\nKeep the FUROSCIX On-Body Infusor and prefilled cartridge out of the reach of children.\n " ], "text": "" }

Prepare for the Infusion

{ "type": "p", "children": [], "text": "\nPrepare for the Infusion\n" }

STEP 1 Wash Hands, Check Expiration Date and Remove Supplies from Carton

{ "type": "p", "children": [], "text": "\nSTEP 1 Wash Hands, Check Expiration Date and Remove Supplies from Carton\n" }

​ 1.1 Wash your hands before using the on-body Infusor (Figure C).

{ "type": "p", "children": [], "text": "​ \n 1.1 Wash your hands before using the on-body Infusor (Figure C).\n " }

1.2 Check the expiration date on the FUROSCIX On-Body Infusor carton (see Figure D). Do not use if the expiration date has passed.

{ "type": "p", "children": [], "text": "\n1.2 Check the expiration date on the FUROSCIX On-Body Infusor carton (see Figure D). \n Do not use if the expiration date has passed.\n " }

1.3 Open the carton and peel away the white paper cover. Remove the plastic cover from the clear tray. Remove supplies from the carton and packaging (see Figure E). Do not use the on-body Infusor or prefilled cartridge if packaging appears to have been previously opened or damaged.

{ "type": "p", "children": [], "text": "\n1.3 Open the carton and peel away the white paper cover. Remove the plastic cover from the clear tray. Remove supplies from the carton and packaging (see Figure E). \n Do not use the on-body Infusor or prefilled cartridge if packaging appears to have been previously opened or damaged.\n " }

1.4 Gather all materials needed for your injection, on a clean, well-lit work surface (Figure F):

{ "type": "p", "children": [], "text": "\n1.4 Gather all materials needed for your injection, on a clean, well-lit work surface (Figure F):\n " }

{ "type": "ul", "children": [ "On-body Infusor and prefilled cartridge (Included)", "Instructions For Use (Included)", "Alcohol wipes (Included)", "Clippers (if needed) (Not included)", "Sharps disposal container (Not included)" ], "text": "" }

STEP 2 Check On-Body Infusor and Prefilled Cartridge

{ "type": "p", "children": [], "text": "\nSTEP 2 Check On-Body Infusor and Prefilled Cartridge\n" }

2.1 Check the on-body Infusor and prefilled cartridge for any damage (see Figure G).

{ "type": "p", "children": [], "text": "\n2.1 Check the on-body Infusor and prefilled cartridge for any damage (see Figure G).\n " }

Do not use the on-body Infusor or prefilled cartridge if either item appears to be damaged.

{ "type": "p", "children": [], "text": "\nDo not use the on-body Infusor or prefilled cartridge if either item appears to be damaged.\n " }

Do not touch the blue start button until the on-body Infusor is on the skin and you are ready to begin the infusion.

{ "type": "p", "children": [], "text": "\nDo not touch the blue start button until the on-body Infusor is on the skin and you are ready to begin the infusion.\n " }

Do not touch or fully open the cartridge holder until you are ready to load the cartridge.

{ "type": "p", "children": [], "text": "\nDo not touch or fully open the cartridge holder until you are ready to load the cartridge.\n " }

2.2 Check the liquid medicine in the prefilled cartridge (see Figure H). The liquid in the prefilled cartridge should be clear to slightly yellow.

{ "type": "p", "children": [], "text": "\n2.2 Check the liquid medicine in the prefilled cartridge (see Figure H). The liquid in the prefilled cartridge should be clear to slightly yellow.\n " }

Do not use the prefilled cartridge if the liquid is discolored or cloudy.

{ "type": "p", "children": [], "text": "\nDo not use the prefilled cartridge if the liquid is discolored or cloudy.\n " }

Call scPharmaceuticals at: 1-855-SCPHARMA (1-855-727-4276) or call your healthcare provider.

{ "type": "p", "children": [], "text": "Call scPharmaceuticals at: 1-855-SCPHARMA (1-855-727-4276) or call your healthcare provider." }

STEP 3 Load Prefilled Cartridge into the On-Body Infusor

{ "type": "p", "children": [], "text": "\nSTEP 3 Load Prefilled Cartridge into the On-Body Infusor\n" }

3.1 Clean the tip (small end) of the prefilled cartridge with an alcohol wipe (see Figure I).

{ "type": "p", "children": [], "text": "\n3.1 Clean the tip (small end) of the prefilled cartridge with an alcohol wipe (see Figure I).\n " }

Do not continue with the process of opening the cartridge holder all the way or loading the prefilled cartridge until you are ready to begin the infusion.

{ "type": "p", "children": [], "text": "\nDo not continue with the process of opening the cartridge holder all the way or loading the prefilled cartridge until you are ready to begin the infusion.\n " }

3.2 Open the cartridge holder all the way to turn on the on-body Infusor. The on-body Infusor “beeps” and the indicator light will begin blinking blue (see Figure J).

{ "type": "p", "children": [], "text": "\n3.2 Open the cartridge holder all the way to turn on the on-body Infusor. The on-body Infusor “beeps” and the indicator light will begin blinking blue (see Figure J).\n " }

Note: Complete steps 3.3 through 6.1 within 30 minutes of fully opening the cartridge holder or the Infusor will alarm and cannot restart.

{ "type": "p", "children": [], "text": "\nNote: Complete steps 3.3 through 6.1 within 30 minutes of fully opening the cartridge holder or the Infusor will alarm and cannot restart.\n " }

3.3 Insert the prefilled cartridge into the cartridge holder with the tip pointed down (see Figure K).

{ "type": "p", "children": [], "text": "\n3.3 Insert the prefilled cartridge into the cartridge holder with the tip pointed down (see Figure K).\n " }

Note: The prefilled cartridge should slide into the cartridge holder easily. If it does not slide in easily, check the prefilled cartridge to make sure the tip is pointed down and try again.

{ "type": "p", "children": [], "text": "\nNote: The prefilled cartridge should slide into the cartridge holder easily. If it does not slide in easily, check the prefilled cartridge to make sure the tip is pointed down and try again.\n " }

Do not press the blue start button until on-body Infusor is applied to skin and you are ready to begin the infusion.

{ "type": "p", "children": [], "text": "\nDo not press the blue start button until on-body Infusor is applied to skin and you are ready to begin the infusion.\n " }

3.4 Close the cartridge holder all the way until it is even with the rest of the on-body Infusor (see Figure L). You may hear a “click” sound when it is closed.

{ "type": "p", "children": [], "text": "\n3.4 Close the cartridge holder all the way until it is even with the rest of the on-body Infusor (see Figure L). You may hear a “click” sound when it is closed.\n " }

Note: If the indicator light blinks red and the on-body Infusor "beeps", the on-body Infusor has experienced an internal error. Do not use the on-body Infusor (see On-Body Infusor Alarm section).

{ "type": "p", "children": [], "text": "\nNote: If the indicator light blinks red and the on-body Infusor \"beeps\", the on-body Infusor has experienced an internal error. \n Do not use the on-body Infusor (see On-Body Infusor Alarm section).\n " }

Apply the On-Body Infusor

{ "type": "p", "children": [], "text": "\nApply the On-Body Infusor\n" }

STEP 4 Select and Prepare Application Site

{ "type": "p", "children": [], "text": "\nSTEP 4 Select and Prepare Application Site\n" }

4.1 Select one site on the stomach on either side of the belly button (navel). The site should be a flat area below the rib cage and above the belt line (see Figure M).

{ "type": "p", "children": [], "text": "\n4.1 Select one site on the stomach on either side of the belly button (navel). The site should be a \n flat area below the rib cage and above the belt line (see Figure M).\n " }

Do not select a site where the skin is irritated or broken.

{ "type": "p", "children": [], "text": "\nDo not select a site where the skin is irritated or broken.\n " }

Do not apply lotions, oils or ointments to the adhesion area of the abdomen.

{ "type": "p", "children": [], "text": "\nDo not apply lotions, oils or ointments to the adhesion area of the abdomen.\n " }

Do not select a site where belts, waistbands or other types of clothing may rub against, disturb, or dislodge the on-body Infusor.

{ "type": "p", "children": [], "text": "\nDo not select a site where belts, waistbands or other types of clothing may rub against, disturb, or dislodge the on-body Infusor.\n " }

Note: Rotate application site (side of the stomach) each time if told by your healthcare provider to repeat dose.

{ "type": "p", "children": [], "text": "\nNote: Rotate application site (side of the stomach) each time if told by your healthcare provider to repeat dose.\n " }

4.2 The site should be hairless or nearly hairless. If needed, remove excess hair by clipping or shaving the hair before applying the on-body Infusor (see Figure N).

{ "type": "p", "children": [], "text": "\n4.2 The site should be hairless or nearly hairless. If needed, remove excess hair by clipping or shaving the hair before applying the on-body Infusor (see Figure N).\n " }

4.3 Wipe the skin where the on-body Infusor will be applied with an alcohol wipe and allow area to dry (see Figure O).

{ "type": "p", "children": [], "text": "\n4.3 Wipe the skin where the on-body Infusor will be applied with an alcohol wipe and allow area to dry (see Figure O).\n " }

STEP 5 Apply the On-Body Infusor

{ "type": "p", "children": [], "text": "\nSTEP 5 Apply the On-Body Infusor\n" }

5.1 Pick up the on-body Infusor. Peel away the adhesive liner by grasping the white tab and pulling it away from the blue tab/adhesive backing (see Figure P).

{ "type": "p", "children": [], "text": "\n5.1 Pick up the on-body Infusor. Peel away the adhesive liner by grasping the white tab and pulling it away from the blue tab/adhesive backing (see Figure P).\n " }

Do not touch the sticky (adhesive) part of the on-body Infusor with your fingers or let it touch any objects or surfaces before the Infusor is placed on the skin.

{ "type": "p", "children": [], "text": "\nDo not touch the sticky (adhesive) part of the on-body Infusor with your fingers or let it touch any objects or surfaces before the Infusor is placed on the skin.\n " }

5.2 Apply the on-body Infusor to the chosen skin site while standing or sitting up straight.

{ "type": "p", "children": [], "text": "\n5.2 Apply the on-body Infusor to the chosen skin site while standing or sitting up straight.\n " }

Position the on-body Infusor so that the cartridge window and the indicator light can be seen during the infusion (see Figure Q).

{ "type": "p", "children": [], "text": "Position the on-body Infusor so that the cartridge window and the indicator light can be seen during the infusion (see Figure Q)." }

Do not bend over when applying the on-body Infusor.

{ "type": "p", "children": [], "text": "\nDo not bend over when applying the on-body Infusor.\n " }

5.3 Press the on-body Infusor firmly onto the skin and hold it for several seconds (see Figure R). Then rub your finger over the edges of the adhesive to get it to stick well.

{ "type": "p", "children": [], "text": "\n5.3 Press the on-body Infusor firmly onto the skin and hold it for several seconds (see Figure R). Then rub your finger over the edges of the adhesive to get it to stick well.\n " }

Do not touch the blue start button until you are ready to start the infusion (see Step 6).

{ "type": "p", "children": [], "text": "\nDo not touch the blue start button until you are ready to start the infusion (see Step 6).\n " }

Do not remove and reapply on-body Infusor. The on-body Infusor adhesive might not work as well.

{ "type": "p", "children": [], "text": "\nDo not remove and reapply on-body Infusor. The on-body Infusor adhesive might not work as well.\n " }

Start the Infusion

{ "type": "p", "children": [], "text": "\nStart the Infusion\n" }

STEP 6 Start the Infusion

{ "type": "p", "children": [], "text": "\nSTEP 6 Start the Infusion\n" }

6.1 Firmly press and release the blue start button to begin the infusion (see Figure S).

{ "type": "p", "children": [], "text": "\n6.1 Firmly \n press and release the blue start button to begin the infusion (see Figure S).\n " }

The on-body Infusor will stick a very small needle just under the skin and begin delivering the medicine. The indicator light will start blinking green and the on-body Infusor "beeps", signifying that the infusion has begun.

{ "type": "p", "children": [], "text": "The on-body Infusor will stick a very small needle just under the skin and begin delivering the medicine. The indicator light will start blinking green and the on-body Infusor \"beeps\", signifying that the infusion has begun." }

Note: At the start of the infusion, you may also hear the on-body Infusor motor running for several seconds.

{ "type": "p", "children": [], "text": "\nNote: At the start of the infusion, you may also hear the on-body Infusor motor running for several seconds.\n " }

STEP 7 Allow Medicine to Deliver for 5 Hours

{ "type": "p", "children": [], "text": "\nSTEP 7 Allow Medicine to Deliver for 5 Hours\n" }

7.1 Relax during the delivery period. The on-body Infusor should remain on the skin until the delivery is complete.

{ "type": "p", "children": [], "text": "\n7.1 Relax during the delivery period. The on-body Infusor should remain on the skin until the delivery is complete.\n " }

Do not exercise or take part in activities that might result in the on-body Infusor falling off. Take care not to bump the on-body Infusor while wearing it. It takes about 5 hours for the on-body Infusor to deliver all of the medicine. During the infusion, the indicator light will continue to blink green periodically, signifying that the infusion is running (see Figure T).

{ "type": "p", "children": [], "text": "\nDo not exercise or take part in activities that might result in the on-body Infusor falling off. Take care not to bump the on-body Infusor while wearing it. It takes about 5 hours for the on-body Infusor to deliver all of the medicine. During the infusion, the indicator light will continue to blink green periodically, signifying that the infusion is running (see Figure T).\n " }

Note: If the on-body Infusor falls off or if the indicator light begins blinking red, call your healthcare provider right away (see On-Body Infusor Alarm section). Do not reapply or reuse the on-body Infusor. Do not apply a new on-body Infusor unless instructed to do so by your healthcare provider.

{ "type": "p", "children": [], "text": "\nNote: If the on-body Infusor falls off or if the indicator light begins blinking red, call your healthcare provider right away (see On-Body Infusor Alarm section). \n Do not reapply or reuse the on-body Infusor. \n Do not apply a new on-body Infusor unless instructed to do so by your healthcare provider.\n " }

If You Have to Stop the Infusion Due to An Emergency, Do the Following:

{ "type": "p", "children": [], "text": "\nIf You Have to Stop the Infusion Due to An Emergency, Do the Following:\n" }

{ "type": "ul", "children": [ "Remove the on-body Infusor from the skin (see Step 8). It will immediately stop infusing and the on-body Infusor will deactivate. \n Do not reuse the on-body Infusor. After the on-body Infusor is removed, it can no longer be used.\n ", "Call your healthcare provider for further instructions." ], "text": "" }

Remove and Dispose of the On-Body Infusor

{ "type": "p", "children": [], "text": "\nRemove and Dispose of the On-Body Infusor\n" }

STEP 8 When Infusion is Complete, Remove the On-Body Infusor from the Skin

{ "type": "p", "children": [], "text": "\nSTEP 8 When Infusion is Complete, Remove the On-Body Infusor from the Skin\n" }

8.1 The infusion is complete and the on-body Infusor is ready to be removed when (see Figure U):

{ "type": "p", "children": [], "text": "\n8.1 The infusion is complete and the on-body Infusor is ready to be removed when (see Figure U):\n " }

{ "type": "ul", "children": [ "The indicator light turns solid green.", "The on-body Infusor \"beeps\".", "The white plunger rod fills the cartridge window all the way." ], "text": "" }

Note: If indicator light begins blinking red instead of green and the on-body Infusor “beeps”, call your healthcare provider (see On-Body Infusor Alarm section).

{ "type": "p", "children": [], "text": "\nNote: If indicator light begins blinking red instead of green and the on-body Infusor “beeps”, call your healthcare provider (see On-Body Infusor Alarm section).\n " }

8.2 Peel the on-body Infusor off the skin by holding the skin down and pulling on the blue tab (see Figure V). When the on-body Infusor is removed, the indicator light will turn off, the needle cover will extend over the needle to protect against accidental needle sticks, and the on-body Infusor will turn off.

{ "type": "p", "children": [], "text": "\n8.2 Peel the on-body Infusor off the skin by holding the skin down and pulling on the blue tab (see Figure V). When the on-body Infusor is removed, the indicator light will turn off, the needle cover will extend over the needle to protect against accidental needle sticks, and the on-body Infusor will turn off.\n " }

Note: You might have some discomfort after you remove the adhesive. This discomfort should quickly go away. However, some redness of the skin may remain.

{ "type": "p", "children": [], "text": "\nNote: You might have some discomfort after you remove the adhesive. This discomfort should quickly go away. However, some redness of the skin may remain.\n " }

8.3 Check the infusion site. If there is any bleeding use a cotton ball or apply a small adhesive bandage.

{ "type": "p", "children": [], "text": "\n8.3 Check the infusion site. If there is any bleeding use a cotton ball or apply a small adhesive bandage.\n " }

STEP 9 Throw Away (Dispose) of Used On-Body Infusor

{ "type": "p", "children": [], "text": "\nSTEP 9 Throw Away (Dispose) of Used On-Body Infusor\n" }

9.1 Dispose of the used FUROSCIX On-Body Infusor and prefilled cartridge together into an FDA-cleared sharps container (see Figure W).

{ "type": "p", "children": [], "text": "\n9.1 Dispose of the used FUROSCIX On-Body Infusor and prefilled cartridge together into an FDA-cleared sharps container (see Figure W).\n " }

Do not attempt to remove the cartridge from the on-body Infusor; it cannot be removed.

{ "type": "p", "children": [], "text": "\nDo not attempt to remove the cartridge from the on-body Infusor; it cannot be removed.\n " }

Do not throw away the used on-body Infusor into household trash.

{ "type": "p", "children": [], "text": "\nDo not throw away the used on-body Infusor into household trash.\n " }

If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:

{ "type": "p", "children": [], "text": "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:" }

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When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used Needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.

{ "type": "p", "children": [], "text": "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used Needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal." }

Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this.

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Do not recycle the on-body Infusor or sharps disposal container or throw them into household trash.

{ "type": "p", "children": [], "text": "\nDo not recycle the on-body Infusor or sharps disposal container or throw them into household trash.\n " }

Important: Always keep the sharps disposal container out of the reach of children.

{ "type": "p", "children": [], "text": "\nImportant: Always keep the sharps disposal container out of the reach of children.\n " }

For more information refer to: http://www.safeneedledisposal.org

{ "type": "p", "children": [], "text": "For more information refer to: http://www.safeneedledisposal.org" }

Infusor Alarm

{ "type": "p", "children": [], "text": "\nInfusor Alarm\n" }

What happened?

{ "type": "p", "children": [], "text": "\nWhat happened?\n" }

The Indicator light blinks red and the on-body Infusor "beeps" (see Figure X).

{ "type": "p", "children": [], "text": "The Indicator light blinks red and the on-body Infusor \"beeps\" (see Figure X)." }

What does it mean?

{ "type": "p", "children": [], "text": "\nWhat does it mean?\n" }

There has been an internal error or the on-body Infusor came off the skin during the infusion.

{ "type": "p", "children": [], "text": "There has been an internal error or the on-body Infusor came off the skin during the infusion." }

What to do?

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Stop using the on-body Infusor. If the on-body Infusor is on the skin, carefully remove it. Call your healthcare provider for further instructions.

{ "type": "p", "children": [], "text": "Stop using the on-body Infusor. If the on-body Infusor is on the skin, carefully remove it. Call your healthcare provider for further instructions." }

Do not reapply or reuse the on-body Infusor. It can no longer be used.

{ "type": "p", "children": [], "text": "\nDo not reapply or reuse the on-body Infusor. It can no longer be used.\n " }

Do not apply a new on-body Infusor unless instructed to do so by your healthcare provider.

{ "type": "p", "children": [], "text": "\nDo not apply a new on-body Infusor unless instructed to do so by your healthcare provider.\n " }

Symbols Legend

{ "type": "p", "children": [], "text": "\nSymbols Legend\n" }

scPharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "scPharmaceuticals, Inc." }

25 Mall Road, Suite 203, Burlington, MA 01803

{ "type": "p", "children": [], "text": "25 Mall Road, Suite 203, Burlington, MA 01803" }

1-855-SCPHARMA (1-855-727-4276)

{ "type": "p", "children": [], "text": "1-855-SCPHARMA (1-855-727-4276)" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Issued: 10/2023

{ "type": "p", "children": [], "text": "Issued: 10/2023" }

Reg-0017 Rev 01

{ "type": "p", "children": [], "text": "Reg-0017 Rev 01" }

Cartridge Carton

{ "type": "p", "children": [], "text": "Cartridge Carton" }

NDC 71767-100

{ "type": "p", "children": [], "text": "NDC 71767-100" }

FUROSCIX ®

{ "type": "p", "children": [], "text": "FUROSCIX \n ®\n" }

(furosemide injection)

{ "type": "p", "children": [], "text": "(furosemide injection)" }

80 mg/10 mL

{ "type": "p", "children": [], "text": "80 mg/10 mL" }

(8 mg/mL)

{ "type": "p", "children": [], "text": "(8 mg/mL)" }

10 mL Single Dose Cartridge

{ "type": "p", "children": [], "text": "10 mL Single Dose Cartridge" }

FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "FOR SUBCUTANEOUS USE ONLY" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Cartridge

{ "type": "p", "children": [], "text": "Cartridge" }

NDC 71767-100

{ "type": "p", "children": [], "text": "NDC 71767-100" }

FUROSCIX ®

{ "type": "p", "children": [], "text": "FUROSCIX \n ®\n" }

(furosemide injection)

{ "type": "p", "children": [], "text": "(furosemide injection)" }

80 mg/10 mL

{ "type": "p", "children": [], "text": "80 mg/10 mL" }

(8 mg/mL)

{ "type": "p", "children": [], "text": "(8 mg/mL)" }

10 mL Single Dose Cartridge

{ "type": "p", "children": [], "text": "10 mL Single Dose Cartridge" }

FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "FOR SUBCUTANEOUS USE ONLY" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Device Tyvek Lid

{ "type": "p", "children": [], "text": "Device Tyvek Lid" }

On-Body Infusor for

{ "type": "p", "children": [], "text": "On-Body Infusor for" }

FUROSCIX®

{ "type": "p", "children": [], "text": "FUROSCIX®" }

(furosemide injection) 80 mg/10 mL (8 mg/mL) For subcutaneous use

{ "type": "p", "children": [], "text": "(furosemide injection)\n \n\n80 mg/10 mL (8 mg/mL)\n \n\nFor subcutaneous use\n " }

Device (Direct Pad Printing)

{ "type": "p", "children": [], "text": "Device (Direct Pad Printing)" }

On-Body Infusor for

{ "type": "p", "children": [], "text": "On-Body Infusor for" }

FUROSCIX ®

{ "type": "p", "children": [], "text": "FUROSCIX\n \n \n \n \n \n \n ®\n" }

(furosemide injection) 80 mg/10 mL (8 mg/mL) For subcutaneous use

{ "type": "p", "children": [], "text": "(furosemide injection)\n \n \n \n \n \n \n \n80 mg/10 mL (8 mg/mL)\n \n \n \n \n \n \n \nFor subcutaneous use\n \n \n\n \n \n\n " }

Combination Product Primary Carton

{ "type": "p", "children": [], "text": "Combination Product Primary Carton" }

NDC 71767-100-01

{ "type": "p", "children": [], "text": "NDC 71767-100-01" }

1 X 10 mL Single Dose Prefilled Cartridge

{ "type": "p", "children": [], "text": "1 X 10 mL Single Dose Prefilled Cartridge" }

1 X Single Use On-Body Infusor

{ "type": "p", "children": [], "text": "1 X Single Use On-Body Infusor" }

FUROSCIX ®

{ "type": "p", "children": [], "text": "FUROSCIX\n \n \n \n \n \n \n ®\n" }

(furosemide injection)

{ "type": "p", "children": [], "text": "(furosemide injection)" }

80 mg/10 mL

{ "type": "p", "children": [], "text": "80 mg/10 mL" }

(8 mg/mL)

{ "type": "p", "children": [], "text": "(8 mg/mL)" }

FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "FOR SUBCUTANEOUS USE ONLY" }

Single Dose

{ "type": "p", "children": [], "text": "Single Dose" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Combination Product Physician Sample Primary Carton

{ "type": "p", "children": [], "text": "Combination Product Physician Sample Primary Carton" }

NDC 71767-100-01

{ "type": "p", "children": [], "text": "NDC 71767-100-01" }

PHYSICIAN SAMPLE ONLY

{ "type": "p", "children": [], "text": "\nPHYSICIAN SAMPLE ONLY\n" }

NOT FOR SALE

{ "type": "p", "children": [], "text": "\nNOT FOR SALE\n" }

1 X 10 mL Single Dose Prefilled Cartridge

{ "type": "p", "children": [], "text": "1 X 10 mL Single Dose Prefilled Cartridge" }

1 X Single Use On-Body Infusor

{ "type": "p", "children": [], "text": "1 X Single Use On-Body Infusor" }

FUROSCIX ®

{ "type": "p", "children": [], "text": "FUROSCIX\n \n \n \n \n \n \n ®\n" }

(furosemide injection)

{ "type": "p", "children": [], "text": "(furosemide injection)" }

80 mg/10 mL

{ "type": "p", "children": [], "text": "80 mg/10 mL" }

(8 mg/mL)

{ "type": "p", "children": [], "text": "(8 mg/mL)" }

FOR SUBCUTANEOUS USE ONLY

{ "type": "p", "children": [], "text": "FOR SUBCUTANEOUS USE ONLY" }

Single Dose

{ "type": "p", "children": [], "text": "Single Dose" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

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.

Furosemide Injection is indicated as adjunctive therapy in acute pulmonary edema.

Inspect Furosemide Injection visually for particulate matter and discoloration before administration.

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).

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)].

Injection: Furosemide Injection, USP is supplied as a sterile, colorless solution as

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{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

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, CO2, 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.

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)].

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)].

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.

The following adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following adverse reactions are described elsewhere in the labeling:" }

{ "type": "", "children": [], "text": "" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nGastrointestinal 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.

{ "type": "p", "children": [], "text": "\nSystemic 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.

{ "type": "p", "children": [], "text": "\nCentral 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.

{ "type": "p", "children": [], "text": "\nHematologic 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.

{ "type": "p", "children": [], "text": "\nDermatologic-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.

{ "type": "p", "children": [], "text": "\nCardiovascular 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.

{ "type": "p", "children": [], "text": "\nOther Reactions: glycosuria, muscle spasm, weakness, restlessness, urinary bladder spasm, thrombophlebitis, transient injection site pain following intramuscular injection, fever." }

<div class="scrollingtable"><table width="100%"> <col width="32%"/> <col width="34%"/> <col width="34%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Drug/Substance Class or Name</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Drug Interaction Effect</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Recommendations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Aminoglycoside antibiotics</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function <span class="Italics">[see Warnings and Precautions (<a href="#s15">5.3</a>)].</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Avoid combination except in life-threatening situations.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ethacrynic acid </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Possibility of ototoxicity <span class="Italics">[see Warnings and Precautions (<a href="#s15">5.3</a>)].</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Avoid concomitant use with ethacrynic acid.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Salicylates</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">May experience salicylate toxicity at lower doses because of competitive renal excretory sites. </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor for symptoms of salicylate toxicity.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cisplatin<br/> <br/> <br/> <br/> <br/>Cisplatin and nephrotoxic drugs </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly <span class="Italics">[see Warnings and Precautions (<a href="#s15">5.3</a>)].</span> <br/> <br/> <br/> <br/>Nephrotoxicity </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <br/> <br/> <br/> <br/> <br/>Administer furosemide at lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment. Monitor renal function.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Paralytic agents</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine. </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor for skeletal muscle effect.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lithium</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide reduces lithium's renal clearance and add a high-risk of lithium toxicity.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Avoid concomitant use with lithium.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">May lead to severe hypotension and deterioration in renal function, including renal failure.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Antihypertensive drugs</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor for changes in blood pressure and adjust the dose of other antihypertensive drugs if needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Adrenergic blocking drugs or peripheral adrenergic<br/>blocking drugs</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Potentiation occurs.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor for changes in blood pressure and adjust the dose of adrenergic blocking drugs if needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Norepinephrine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide may decrease arterial responsiveness (vasoconstricting effect) to norepinephrine.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor blood pressure (or mean arterial pressure).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Chloral hydrate</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">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.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Concomitant use with chloral hydrate is not recommended.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Methotrexate and other drugs undergoing renal tubular secretion</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide may decrease renal elimination of other drugs that undergo tubular secretion.<br/>High-dose treatment of furosemide may result in elevated serum levels of these drugs and may potentiate their toxicity.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor serum levels of drugs undergoing renal tubular secretion and adjust the dose if needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cephalosporin</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor for changes in renal function.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cyclosporine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Increased risk of gouty arthritis secondary to furosemide-induced hyperuricemia and cyclosporine impairment of renal urate excretion.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor serum urate levels.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Thyroid hormones</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">High-doses (&gt; 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.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor the total thyroid hormone levels.</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <col width="32%"/> <col width="38%"/> <col width="30%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Drug/Substance Class or Name</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Drug Interaction Effect</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Recommendations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Phenytoin</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Interferes directly with renal action of furosemide.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor diuretic effects of furosemide and adjust the dose of furosemide if needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Methotrexate and other drugs undergoing renal tubular secretion</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">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.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor for enhanced toxicity of furosemide.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Indomethacin</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">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.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Patients receiving both indomethacin and furosemide should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved.</p> </td> </tr> </tbody> </table></div>

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.

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.

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.

Risk Summary

The presence of furosemide has been reported in human 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. 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.

Published reports indicate that premature infants with post conceptual age (gestational plus postnatal) less than 31 weeks receiving doses exceeding 1 mg/kg/24 hours may develop plasma levels which could be associated with potential toxic effects including ototoxicity [see Warnings and Precautions (5.3)].

Furosemide in the first year of life, especially in patients born pre-term, may precipitate nephrocalcinosis/nephrolithiasis [see Warnings and Precautions (5.2)].

Controlled clinical studies of furosemide did not include sufficient numbers of subjects aged 65 and over to determine whether they 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 patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug 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)].

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.

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The concentration of furosemide in biological fluids associated with toxicity or death is not known.

{ "type": "p", "children": [], "text": "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).

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Hemodialysis does not accelerate furosemide elimination." }

Furosemide is a diuretic which is an anthranilic acid derivative.

{ "type": "p", "children": [], "text": "Furosemide is a diuretic which is an anthranilic acid derivative." }

Chemically, it is 4-chloro-N-furfuryl-5- sulfamoylanthranilic acid.

{ "type": "p", "children": [], "text": "Chemically, it is 4-chloro-N-furfuryl-5- sulfamoylanthranilic acid." }

Furosemide is a white to slightly yellow, odorless, crystalline powder. Practically insoluble in water; freely soluble in acetone, in dimethylformamide, and in solutions of alkali hydroxides; soluble in methanol; sparingly soluble in alcohol; slightly soluble in ether; very slightly soluble in chloroform. The structural formula is as follows:

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Furosemide Injection, USP is a sterile, nonpyrogenic solution of furosemide in Water for Injection prepared with the aid of sodium hydroxide for intramuscular (IM) or intravenous (IV) use. Each mL contains: Furosemide 10 mg; sodium hydroxide 1.6 mg; Water for Injection q.s.; sodium chloride to adjust isotonicity; hydrochloric acid (q.s.) and/or sodium hydroxide (q.s.) to adjust pH between 8.0 and 9.3 if necessary.

{ "type": "p", "children": [], "text": "Furosemide Injection, USP is a sterile, nonpyrogenic solution of furosemide in Water for Injection prepared with the aid of sodium hydroxide for intramuscular (IM) or intravenous (IV) use. Each mL contains: Furosemide 10 mg; sodium hydroxide 1.6 mg; Water for Injection q.s.; sodium chloride to adjust isotonicity; hydrochloric acid (q.s.) and/or sodium hydroxide (q.s.) to adjust pH between 8.0 and 9.3 if necessary." }

Furosemide inhibits primarily the reabsorption of sodium and chloride not only in the proximal and distal tubules but also in the loop of Henle. The high degree of efficacy is largely due to this unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase and aldosterone.

The onset of diuresis following intravenous administration is within 5 minutes and somewhat later after intramuscular administration. The peak effect occurs within the first half hour. The duration of diuretic effect is approximately 2 hours.

Distribution

Furosemide is extensively bound to plasma proteins, mainly to albumin.

Plasma concentrations ranging from 1 to 400 mcg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations.

Elimination

The terminal half-life of furosemide is approximately 2 hours.

Metabolism

Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man.

Excretion

Significantly more furosemide is excreted in urine following the intravenous injection than after the tablet or oral solution.

Specific Populations

Geriatric Patients

Furosemide binding to albumin may be reduced in elderly patients. Furosemide is predominantly excreted unchanged in the urine. The renal clearance of furosemide after intravenous administration in older healthy male subjects (60 to 70 years of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects [see Use in Specific Populations (8.5)].

Patients with Renal Impairment

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.

Carcinogenesis

Furosemide was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. A small but significantly increased incidence of mammary gland carcinomas occurred in female mice at a dose approximately 8 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg/kg but not at 30 mg/kg.

Mutagenesis

Furosemide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system, and questionably positive for gene mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister chromatid exchange in human cells in vitro, but other studies on chromosomal aberrations in human cells in vitro gave conflicting results. In Chinese hamster cells it induced chromosomal damage but was questionably positive for sister chromatid exchange. Studies on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of rats treated with this drug did not induce gene conversion in Saccharomyces cerevisiae.

Impairment of Fertility

Furosemide produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic dose in the rat), approximately 7 times a human i.v. dose of 80 mg based on BSA and oral bioavailability corrections.

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature.] Protect from light.

{ "type": "p", "children": [], "text": "Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature.] Protect from light.\n" }

Furosemide Injection, USP is a sterile, colorless solution for injection, available as a single-dose vial that contains 10 mg/mL of furosemide, and is supplied as follows:

{ "type": "p", "children": [], "text": "Furosemide Injection, USP is a sterile, colorless solution for injection, available as a single-dose vial that contains 10 mg/mL of furosemide, and is supplied as follows:" }

<div class="scrollingtable"><table width="89%"> <col width="25%"/> <col width="25%"/> <col width="28%"/> <col width="22%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Unit of Sale</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Volume</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC No.</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> <p class="First">Overbagged with 5 vials per bag</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">20 mg per 2 mL<br/>(10 mg per mL) </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2 mL fill in a 2 mL amber vial. </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">55154-9581-5</p> </td> </tr> </tbody> </table></div>

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WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children.

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Preservative Free.

{ "type": "p", "children": [], "text": "\nPreservative Free.\n" }

Discard unused portion. Do not use if solution is discolored or contains particulate.

{ "type": "p", "children": [], "text": "\nDiscard unused portion. Do not use if solution is discolored or contains particulate.\n" }

Fluid, Electrolyte, and Metabolic Abnormalities

Advise patients that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia [see Warnings and Precautions (5.1)].

Advise patients that furosemide may increase blood glucose levels and thereby affect urine glucose tests [see Warnings and Precautions (5.1)].

Photosensitivity

The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide [see Adverse Reactions (6)].

Advise hypertensive patients to avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms [see Drug Interactions (7.1)].

For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Distributed By:

Cardinal Health

Dublin, OH 43017

L55232950525

45788H

NDC 55154-9581-5

{ "type": "p", "children": [], "text": "NDC 55154-9581-5" }

FUROSEMIDE INJECTION, USP

{ "type": "p", "children": [], "text": "\nFUROSEMIDE INJECTION, USP\n" }

20 mg per 2 mL (10 mg per mL)

{ "type": "p", "children": [], "text": "\n20 mg per 2 mL (10 mg per mL)\n" }

5 x 2 mL SINGLE DOSE VIALS

{ "type": "p", "children": [], "text": "5 x 2 mL SINGLE DOSE VIALS" }