Lasix (Furosemide)

LASIX® SPECIAL

Hoechst Marion Roussel

Furosemide

Diuretic

Action And Clinical Pharmacology: Animal experiments using stop-flow and micropuncture techniques have demonstrated that furosemide inhibits sodium reabsorption in the ascending limb of Henle’s loop as well as in both proximal and distal tubules. The action of furosemide on the distal tubule is independent of any inhibitory effect on carbonic anhydrase or aldosterone.

The diuretic effect of furosemide is exerted even when glomerular filtration is markedly impaired. Furosemide may promote diuresis in cases which have previously proved resistant to other diuretics.

Furosemide has no significant pharmacological effects other than on renal function.

Absorption, Metabolism and Excretion: In man, furosemide is rapidly absorbed from the gastrointestinal tract. The diuretic effect of furosemide is apparent within 1 hour following oral administration and the peak effect occurs in the first or second hour. The duration of action is 4 to 6 hours but may continue up to 8 hours. Following i.v. administration of the drug, the diuresis occurs within 30 minutes and the duration of action is about 2 hours.

Urinary excretion is accomplished both by glomerular filtration and proximal tubular secretion, together this accounts for roughly only 2/3 of the ingested dose, the remainder being excreted in the feces. A small fraction is metabolized by cleavage of the side chain.

Table I summarizes the elimination kinetics of furosemide in both normal subjects and patients with renal insufficiency.

Indications And Clinical Uses: Lasix Special 500 mg tablets and 250 mg ampuls are high-dosage formulations of furosemide and are intended exclusively for patients with severely impaired renal function. They are to be used under strict medical supervision only within a hospital setting (see Dosage).

High doses of furosemide may be used as an adjuvant treatment of oliguria and in the promotion of diuresis in the treatment of edema; in selected patients with acute renal failure, e.g., in the postoperative phase and in association with septic infections; in selected patients with chronic renal failure with fluid retention, both in the predialysis phase and when dialysis has become unavoidable, especially in the presence of acute pulmonary edema; in selected patients with the nephrotic syndrome with severe impairment of renal function, e.g., in chronic glomerular nephritis, lupus erythematosus and Kimmelstiel-Wilson syndrome.

Contra-Indications: In patients with complete renal shutdown and glomerular filtration rate below 5 mL/minute. In patients whose glomerular filtration rate is above 20 mL/minute. In such cases, it might cause extremely severe water and electrolyte losses.

Patients with hepatic cirrhosis, with renal failure due to poisoning with nephrotoxic or hepatotoxic substances and in patients with renal failure accompanied by hepatic coma and precoma.

Severe hyponatremia, hypokalemia, hypovolemia or hypotension must be regarded as contraindications until serum electrolytes and fluid balance and blood pressure have been restored to normal levels.

Known history of hypersensitivity to furosemide.

Children: As furosemide may be capable of displacing bilirubin from albumin at least in vitro, it should not be administered to jaundiced newborn infants or to infants suffering from diseases (e.g., Rh incompatibility, familial non-hemolytic jaundice, etc.) with the potential of causing hyperbilirubinemia and possibly kernicterus.

Manufacturers’ Warnings In Clinical States: 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 have to be adjusted to the individual patient’s needs (see Dosage).

Cases of tinnitus and reversible deafness have been reported. There have also been some reports of cases, the majority in children undergoing renal transplantation, in which permanent deafness has occurred. In these latter cases, the onset of deafness was usually insidious and gradually progressive up to 6 months after furosemide therapy. Hearing impairment is more likely to occur in patients with severely reduced renal function who are given large doses of furosemide parenterally, at a rate exceeding 4 mg/minute or in patients who are also receiving drugs known to be ototoxic.

Sulfonamide diuretics have been reported to decrease arterial responsiveness to pressor amines and to enhance the effect of tubocurarine. Great caution should be exercised in administering curare or its derivatives to patients undergoing therapy with furosemide and it is advisable to discontinue furosemide for 1 week prior to any elective surgery.

Pregnancy: The teratogenic and embryotoxic potential of furosemide in humans is unknown. The drug should not be used in pregnant women or in women of childbearing potential unless in the opinion of the attending physician the benefits to the patient outweigh the possible risk to the fetus.

Lactation: It should be noted that diuretics may partially inhibit lactation and that furosemide passes into the breast milk.

Precautions: General: During long-term therapy a high-potassium diet is recommended. Potassium supplements may be required especially when high doses are used for prolonged periods. Particular caution with potassium levels is necessary when the patient is on digitalis glycosides, potassium-depleting steroids, or in the case of infants and children. Potassium supplementation, diminution in dose, or discontinuation of furosemide therapy may be required.

Since rigid sodium restriction is conducive to both hyponatremia and hypokalemia, strict restriction in sodium intake is not advisable in patients receiving furosemide therapy.

Furosemide may lower the state of patient alertness and/or reactivity particularly at the start of treatment as a result of a reduction in blood pressure and other adverse reactions (see Adverse Effects).

During treatment with furosemide in high-dosage formulations (250 mg ampuls or 500 mg tablets), extreme care must always be taken to adjust dosage to individual requirements. Rate of infusion must not exceed 4 mg/minute.

Geriatrics: Excessive diuresis induced by furosemide may result in dehydration and reduction of blood volume, with circulatory collapse and with the possibility of vascular thrombosis and embolism particularly in elderly patients. Furosemide may cause electrolyte depletion.

Children: In children, urge to defecate, complaints of abdominal pain and cramping have been reported after i.v. furosemide. An association of these symptoms with a low serum calcium and/or a low calcium: protein ratio is possible. Calcium levels should be monitored when children are to receive i.v. furosemide for durations longer than a few days. Furosemide may lower serum calcium levels, and rare cases of tetany have been reported. Accordingly, periodic serum calcium levels should be obtained.

Patients with Special Diseases and Conditions: Increases in blood glucose and alterations in glucose tolerance tests with abnormalities of the fasting and 2-hour postprandial blood sugar levels have been observed. Rare cases of precipitation of diabetes mellitus have been reported. Asymptomatic hyperuricemia can occur and gout may rarely be precipitated.

Laboratory Test: Frequent serum electrolyte and CO2 content determinations should be performed during the first few months of therapy and periodically thereafter. It is essential to replace electrolyte losses and to maintain fluid balance so as to avoid any risk of electrolyte depletion (hyponatremia, hypochloremia, hypokalemia, hypomagnesemia or hypocalcemia), hypovolemia, or hypotension.

Checks on urine and blood glucose should be made at regular intervals especially in diabetics and in those suspected of latent diabetes when receiving furosemide. Increases in blood glucose and alterations in glucose tolerance tests with abnormalities of the fasting and 2-hour postprandial blood sugar levels have been observed.

Frequent BUN determinations during the first few months of therapy and periodically therafter, as well as regular observations for possible occurrence of blood dyscrasias, liver damage or idiosyncratic reactions are advisable.

Drug Interactions: Sulfonamide diuretics have been reported to decrease arterial responsiveness to pressor amines and to enhance the effect of tubocurarine or curare-type muscle relaxants.

In edematous hypertensive patients being treated with antihypertensive agents, care should be taken to reduce the dose of these drugs when furosemide is administered, since this drug potentiates their hypotensive effect.

Especially in combination with ACE inhibitors, a marked hypotension may be seen sometimes progressing to shock. The concomitant administration of furosemide with ACE-inhibition may lead to deterioration in renal function and, in isolated cases, to acute renal failure.

Since furosemide is a sulfonamide derivative, it should be used with caution in patients with known sulfonamide sensitivity.

In case of concomitant abuse of laxatives, the risk of an increased potassium loss should be considered.

Glucocorticoids, carbenoxolone and licorice may also increase potassium loss.

It has been reported in the literature that diuretics such as furosemide may enhance the nephrotoxicity of cephaloridine. Therefore the simultaneous administration of both drugs is not advisable.

Administration of furosemide to diabetic patients may result in possible decrease of diabetic control. Dosage adjustments of the antidiabetic agent may be needed.

Renal clearance of lithium is decreased in patients receiving furosemide, and lithium toxicity may result.

Concurrent administration of furosemide and sucralfate should be avoided, as sucralfate reduces the absorption of furosemide and hence weakens its effect.

Patients receiving high doses of salicylates in conjunction with furosemide may experience salicylate toxicity at lower doses because of competition for renal excretory sites.

Nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ASA) may attenuate the effect of furosemide and may cause renal failure in case of pre-existing hypovolemia. Probenecid and anticonvulsants drugs (phenytoin, carbamazepine, phenobarbital) may also attenuate the effect of furosemide.

Clinical studies have shown that the administration of indomethacin can reduce the natriuretic and antihypertensive effect of furosemide in some patients. This response has been attributed to inhibition of prostaglandin synthesis by indomethacin. Therefore, when indomethacin is added to the treatment of a patient receiving furosemide, or furosemide is added to the treatment of a patient receiving indomethacin, the patient should be closely observed to determine if the desired effect of furosemide is obtained. Indomethacin blocks the furosemide-induced increase in plasma-renin activity. This fact should be kept in mind when evaluating plasma-renin activity in hypertensive patients.

Hearing impairment is more likely to occur in patients who are also receiving drugs known to be ototoxic (e.g., aminoglycosides antibiotics, ethacrynic acid and cisplatin) (see Warnings).

Administration of i.v. furosemide within 24 hours after the ingestion of chloral hydrate has caused the sensation of heat, sweating, restlessness, nausea, rise in blood pressure and tachycardia in isolated cases.

Pediatrics: Renal calcifications (nephrolithiasis and nephrocalcinosis), from barely visible on x-ray to staghorn, have occurred in some severely premature infants treated with i.v. furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent use of chlorothiazide has been reported to decrease hypercalciuria and to dissolve some calculi.

When administered to premature infants with respiratory distress syndrome in the first few weeks of life, diuretic treatment with furosemide may accentuate the risk of a patent ductus arteriosus.

Adverse Reactions: Adverse reactions are categorized below by body system.

Metabolic: Electrolyte depletion has occurred during therapy with furosemide, especially in patients receiving higher doses with a restricted salt intake. Electrolyte depletion manifests itself by adverse reactions attributed to various body systems: weakness, dizziness, drowsiness, polyuria, polydipsia, orthostatic hypotension, lethargy, leg cramps, sweating, bladder spasms, anorexia, vomiting, mental confusion and meteorism (see Precautions).

Transient elevations of BUN have been observed, especially in patients with renal insufficiency.

As with other diuretics, there may be a transient rise in serum creatinine, uric acid (this may lead to gout attack in predisposed patients), cholesterol and trigylceride levels during furosemide treatment.

Treatment with furosemide has occasionally caused some deterioration in cases of manifest diabetes, or has made latent diabetes manifest.

Pre-existing metabolic alkalosis (e.g., decompensated cirrhosis of the liver) may be aggravated.

Cardiovascular: Too vigorous diuresis may induce orthostatic hypotension or acute hypotensive episodes.

In extreme cases, hypovolemia may lead to dehydration, circulatory collapse and thrombophilia. Thrombophlebitis and emboli have been reported.

CNS and Special Senses: At the commencement of treatment, excessive diuresis may give rise, especially in elderly patients, to a feeling of pressure in the head, dizziness, dryness of the mouth or blurring of vision.

Paresthesia, vertigo and xanthopsia have been reported.

Cases of tinnitus and reversible deafness have been reported. There have also been some reports of cases, the majority in children undergoing renal transplantation, in which permanent deafness has occurred. In these latter cases, the onset of deafness is usually insidious and gradually progressive up to 6 months after furosemide therapy. Hearing impairment is more likely to occur in patients with severely reduced renal function who are given large doses of furosemide parenterally, at a rate exceeding 4 mg/minute or in patients who are also receiving drugs known to be ototoxic (see Warnings).

Dermatologic and Hypersensitivity: Various forms of dermatitis, including urticaria, erythema multiforme, exfoliative dermatitis, pruritus and epidermolysis bullosa have occurred. Dermatologic and hypersensitivity reactions to furosemide also include purpura, photosensitivity, rash. Systemic hypersensitivity reactions include vasculitis, interstitial nephritis and necrotizing angiitis. Anaphylactic shock is rare and can occur with the i.v. administration of furosemide.

Hematologic: Anemia, eosinophilia, leukopenia and thrombocytopenia (with purpura) have occurred, as well as agranulocytosis, aplastic anemia and hemolytic anemia.

Urogenital: Symptoms of obstructed micturition (e.g., in hydronephrosis, prostatic hypertrophy, ureterostenosis) may become manifest or may be aggravated during medication with diuretics.

Gastrointestinal: In children, urge to defecate, complaints of abdominal pain and cramping have been reported after i.v. furosemide (see Precautions). Pancreatitis, anorexia, jaundice (intrahepatic cholestatic jaundice) oral and gastric burning, diarrhea, nausea, vomiting and constipation have been reported. Rare occurrence of sweet taste have been reported.

Other reactions: In addition, the following adverse reactions have been reported: transient pain at injection site following i.m. injection and paradoxical swelling.

Symptoms And Treatment Of Overdose: Symptoms: Dehydration, electrolyte depletion and hypotension may be caused by overdosage or accidental ingestion. tag_Treatment

Treatment: The drug should be discontinued and appropriate corrective treatment applied: 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).

Dosage And Administration: The high-dosage formulations, furosemide 250 mg (solution for i.v. infusion) and furosemide 500 mg (tablets), are intended exclusively for selected patients with severely impaired glomerular filtration (GFR of less than 20 mL/min but greater than 5 mL/min), who have not responded to conventional doses of furosemide (see Indications).

When furosemide is used in high doses careful attention must be paid to the following points: If the patient is in shock, hypovolemia and hypotension must be corrected by appropriate measures before starting therapy. Any serious abnormalities of serum electrolytes or acid-base balance must be corrected beforehand. When treating patients with conditions likely to interfere with micturition, such as prostatic hypertrophy or disturbed consciousness, it is absolutely essential to ensure free urinary drainage. Because of the wide and unpredictable individual variations in responsiveness it is important to adjust dosage and route of administration to individual needs. Once the desired rise in urinary output has begun, exact balance of water intake and water output must be maintained throughout the course of treatment, so as to avoid hypovolemia or hypotension. Careful electrolyte replacement is also necessary.

The dosage of high strength furosemide given below is for adults only. The dosage regimen for children has not yet been determined. The administration of large doses of furosemide in children has been associated with permanent deafness (see Warnings).

Parenteral: If conventional doses (40 to 80 mg i.v.) fail to produce an adequate diuresis within 30 minutes, infusion treatment with Lasix Special 250 mg may be started:

Infusion fluid: Lasix Special for i.v. use is a mildly buffered alkaline solution. Lasix Special can be added to 5% Dextrose in Water, Isotonic Saline or Lactated Ringer’s Injection when mixed as directed and prepared immediately before use. Furosemide may precipitate in and therefore is incompatible with solutions in which the pH of the resulting mixture is less than 5.5.

Furosemide should not be added into the tubing of a running infusion solution. It should also not be mixed with any other drugs in the infusion bottle.

Initial dose: 250 mg (25 mL ampul) are mixed with 250 mL of a suitable solution (see above) and given by i.v. drip at a rate not exceeding 4 mg/minute (infusion time for 275 mL is approximately 1 hour).

Additional dose: Should the initial dose fail to produce an adequate increase (at least 40 to 50 mL/hour) in urinary output, a second infusion of 500 mg (appropriately diluted) should be started 1 hour after the conclusion of the first. The duration of this infusion is determined by the maximum rate of furosemide 4 mg/minute. A maximum daily dose of 1 000 mg should not be exceeded.

For hypervolemic patients, it is advisable to give the high-dosage formulation of furosemide undiluted, or in a suitable volume (e.g., 250 mg in 50 mL) of infusion fluid so as to avoid the risk of overhydration. I.V. infusions of the undiluted solution must be given with the aid of a motor-driven precision syringe so as to make sure that the upper limit of furosemide 4 mg (0.4 mL)/minute is not exceeded.

If a satisfactory diuretic response is achieved (40 to 50 mL/hour), the effective dose can be repeated every 24 hours.

Parenteral therapy should be replaced by treatment with furosemide 500 mg tablets as soon as this is practical.

Oral: Initial dose: The dose which has been found to produce an effective diuresis when given i.v. is used as the initial dose orally.

Additional dose: Should the initial dose fail to produce an adequate increase (at least 40 to 50 mL) in urinary output within 4 to 6 hours, the dose may be raised by 250 to 500 mg at a time.

For selected patients with advanced chronic renal failure, diuretic therapy may be started with furosemide orally. If conventional doses (80 to 160 mg orally) fail to produce an adequate diuresis, a single dose of 250 mg is given as a starting dose. If a satisfactory diuresis does not ensue within 4 to 6 hours, the initial dose may be doubled to 500 mg.

The criterion of optimal dosage is a urinary output of at least 2.5 L/day. A maximum daily dose of 1 000 mg should not be exceeded.

Availability And Storage: Ampuls: Each 25 mL amber ampul contains: furosemide 250 mg (10 mg/mL) in a sterile solution at a pH of 9.1. Boxes of 10.

Tablets: Each yellow, round, quarter-scored tablet (Code DLX) contains: furosemide 500 mg. Amber bottles of 20. (Shown in Product Recognition Section)

LASIX® SPECIAL Hoechst Marion Roussel Furosemide Diuretic

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