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Product Name
:
FRUMIX (amp)
Chemical Name
:
Furosemide
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Diuretic, Loop
Pharmaceutical Form
:
Ampoule
Composition
:
Furosemide 20mg/ 40mg
Monitoring Parameters
Dosing
 
Dosing: Adult
Edema, heart failure:
Oral: Initial: 20-80 mg/dose; if response is not adequate, may repeat the same dose or increase dose in increments of 20-40 mg/dose at intervals of 6-8 hours; may be titrated up to 600 mg/day with severe edematous states; usual maintenance dose interval is once or twice daily. Note: Dosing frequency may be adjusted based on patient-specific diuretic needs.
I.M., I.V.: Initial: 20-40 mg/dose; if response is not adequate, may repeat the same dose or increase dose in increments of 20 mg/dose and administer 1-2 hours after previous dose (maximum dose: 200 mg/dose). Individually determined dose should then be given once or twice daily although some patients may initially require dosing as frequent as every 6 hours. Note: ACC/AHA 2009 guidelines for heart failure recommend a maximum single dose of 160-200 mg.
Continuous I.V. infusion (Howard, 2001; Hunt, 2009): Initial: I.V. bolus dose 20-40 mg over 1-2 minutes, followed by continuous I.V. infusion doses of 10-40 mg/hour. If urine output is <1 mL/kg/hour, double as necessary to a maximum of 80-160 mg/hour. The risk associated with higher infusion rates (80-160 mg/hour) must be weighed against alternative strategies. Note: ACC/AHA 2009 guidelines for heart failure recommend 40 mg I.V. load, then 10-40 mg/hour infusion.

Acute pulmonary edema:
I.V.: 40 mg over 1-2 minutes. If response not adequate within 1 hour, may increase dose to 80 mg. Note: ACC/AHA 2009 guidelines for heart failure recommend a maximum single dose of 160-200 mg.
Hypertension, resistant (Chobanian, 2003; JNC 7): Oral: 20-80 mg/day in 2 divided doses
Refractory heart failure: Oral, I.V.: Doses up to 8 g/day have been used.

Dosing: Pediatric

Edema, heart failure: Infants and Children:
Oral: Initial: 2 mg/kg/dose increased in increments of 1-2 mg/kg/dose with each succeeding dose at intervals of 6-8 hours until a satisfactory response is achieved; maximum dose: 6 mg/kg/dose
I.M., I.V.: Initial: 1 mg/kg/dose; if response not adequate, may increase dose in increments of 1 mg/kg/dose and administer not sooner than 2 hours after previous dose, until a satisfactory response is achieved; may administer maintenance dose at intervals of every 6-12 hours; maximum dose: 6 mg/kg/dose
Hypertension, resistant (unlabeled; AAP, 2004): Children 1-17 years: Oral: Initial: 0.5-2 mg/kg/dose once or twice daily; maximum dose: 6 mg/kg/dose

Dosing: Geriatric

Oral, I.M., I.V.: Initial: 20 mg/day; increase slowly to desired response.

Dosing: Renal Impairment

Acute renal failure: Doses up to 1-3 g/day may be necessary to initiate desired response; avoid use in oliguric states.
Not removed by hemo- or peritoneal dialysis; supplemental dose is not necessary.

Dosing: Hepatic Impairment

Diminished natriuretic effect with increased sensitivity to hypokalemia and volume depletion in cirrhosis. Monitor effects, particularly with high doses.
Use
 
Management of edema associated with heart failure and hepatic or renal disease; acute pulmonary edema; treatment of hypertension (alone or in combination with other antihypertensives)
Canadian labeling: Additional use: Furosemide Special Injection and FRUMIX® Special (products not available in the U.S.): Adjunctive treatment of oliguria in patients with severe renal impairment
Adverse Reactions
 
Frequency not defined.
Cardiovascular: Acute hypotension, chronic aortitis, necrotizing angiitis, orthostatic hypotension, vasculitis
Central nervous system: Dizziness, fever, headache, hepatic encephalopathy, lightheadedness, restlessness, vertigo
Dermatologic: Bullous pemphigoid, cutaneous vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity, pruritus, purpura, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Cholesterol and triglycerides increased, glucose tolerance test altered, gout, hyperglycemia, hyperuricemia, hypocalcemia, hypochloremia, hypokalemia, hypomagnesemia, hyponatremia, metabolic alkalosis
Gastrointestinal: Anorexia, constipation, cramping, diarrhea, nausea, oral and gastric irritation, pancreatitis, vomiting
Genitourinary: Urinary bladder spasm, urinary frequency
Hematological: Agranulocytosis (rare), anemia, aplastic anemia (rare), eosinophilia, hemolytic anemia, leukopenia, thrombocytopenia
Hepatic: Intrahepatic cholestatic jaundice, ischemic hepatitis, liver enzymes increased
Local: Injection site pain (following I.M. injection), thrombophlebitis
Neuromuscular & skeletal: Muscle spasm, paresthesia, weakness
Ocular: Blurred vision, xanthopsia
Otic: Hearing impairment (reversible or permanent with rapid I.V. or I.M. administration), tinnitus
Renal: Allergic interstitial nephritis, fall in glomerular filtration rate and renal blood flow (due to overdiuresis), glycosuria, transient rise in BUN
Miscellaneous: Anaphylaxis (rare), exacerbate or activate systemic lupus erythematosus
Contraindications
 
Hypersensitivity to furosemide or any component of the formulation; anuria
Canadian labeling: Additional Contraindications (not in U.S. labeling): Hypersensitivity to sulfonamide-derived drugs; complete renal shutdown; hepatic coma and precoma; uncorrected states of electrolyte depletion, hypovolemia, or hypotension; jaundiced newborn infants or infants with disease(s) capable of causing hyperbilirubinemia and possibly kernicterus; breast-feeding. Note: Manufacturer labeling for FRUMIX° Special and Furosemide Special Injection also includes: GFR <5 mL/minute or GFR >20 mL/minute; hepatic cirrhosis; renal failure accompanied by hepatic coma and precoma; renal failure due to poisoning with nephrotoxic or hepatotoxic substances.
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Fluid/electrolyte loss: [U.S. Boxed Warning]: If given in excessive amounts, furosemide, similar to other loop diuretics, can lead to profound diuresis, resulting in fluid and electrolyte depletion. Close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration. When electrolyte depletion is present, therapy should not be initiated unless serum electrolytes, especially potassium, are normalized. Risk of hypokalemia may be increased by: rapid diuresis, poor oral potassium intake, cirrhosis, and combined use with large amounts of licorice, corticosteroids, or laxatives (chronic use).
• Hyperuricemia: Asymptomatic hyperuricemia has been reported with use; rarely, gout may precipitate.
• Nephrotoxicity: Monitor fluid status and renal function in an attempt to prevent oliguria, azotemia, and reversible increases in BUN and creatinine; close medical supervision of aggressive diuresis required. May increase risk of radiocontrast-induced nephropathy in high-risk patients.
• Ototoxicity: Rapid I.V. administration, renal impairment, excessive doses, hypoproteinemia, and concurrent use of other ototoxins is associated with ototoxicity.
• Photosensitivity: Photosensitization may occur.
• Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). A risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.

Disease-related concerns:

• Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy; correct electrolyte and acid/base imbalances prior to initiation when hepatic coma is present.
• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.
• Prostatic hyperplasia/urinary stricture: May cause urinary retention due to increased urine production, especially upon initiation of therapy.
• Systemic lupus erythematosus (SLE): May cause SLE exacerbation or activation.

Concurrent drug therapy issues:

• Antihypertensives: Coadministration of antihypertensives may increase the risk of hypotension; reduction in antihypertensive dosage may be necessary.
• Digoxin: Diuretic-induced hypokalemia may potentiate digoxin-related cardiac toxicity.

Special populations:

• Pediatrics: May lead to nephrocalcinosis or nephrolithiasis in premature infants or in children <4 years of age with chronic use. May prevent closure of patent ductus arteriosus in premature infants.
Interactions
 
ACE Inhibitors: Loop Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Aliskiren: May decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Allopurinol: Loop Diuretics may enhance the adverse/toxic effect of Allopurinol. Loop Diuretics may increase the serum concentration of Allopurinol. Specifically, Loop Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Aminoglycosides: Loop Diuretics may enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Loop Diuretics. Risk D: Consider therapy modification
Cardiac Glycosides: Loop Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. This by increasing the risk of hypokalemia. Risk C: Monitor therapy
Chloral Hydrate: Furosemide may enhance the adverse/toxic effect of Chloral Hydrate. Risk X: Avoid combination
CISplatin: Loop Diuretics may enhance the nephrotoxic effect of CISplatin. Loop Diuretics may enhance the ototoxic effect of CISplatin. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
CycloSPORINE (Systemic): May enhance the adverse/toxic effect of Loop Diuretics. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Dofetilide: Loop Diuretics may enhance the QTc-prolonging effect of Dofetilide. Risk C: Monitor therapy
Ethacrynic Acid: Furosemide may enhance the ototoxic effect of Ethacrynic Acid. Risk X: Avoid combination
Fosphenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Licorice: May enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
Lithium: Loop Diuretics may decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methotrexate: May diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics. Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic dose reductions may be necessary. Risk D: Consider therapy modification
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Neuromuscular-Blocking Agents: Loop Diuretics may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Loop Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phenytoin: May diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Probenecid: May enhance the adverse/toxic effect of Loop Diuretics. Probenecid may diminish the diuretic effect of Loop Diuretics. Probenecid may increase the serum concentration of Loop Diuretics. Management: Monitor for decreased diuretic effects or increased adverse effects of loop diuretics with concomitant use of probenecid. Bumetanide prescribing information recommends against concomitant use of probenecid. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RisperiDONE: Loop Diuretics may enhance the adverse/toxic effect of RisperiDONE. Management: Consider alternative diuretic therapy (e.g., thiazides) to more potent diuretics (e.g., furosemide) in elderly patients receiving risperidone. Patients who require use of more potent diuretic therapy should be closely monitored and adequately hydrated. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification
Sucralfate: May decrease the serum concentration of Furosemide. Sucralfate may impair the absorption of furosemide. Management: Avoid concomitant oral administration of furosemide and sucralfate. Separate administration by at least 2 hours. Does not apply to parenterally administered furosemide. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pregnancy
 
C
Pregnancy Implications
Animal studies have demonstrated maternal death, fetal toxicity, and fetal loss. There are no adequate and well-controlled studies in pregnant women. Crosses the placenta. Increased fetal urine production, electrolyte disturbances reported. Generally, use of diuretics during pregnancy is avoided due to risk of decreased placental perfusion. Monitor fetal growth if used during pregnancy; may increase birth weight.
Lactation
 
Enters breast milk/use caution
Breast-Feeding Considerations
Crosses into breast milk; may suppress lactation
Mechanism of Action
 
Inhibits reabsorption of sodium and chloride in the ascending loop of Henle and distal renal tubule, interfering with the chloride-binding cotransport system, thus causing increased excretion of water, sodium, chloride, magnesium, and calcium
Pharmacodynamics / Kinetics
 
Onset of action: Diuresis: Oral, S.L: 30-60 minutes; I.M.: 30 minutes; I.V.: ~5 minutes
Symptomatic improvement with acute pulmonary edema: Within 15-20 minutes; occurs prior to diuretic effect
Peak effect: Oral, S.L.: 1-2 hours
Duration: Oral, S.L.: 6-8 hours; I.V.: 2 hours
Protein binding: 91% to 99%; primarily to albumin
Metabolism: Minimally hepatic
Bioavailability: Oral tablet: 47% to 64%; Oral solution: 50%; S.L. administration of oral tablet: ~60%; results of a small comparative study (n=11) showed bioavailability of S.L. administration of tablet was ~12% higher than oral administration of tablet (Haegeli, 2007)
Half-life elimination: Normal renal function: 0.5-2 hours; End-stage renal disease: 9 hours
Excretion: Urine (Oral: 50%, I.V.: 80%) within 24 hours; feces (as unchanged drug); nonrenal clearance prolonged in renal impairment
 
   
 
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