FUROSEMIDE
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furosemide tablet
Med-Health Pharma, LLC
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WARNING
Furosemide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required and dose and dose schedule must be adjusted to the individual patient’s needs. (See “DOSAGE AND ADMINISTRATION”.)
DESCRIPTION
Furosemide is a diuretic which is an anthranilic acid derivative. Furosemide is a white to slightly yellow odorless, crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in solutions of dilute alkali solutions and insoluble in dilute acids. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid with the following structural formula:
Furosemide is available in 20 mg, 40 mg and 80 mg tablets for oral administration. The inactive ingredients include corn starch, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Tested by Dissolution Test 1.
CLINICAL PHARMACOLOGY
Investigations into the mode of action of furosemide have utilized micropuncture studies in rats, stop flow experiments in dogs, and various clearance studies in both humans and experimental animals. It has been demonstrated that furosemide inhibits primarily the absorption 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 the unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic
anhydrase and aldosterone.
Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man. 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.
The onset of diuresis following oral administration is within 1 hour. The peak effect occurs within the first or second hour. The duration of diuretic effect is 6 to 8 hours.
In fasted normal men, the mean bioavailability of furosemide from furosemide tablets is 64% of that from an intravenous injection of the drug. Peak plasma concentrations increase with increasing dose but times-to-peak do not differ among doses. The terminal half-life of furosemide is approximately 2 hours.
Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral solution. There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine.
INDICATION AND USAGE
Edema: Furosemide is indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephritic syndrome. Furosemide is particularly useful when an agent with greater diuretic potential is desired.
Hypertension: Oral furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with furosemide alone.
CONTRAINDICATIONS
Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.
In patients with hepatic cirrhosis and ascites, furosemide therapy is best initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is necessary during the period of diuresis.
Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and metabolic
alkalosis.
If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, furosemide should be discontinued. Cases of tinnitus and reversible or irreversible hearing impairment have been reported. Usually, reports indicate that furosemide ototoxicity is associated with rapid injection, severe renal impairment, doses exceeding several times the usual recommended dose, 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).
General
Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients. As with any effective diuretic, electrolyte depletion may occur during furosemide therapy, especially in patients receiving higher doses and a restricted salt intake. Hypokalemia may develop with furosemide, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids or ACTH.
Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects.
All patients receiving furosemide therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or gastrointestinal disturbances such as nausea and vomiting. Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been reported.
Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Patients allergic to sulfonamides may also be allergic to furosemide. The possibility exists of exacerbation or activation of systemic lupus erythematosus. As with many other drugs, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver or kidney
damage, or other idiosyncratic reactions.
Information for Patients
Patients receiving furosemide should be advised 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.
Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and thereby affect urine glucose tests.
The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide. Hypertensive patients should avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms.
Laboratory Tests
Serum electrolytes, (particularly potassium), CO
2, creatinine and BUN should be determined frequently during the first few months of furosemide therapy and periodically thereafter. Serum and urine electrolyte determinations are particularly important when the patient is vomiting profusely or receiving parenteral fluids. Abnormalities should be corrected or the drug temporarily withdrawn.
Other medications may also influence serum electrolytes.
Reversible elevations of BUN may occur and are associated with dehydration, which should be avoided, particularly in patients with renal insufficiency.
Urine and blood glucose should be checked periodically in diabetics receiving furosemide, even in those suspected of latent diabetes.
Furosemide may lower serum levels of calcium (rarely cases of tetany have been reported) and magnesium. Accordingly, serum levels of these electrolytes should be determined periodically.
Drug Interactions
Furosemide
may increase the ototoxic potential of aminoglycoside antibiotics,
especially in the presence of impaired renal function. Except in
life-threatening situations, avoid this combination.
Furosemide
tablets should not be used concomitantly with ethacrynic acid because
of the possibility of ototoxicity. Patients receiving high doses of
salicylates concomitantly with furosemide, as in rheumatic disease, may
experience salicylate toxicity at lower doses because of competitive
renal excretory sites.
Furosemide has a tendency to antagonize
the skeletal muscle relaxing effect of tubocurarine and may potentiate
the action of succinylcholine.
Lithium generally should not be
given with diuretics because they reduce lithium’s renal clearance and
add a high risk of lithium toxicity.
Furosemide may add to or
potentiate the therapeutic effect of other antihypertensive drugs.
Potentiation occurs with ganglionic or peripheral adrenergic blocking
drugs.
Furosemide may decrease arterial responsiveness to
norepinephrine. However, norepinephrine may still be used effectively.
Simultaneous administration of sucralfate and furosemide tablets may
reduce the natriuretic and antihypertensive effects of furosemide.
Patients receiving both drugs should be observed closely to determine
if the desired diuretic and/or antihypertensive effect of furosemide is
achieved. The intake of furosemide and sucralfate should be separated
by at least two hours.
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 tablets were used in conjunction with NSAIDs.
Literature
reports indicate that co-administration of indomethacin may reduce the
natriuretic and antihypertensive effects of furosemide in some patients
by inhibiting prostaglandin synthesis. Indomethacin may also affect
plasma renin levels, aldosterone excretion, and renin profile
evaluation. Patients receiving both indomethacin and furosemide should
be observed closely to determine if the desired diuretic and/or
antihypertensive effect of furosemide is achieved.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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
17.5 times the maximum human dose of 600 mg. There were marginal
increases in uncommon tumors in male rats at a dose of 15 mg/kg
(slightly greater than the maximum human dose) but not at 30 mg/kg.
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.
Furosemide
produced no impairment of fertility in male or female rats at 100
mg/kg/day (the maximum effective diuretic dose in the rat and 8 times
the maximal human dose of 600 mg/day).
Pregnancy
Teratogenic Effects
Pregnancy Category C. Furosemide has been shown
to cause unexplained maternal deaths and abortions in rabbits at 2, 4
and 8 times the maximal recommended human dose. There are no adequate
and well-controlled studies in pregnant women. Furosemide should be
used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
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 (2 times the maximal recommended human dose of
600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal
recommended human dose of 600 mg/day) 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 a
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 derived from the treated dams as
compared with the incidence in fetuses from the control group.
Nursing Mothers
Because it appears in breast milk, caution should be exercised when furosemide tablets are administered to a nursing mother.
ADVERSE REACTION
Adverse reactions are categorized below by organ system and listed by decreasing severity.
Gastrointestinal System Reactions
1. pancreatitis
| 4. Oral and gastric irritation
| 7. constipation
|
2. jaundice (intrahepatic cholestatic jaundice
| 5. cramping
| 8. nausea
|
3. anorexia
| 6. diarrhea
| 9. vomiting
|
Systemic Hypersensitivity Reactions
1. Systemic vasulitis
| 2. interstitial nephritis
| 3. necrotizing angiitis
|
Central Nervous System Reactions
1. tinnitus and hearing loss
| 4. dizziness
| 6. blurred vision
|
2. paresthesias
| 5. headache
| 7. xanthopsia
|
3. vertico
|
|
|
Hematologic Reactions
1. aplastic anemia (rare)
| 3. agranulocytosis (rare)
| 5. leukopenia
|
2. thrombocytopenia
| 4. hemolytic anemia
| 6. anemia
|
Dermatologic-Hypersensitivity Reactions
1. exfoliative dermatits
| 4. photosensitivity
| 7. pruritus
|
2. erythema multiforme
| 5. urticaria
|
|
3. purpura
| 6. rash
|
|
Cardiovascular Reaction
Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics.
Other Reactions
1. hyperglycemia
| 4. muscle spasm
| 7. urinary bladder spasm
|
2. glycosuria
| 5. weakness
| 8. thrombophlebitis
|
3. hyperuricemia
| 6. restlessness
| 9. fever
|
Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn.
OVERDOSAGE
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.
The acute toxicity of furosemide has been determined in mice, rats and dogs. In all three, the oral LD50 exceeded 1000 mg/kg body weight, while the intravenous LD50 ranged from 300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats.
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).
Hemodialysis does not accelerate furosemide elimination.
DOSAGE AND ADMINISTRATION
Edema
Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.
Adults: The usual initial dose of furosemide is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (e.g., at 8 am and 2 pm). The dose of furosemide may be carefully titrated up to 600 mg/day in patients with clinically severe edematous states.
Edema may be most efficiently and safely mobilized by giving furosemide tablets on 2 to 4 consecutive days each week.
When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable. (See
PRECAUTIONS: Laboratory Tests.)
Pediatric Patients: The usual initial dose of oral furosemide in pediatric patients is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory after the initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy in pediatric patients, the dose should be adjusted to the minimum effective level. For ease of administration, and to allow maximum flexibility in dosing, the
use of Furosemide Oral Solution is suggested.
Hypertension
Therapy should be individualized according to the patient’s response to gain maximal therapeutic response and to determine the minimal dose needed to maintain the therapeutic response.
Adults: The usual initial dose of furosemide for hypertension is 80 mg, usually divided into 40 mg twice a day. Dosage should then be adjusted according to response. If response is not satisfactory, add other antihypertensive agents.
Changes in blood pressure must be carefully monitored when furosemide is used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50% when furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of furosemide, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary.
HOW SUPPLIED
Furosemide Tablets 20 mg are supplied as white, round unscored tablets, debossed
WATSON 300 on one side in bottles of 30.
Furosemide Tablets 40 mg are supplied as white, round, scored tablets debossed
WATSON 301 on one side in bottles of 30.
Furosemide Tablets 80 mg are supplied as white, round, scored tablets debossed
WATSON 302 on one side in bottles of 30.
Note: Dispense in a tight, light-resistant container, as defined in USP, with child-resistant closure. Exposure to light might cause a slight discoloration. Discolored tablets should not be dispensed.
Store at controlled room temperature: 20°-25°C (68°-77°F). [See USP.] Protect from light.
Watson Laboratories, Inc.
Corona, CA 92880 USA
10055-13
Revised: September 2005
Repackaged By:
Med-Health Pharma, LLC
North Las Vegas, NV 89032
LB60045 rev00
PRINCIPAL DISPLAY PANEL
Furosemide Tablets 20mg
Furosemide Tablets 40mg
Furosemide Tablets 80mg
FUROSEMIDE
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FUROSEMIDE
furosemide
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FUROSEMIDE
furosemide
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Revised: 01/2011Med-Health Pharma, LLC