Burinex
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Burinex - Scientific Information

Manufacture: LEO Pharma
Country: Australia
Condition: Ascites, Edema, Pulmonary Edema
Class: Loop diuretics
Form: Tablets
Ingredients: bumetanide, starch, lactose, coloidal silica, vinyl acetate copolymer, polysorbate 80 (E433), agar (E406), magnesium stearate (E572), purified talc (E553(b))

Pharmaceutical Information

Drug Substance

Proper Name: Bumetanide
Molecular Formula: C17H20N2O5S
Molecular Weight: 364.41
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 233-234oC and
approximate pka values 0.3-4-10.

Composition

1 mg Tablet 5 mg Tablet
Bumetanide 1 5
Maize starch 100 200
Microcrystalline cellulose - -
Lactose 52.3 92
Colloidal Anhydrous Silica 5 10
Magnesium stearate 0.5 1
Agar 3 6
Polysorbate 80 0.1 0.2
Povidone 8 16
Talc 02-09-16 18

*quantities expressed as mg per tablet.

Stability and Storage Conditions

Store at 15-25 oC. 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.

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 0.005 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.

Toxicology

Acute Toxicity

Species Route LD (mg/kg) mean + SD
Mice P.O. 930 + 49
I.P. 280 + 13
S.C. 570 + 33
I.V. > 150 **
Adult rats P.O. > 2000
I.P. 310 + 15
I.V. > 150 **
Neonatal rats P.O. 480 + 47
Rabbits P.O. 800 + 125
I.V. 70 *

* 14 day observation period

** 2 day observation period

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 dose-related) 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.

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. Dose-related 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 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 (N1) and cochlear microphonics following intravenous administration.