PRODUCT MONOGRAPH. Bumetanide, LEO Standard. Tablets 1 and 5 mg. Diuretic

Transcription

1 PRODUCT MONOGRAPH PR BURINEX Bumetanide, LEO Standard Tablets 1 and 5 mg Diuretic LEO Pharma Inc. Thornhill, Ontario L3T 7W8 Date of Revision: 02-OCT-2010 NC Control No Registered trademark of LEO Pharma A/S used under license by LEO Pharma Inc., Thornhill, ON

2 NAME OF DRUG PR BURINEX Bumetanide, Leo Standard Tablets 1 and 5 mg THERAPEUTIC CLASSIFICATION Diuretic ACTION AND CLINICAL PHARMACOLOGY BURINEX (bumetanide) is a loop diuretic. The diuretic effect of BURINEX results largely from the inhibition of sodium reabsorption in the ascending limb of the loop of Henle. This is shown by a marked reduction in freewater clearance during hydration and tubular solute-free water reabsorption during hydropenia. BURINEX may have an additional action in the proximal tubule, since phosphaturia has been observed during BURINEX induced diuresis and the renal clearance of BURINEX is decreased by probenecid. The proximal tubular activity does not seem to be related to an inhibition of carbonic anhydrase. Potassium excretion is increased by BURINEX in a dose-related fashion. Following oral administration to normal subjects, BURINEX is rapidly and almost completely (>80%) absorbed from the gastrointestinal tract. The time to reach peak blood levels is hours. Plasma protein binding of BURINEX is approximately 95%. BURINEX is rapidly eliminated, the plasma half-life being 1.5 hours. The majority (approx. 80%) of an oral dose of BURINEX is recovered in the urine (about 60% of this BURINEX (bumetanide) Product Monograph, version 2.0 Page 2 of 19

3 as unchanged bumetanide, the remainder as metabolites). After oral administration of 1 mg of BURINEX diuresis begins within 30 minutes with a peak effect between 1 and 2 hours. Diuresis is nearly completed after 3 to 4 hours. Pharmacological and clinical studies have shown that 1 mg BURINEX produces a diuretic response similar to that of approximately 40 mg furosemide. Summary Table Of Comparative Bioavailability Data Burinex (Bumetanide) (2 X 0.5 Mg Tablets Vs. 1 X 1.0 Mg Tablet) Geometric Mean Arithmetic Mean (CV%) BURINEX 2 x 0.5 mg tablets BURINEX 1 x 1.0 mg tablet % RATIO OF GEOMETRIC MEANS AUC T (µg.hr/l) AUC I (µg.hr/l) C max (µg/l) T max (h) T 1/2 (h) The T max and T 1/2 parameters are expressed as the arithmetic means (CV%) only. INDICATIONS AND CLINICAL USE BURINEX (bumetanide) is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver and renal disease including the nephrotic syndrome. BURINEX (bumetanide) Product Monograph, version 2.0 Page 3 of 19

4 CONTRAINDICATIONS BURINEX (bumetanide) is contraindicated in patients who are anuric, in patients in hepatic coma and in states of severe electrolyte depletion until the condition is improved or corrected. BURINEX is contraindicated in patients hypersensitive to bumetanide and other sulfonamide derivatives. WARNINGS BURINEX (bumetanide) is a potent diuretic which, if given in excessive amounts, can lead to profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required and dose and dosage schedule have to be adjusted to the individual patient's needs. (See Dosage and Administration) The dose of BURINEX should be adjusted to patient's need. Excessive doses or too frequent administration can lead to profound water loss, electrolyte depletion, dehydration, reduction in blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism, particularly in elderly patients. Hypokalemia can occur as a consequence of BURINEX administration. Prevention of hypokalemia requires particular attention in the following conditions: patients receiving digitalis and diuretics for congestive heart failure, hepatic cirrhosis and ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, certain diarrheal states, or other states where hypokalemia is thought to represent particular added risks to the patient, (i.e.) history of ventricular arrhythmias. In patients with hepatic cirrhosis and ascites, sudden alterations of electrolyte balance may precipitate hepatic encephalopathy and coma. BURINEX (bumetanide) Product Monograph, version 2.0 Page 4 of 19

5 Serum electrolyte determination should be performed frequently. Ototoxicity In cats, dogs and guinea pigs, BURINEX has been shown to produce ototoxicity. In these test animals BURINEX was 5 to 6 times more potent than furosemide and, since the diuretic potency of BURINEX is about 40 to 60 times greater, it is anticipated that blood levels necessary to produce ototoxicity will rarely be achieved. The potential exists, however, and must be considered a risk particularly with therapy at high doses, repeated frequently in the face of renal excretory function impairment. Potentiation of aminoglycoside ototoxicity has not been tested for BURINEX. Like other members of this class of diuretics, BURINEX probably shares this risk. Patients allergic to sulphonamides may show hypersensitivity to BURINEX. PRECAUTIONS Serum potassium should be measured periodically and potassium supplements or potassium sparing diuretics may be required especially when high doses are used for prolonged periods. Particular caution with potassium concentration is necessary in patients receiving digitalis glycosides or potassium depleting steroids. Periodic determination of other electrolytes are also advised, particularly in patients on low salt diets. It may be advisable to hospitalize patients with hepatic cirrhosis and ascites prior to initiating therapy. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic encephalopathy and 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 BURINEX (bumetanide) Product Monograph, version 2.0 Page 5 of 19

6 metabolic alkalosis. It is essential to replace electrolyte losses and to maintain fluid balance so as to avoid any risk of electrolyte depletion, hypovolemia or hypotension. Since rigid sodium restriction is conducive to both hyponatremia and hypokalemia, such restriction is not advisable in patients on BURINEX (bumetanide) therapy. BURINEX may increase urinary calcium excretion with resultant hypocalcemia. Reversible elevation of BUN and creatinine may occur, especially in association with dehydration and in patients with renal insufficiency. Marked increases in BUN and creatinine or the development of oliguria during treatment of patients with progressive renal disease is an indication for discontinuation. Hyperuricemia may occur; it has been asymptomatic in cases reported to date. Studies in normal subjects receiving BURINEX revealed no adverse effects on glucose tolerance, plasma insulin, glucagon and growth hormone levels but the possibility of an effect on glucose metabolism exists. Periodic determinations of blood sugar should be done, particularly in patients with diabetes or suspected of latent diabetes. Patients under treatment should be observed regularly for possible occurrence of blood dyscrasias, liver damage, or idiosyncratic reactions which have been reported rarely in foreign marketing experience. BURINEX (bumetanide) Product Monograph, version 2.0 Page 6 of 19

7 DRUG INTERACTIONS Drugs With Ototoxic Potential BURINEX (bumetanide) may, in view of its ototoxic potential, enhance the ototoxic effect of aminoglycosides and simultaneous administration should generally be avoided especially in patients with impaired renal function. Drugs With Nephrotoxic Potential There has been no experience on the concurrent use of BURINEX with drugs known to have nephrotoxic potential. Simultaneous administration of these drugs should be avoided. Cardiac Glycosides Low serum potassium levels can occur as a consequence of BURINEX administration. Hypokalemia may increase the sensitivity of the myocardium to the toxic effects of digitalis. Thus correction of the hypokalemic state is required and the dose may need adjustment. Lithium Lithium should generally not be given with diuretics such as BURINEX. Concurrent administration of diuretics such as BURINEX and lithium may reduce lithium clearance. Adjustment of lithium dosage may be necessary. To minimize potential lithium toxicity close clinical observation and more frequent determination of serum lithium are required. Probenecid Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by BURINEX. This antagonistic effect of probenecid on BURINEX natriuresis is not due to a direct action on sodium excretion but is probably secondary to its inhibitory effect on renal tubular secretion of BURINEX. Thus, probenecid should not be BURINEX (bumetanide) Product Monograph, version 2.0 Page 7 of 19

8 administered concurrently with BURINEX. Indomethacin Indomethacin blunts the increases in urine volume and sodium excretion seen during BURINEX treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent therapy with BURINEX is thus not recommended. Antihypertensives BURINEX may potentiate the effect of antihypertensive drugs. Therefore, the dose of the latter may need adjustment when BURINEX is used to treat edema in hypertensive patients. Use In Pregnancy Bumetanide is neither teratogenic nor embryotoxic in mice when given in doses up to 3400 times the maximum human therapeutic dose. Bumetanide has been shown to be nonteratogenic, but it has a slight embryotoxic effect in rats when given in oral doses of 100 mg/kg/day and in rabbits at doses of 0.1 mg/kg/day. In one study, moderate growth retardation and increased incidence of delayed ossification of sternebrae were observed in rats at oral doses of 100 mg/kg/day. These effects were associated with maternal weight reduction during dosing. No such adverse effects were observed at 30 mg/kg/day. In rabbits, a dose-related decrease in litter size and an increase in resorption rate were noted at oral doses of 0.1 and 0.3 mg/kg/day. A slightly increased incidence of delayed ossification of sternebrae occurred at 0.3 mg/kg/day; however, no effects were seen at 0.03 mg/kg/day. The sensitivity of the rabbit to bumetanide parallels the marked pharmacologic and toxicologic effects of the drug in this species. BURINEX (bumetanide) Product Monograph, version 2.0 Page 8 of 19

9 Bumetanide was not teratogenic in the hamster at an oral dose of 0.5 mg/kg/day. There are no studies in pregnant women. BURINEX should be given to a pregnant woman only if the potential benefit justifies the potential risk to the fetus. Use In Nursing Mothers Since BURINEX passes into the breast milk, the drug should not be given to nursing mothers. Use In Children The safety and effectiveness of BURINEX in the pediatric age group below the age of 18 have not been established. ADVERSE REACTIONS The most frequent clinical adverse reactions observed with BURINEX (bumetanide) are muscle cramps (1.1%), dizziness (1.1%), hypotension (0.8%), headache (0.6%), nausea (0.6%), and encephalopathy (in patients with preexisting liver disease) (0.6%). One or more of these adverse reactions have been reported in approximately 4.1% of BURINEX-treated patients. Less frequent clinical adverse reactions to BURINEX are impaired hearing (0.5%), pruritus (0.4%), electrocardiogram changes (0.4%), weakness (0.2%), hives (0.2%), abdominal pain (0.2%), arthritic pain (0.2%), musculoskeletal pain (0.2%), rash (0.2%) and vomiting (0.2%). One or more of these adverse reactions have been reported in approximately 2.9% of BURINEX-treated patients. Other clinical adverse reactions, which have each occurred in approximately 0.1% of patients, are vertigo, chest pain, ear discomfort, fatigue, dehydration, sweating, BURINEX (bumetanide) Product Monograph, version 2.0 Page 9 of 19

10 hyperventilation, dry mouth, upset stomach, renal failure, asterixis, itching, nipple tenderness, diarrhea, premature ejaculation and difficulty maintaining an erection. Laboratory abnormalities reported have included hyperuricemia (18.4%), hypochloremia (14.9%), hypokalemia (14.7%), azotemia (10.6%), hyponatremia (9.2%), increased serum creatinine (7.4%), hyperglycemia (6.6%), and variations in phosphorus (4.5%), CO 2 content (4.3%), bicarbonate (3.1%) and calcium (2.4%). Although manifestations of the pharmacologic action of BURINEX, these conditions may become more pronounced by intensive therapy. Diuresis induced by BURINEX may also rarely be accompanied by changes in LDH (1.0%), total serum bilirubin (0.8%), serum proteins (0.7%), SGOT (0.6%), SGPT (0.5%), alkaline phosphatase (0.4%), cholesterol (0.4%) and creatinine clearance (0.3%). Also reported have been thrombocytopenia (0.2%) deviations in hemoglobin (0.8%), prothrombin time (0.8%), hematocrit (0.6%), WBC (0.3%), platelet counts (0.2%) and differential counts (0.1%). Increases in urinary glucose (0.7%) and urinary protein (0.3%) have also been seen. SYMPTOMS AND TREATMENTS OF OVERDOSAGE Symptoms Profound water loss and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment Discontinue the drug. Institute water and electrolyte replacement with careful monitoring BURINEX (bumetanide) Product Monograph, version 2.0 Page 10 of 19

11 of urine and electrolyte output and serum electrolyte levels. DOSAGE AND ADMINISTRATION Dosage should be individualized with careful monitoring of patient response. The usual total oral daily dosage of BURINEX (bumetanide) is 0.5 to 2.0 mg and in most patients may be given as a single dose. If the diuretic response to an initial 1 mg dose of BURINEX is not adequate, a second or third dose may be given at 4 to 5 hour intervals. The maximum recommended daily dose is 10 mg. An intermittent dose schedule, whereby BURINEX is given on alternate days or for 3 to 4 days with rest periods of 1 to 2 days in between is recommended as the safest and most effective method for the continued control of edema. In patients with hepatic failure the dosage should be kept to a minimum, and if necessary, dosage increased very carefully. A maintenance dose as low as 0.5 mg daily should be considered and the daily dose should not exceed 5 mg. (See Warnings) BURINEX (bumetanide) Product Monograph, version 2.0 Page 11 of 19

12 PHARMACEUTICAL INFORMATION Drug Substance Proper Name: Bumetanide Molecular Formula: C 17 H 20 N 2 O 5 S Molecular Weight: Chemical Name: 3-Butylamino-4-phenoxy-5-sulphamoyl-benzoic acid Structural Formula: Description: White crystalline powder with a slightly bitter taste, sensitive to light. Slightly soluble in water, ether and chloroform, moderately soluble in 96% ethanol and acetone with a melting point of o C and approximate pka values BURINEX (bumetanide) Product Monograph, version 2.0 Page 12 of 19

13 Composition 1 mg Tablet 5 mg Tablet Bumetanide Maize starch Microcrystalline cellulose Lactose Colloidal Anhydrous Silica Magnesium stearate Agar Polysorbate 80 Povidone Talc *quantities expressed as mg per tablet. Stability and Storage Conditions Store at o C. To protect from light keep the blister in outer carton.. AVAILABILITY Tablets 1 mg: White, flat, circular (8 mm), uncoated, bevelled edge tablet, marked on one face with a score line and the number 133, and with an Assyrian Lion on the other face. Blister pack of 30 tablets. Tablets 5 mg: White, flat, circular (10 mm), uncoated bevelled edge tablet marked with a score line and 5 mg on one face. Blister pack of 30 tablets. BURINEX (bumetanide) Product Monograph, version 2.0 Page 13 of 19

14 PHARMACOLOGY Renal Effects In the dog, bumetanide causes a marked increase in urine flow without significant alterations in urine osmolality. It enhances excretion of sodium, chloride and potassium at oral doses as low as mg/kg. Sodium reabsorption is reduced from 98% in control periods to 79% during I.V. infusion. Maximum diuresis occurs at 1-2 hours after oral or I.V. administration and lasts 3-6 hours. Bumetanide significantly reduces the clearance of para-aminohippuric acid (PAH) in dogs. Creatinine clearance is not significantly altered. Acute Toxicity TOXICOLOGY Species Route LD (mg/kg) mean + SD Mice Adult rats Neonatal rats Rabbits * 14 day observation period ** 2 day observation period P.O. I.P. S.C. I.V. P.O. I.P. I.V. P.O. P.O. I.V > 150 ** > > 150 ** * BURINEX (bumetanide) Product Monograph, version 2.0 Page 14 of 19

15 In rabbits, ataxia, lacrimation and tremors were observed. These symptoms were not observed in mice or rats. Chronic Toxicity Rats: Bumetanide was administered orally at doses of 10, 30 and 60 mg/kg/day to 3 groups of 60 male and 60 female rats for 78 weeks. Convulsive episodes (not doserelated) were noted in some treated (30%) and one control rat; most convulsions occurred immediately after dosing. A dose related increase in the incidence of renal dystrophic calcifications was noted. Ovarian weight was reduced in the mid and high dose groups and the incidence of testicular atrophy was increased in males in the high dose groups. The incidence of mammary tumors was slightly increased in females of the middle and high dose groups. In order to clarify the tumorigenic potential of bumetanide, the 78 week rat toxicity study was repeated using the same doses in groups of 80 males and 80 females. The oral administration of bumetanide did not increase the prevalence of mammary tumors nor affect the profile of spontaneous tumors in the rat. Dogs: Bumetanide was administered orally for 1 year to 3 groups of 3 male and 3 female dogs at dose levels of 0.12, 0.4 and 1.2 mg/kg/day. Tubular atrophy and dilation associated with varying degrees of chronic inflammatory cell infiltration and fibrosis, atrophic glomeruli, capsular thickening and fluid filled capsular cysts occurred in the kidneys of high and mid-dose group dogs. Baboons: Bumetanide was administered orally to 4 groups of 3 male and 3 female baboons for 26 weeks at dose levels of 0.1, 1.0, 5.0 and 10 mg/kg/day. After 4 weeks of dosing, the 5.0 and 10 mg/kg/day dose levels were reduced to 2.5 and 5.0 respectively because the animals appeared dehydrated. One high dose female was sacrificed because of marked deterioration in general condition. BURINEX (bumetanide) Product Monograph, version 2.0 Page 15 of 19

16 Histological examination showed calcified material associated with macrophages and inflammatory cells with eosinophilic granular casts in the renal tubules of the two high dose groups. Mutagenicity Bumetanide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence of an in vitro metabolic activated system. Reproductive Studies Mice: Doses of 0.05, 0.25 and 0.50 mg/kg/day were administered orally to 3 groups of 15 pregnant Hauschka/Nirand mice from day 6 through day 16 of gestation. A slight increase in fetal deaths and resorptions was noted at the high dose. No malformations were observed. Doses of 10, 30 and 100 mg/kg/day were administered to groups of 22 to 25 Charles River CD-1 mice from day 6 to day 15 of gestation. No signs of toxicity were observed. Rats: Doses of 10, 30 and 100 mg/kg/day were administered orally to 3 respective groups of 40 female rats from day 15 prior to mating. The same doses were administered to 3 respective groups of 20 male rats from day 84 prior to mating. Doserelated increases in fetal mortality were observed. No malformations were observed. Similar doses were administered to 30, 26 and 27 pregnant females from day 6 to day 15 of gestation. No effect on fetal mortality was seen. Moderate growth retardation and an increased incidence of delayed ossification of sternebrae were observed in pups at 100 mg/kg/day. No malformations were observed. Rabbits: Doses of 0.03, 0.10 and 0.30 mg/kg/day were administered orally to groups of 7 to 12 rabbits from day 6 to day 18 of gestation. Dams receiving the high dose showed BURINEX (bumetanide) Product Monograph, version 2.0 Page 16 of 19

17 depressed activity. Other Studies In studies with 49 cats, 55 dogs and guinea pigs, bumetanide was found to produce dose-related depressions of the auditory afferent action potentials (N 1 ) and cochlear microphonics following intravenous administration. BURINEX (bumetanide) Product Monograph, version 2.0 Page 17 of 19

18 BIBLIOGRAPHY 1. ASBURY, M.J. et al: Bumetanide: Potent new "loop" diuretic. Br. Med. J. 1972; 1: BOURKE, E. et al: The sites of action of bumetanide in man. Eur. J. Pharmacol. 1973; 23: BOURKE, E.: Some aspects of the renal action and clinical pharmacology of oral bumetanide in man. Postgrad. Med. J. 1975; 51 (Suppl. 6): BRATER, D.C. et al: Bumetanide and furosemide in heart failure. Kidney Int. 1984; 26: CARRIERE, S., Dandavino, S.: Bumetanide, a new loop diuretic. Clin. Pharmacol. Ther. 1976; 20: DAVIES, D.L. et al: Renal action, therapeutic use and pharmacokinetics of the diuretic bumetanide. Clin. Pharmacol. Ther. 1974; 15: HALLADAY, S.C. et al: Evidence for metabolism of bumetanide in man. Life Sci. 1975; 17: JAYAKUMAR, S., Puschett, J.B.: Study of the sites and mechanism of action of bumetanide in man. J. Pharmacol. Exp. Ther. 1977; 201: MARCANTONIO, L.A. et al: The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease. Br. J. Clin. Pharmacol. 1983; 15 (2): BURINEX (bumetanide) Product Monograph, version 2.0 Page 18 of 19

19 10. MOULT, P.J.A. et al: Use of bumetanide in the treatment of ascites due to liver disease. Postgrad Med. J. 1975; 51 (Suppl. 6): NIELSEN, H.R. and Bay, C.: Evaluation of the bioavailability of a 0.5 mg tablet of bumetanide in healthy volunteers. LEO Pharma A/S, Denmark. Data on file. 12. OLESEN, K.H. et al: Bumetanide, a new potent diuretic. A clinical evaluation in congestive heart failure. Act. Med. Scand. 1973; 193: VALASQUEZ, M.T. et al: Bumetanide induced rise in plasma renin activity. Clin. Pharmacol. Ther. 1978; 24 (2): WARD, A., Heel, R.C.: Bumetanide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs 1984; 28: BURINEX (bumetanide) Product Monograph, version 2.0 Page 19 of 19