INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
LASIX® 500 mg Tablets
LASIX® 250 mg Ampoules

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

LASIX^® 500 mg Tablets
LASIX^® 250 mg Ampoules

COMPOSITION:

LASIX® 500 mg Tablet	: Each tablet contains 500 mg furosemide
LASIX® 250 mg Ampoules	: Each ampoule contains 250 mg furosemide

PHARMACOLOGICAL CLASSIFICATION:
A:18.1: Diuretics

PHARMACOLOGICAL ACTION:
LASIX^® inhibits the re-absorption of sodium and water, predominantly in the ascending loop of Henle but also in the proximal convoluted tubule. It is often possible, in situations where other methods of treatment fail to induce diuresis, to increase the excretion of sodium and water with LASIX^®, even when glomerular filtration rate is markedly impaired. LASIX^® lowers pathologically raised blood pressure, but does not affect normal levels. With oral administration of LASIX^®, the onset of action is rapid, usually within half an hour. Peak action is usually achieved after two hours, and the duration of action is 4 to 5 hours. With parenteral administration, the onset of action is even more rapid.

INDICATIONS:
These high dose preparations are indicated only in cases of greatly reduced glomerular filtration.
The use of LASIX^® high dose tablet (500 mg) and injection (250 mg) is indicated in the treatment of oliguria due to acute or chronic renal insufficiency with a glomerular filtration rate below 20 mL/min (GFR< 0,33 mL/sec).
Acute renal failure (oliguria, anuria) in the postoperative phase and in association with septic processes.
In chronic renal insufficiency in the predialytic stage and in terminal renal failure.
Renal oedema (in nephrotic syndrome usually in conjunction with ACTH or corticosteroids).

CONTRA-INDICATIONS:
Hypersensitivity to furosemide and sulphonamides.
Renal failure due to sublimate of mercury which causes nephrotoxicity and in renal failure with anuria.
Normal renal function.
Carbon tetrachloride poisoning which causes hepatotoxicity.

In early pregnancy:
LASIX^® is contra-indicated if increasing azotaemia and oliguria occur during treatment of severe progressive renal disease. In these cases the drug should be discontinued. Furosemide should not be given to lactating women.

In hepatic coma:
In states of electrolyte depletion (hypokalaemia, hyponatraemia, hypovolaemia and hypotension), therapy with LASIX^® should not be instituted until the basic condition is corrected or improved.

WARNINGS:
In patients with shock, measures should be taken to correct the blood pressure and circulating blood volume before commencing treatment with high-dose LASIX^®.
Fluid balance and serum electrolytes should be carefully controlled and careful laboratory control is essential.
Anaphylactic shock may occur and, although rare, it is always a life threatening occurrence.

DOSAGE AND DIRECTIONS FOR USE:
Intravenous drip:
On principle, the drip rate should not exceed 4 mg per minute. The minimum infusion dose is 50 -100 mg/hour. The pH of the prepared infusion fluid must not be less than 7. Acid solutions must not be used, because they may cause precipitation of furosemide.
LASIX^® must not be infused together with other medicines in the same drip.
Treatment should be started with one ampoule of LASIX^® 250 mg (25 mL). The content of one ampoule is infused together with a total of 250 mL of a 1:1 mixture of isotonic Ringer's and glucose solutions. The duration of this infusion should be about 60 minutes, care being taken that the maximum rate of infusion (4 mg per minute) is not exceeded. If the patient responds to this dose the diuresis will start even during the infusion.
If an increase in excretion of at least 40 to 50 mL per hour is not achieved with the first infusion, a second infusion must be started one hour after the first using twice the initial dose in twice the initial amount of infusion fluid (2 x 250 mg LASIX^® ampoules = 500 mg in 500 mL infusion fluid). The duration of this infusion is about 2 hours again calculated on the maximum rate of infusion (4 mg per minute).
If this still fails to produce the desired effect, a third infusion is started one hour after the end of the second using 4 ampoules LASIX^® 250 mg (1000 mg) in 400 mL Ringer's injection with glucose (1:1). The duration of this infusion is 4 hours. If still no satisfactory diuretic effect is obtained, dialysis should be considered.
The prepared solution should be used as soon as possible.

Oral administration:
The tablets should be taken with some fluid after breakfast.
The minimum dose is 250 mg. The maximum dose is 1500 mg/24 hours. In exceptional cases the dose may be increased up to 2000 mg/24 hours.
Oral administration of LASIX^® 500 mg tablets is suitable for continuation of treatment after beginning parenterally.
The guiding principle for oral dosage is the effective dose determined individually by intravenous infusion. This is generally 1 - 4 tablets. If no adequate dieresis is achieved within 4 to 6 hours of ingestion, the initial dose should be increased by ½ to 1 tablet. (Example: initial dose, 2 tablets; second dose, 2½ to 3 tablets).
In patients with chronic renal insufficiency, therapy can be started with LASIX^® 500 mg tablets. The initial dose is 250 mg (½ tablet). If this dose produces no adequate response within 4 to 6 hours, it can be increased by ½ a tablet (250 mg)every 4 to 6 hours until the individual effective dose is reached. This is generally between ½ to 4 tablets.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side effects of LASIX^® therapy have been reported infrequently but the following may occur:

1.	With parenteral use of LASIX® in high doses reversible deafness and tinitus have been reported when the infusion is faster than 4 mg per minute.
2.	Various forms of dermatitis including urticaria, exfoliative dermatitis and pruritis, as well as paraesthesia, blurring of vision, postural hypotension, nausea, vomiting or diarrhoea may occur. Allergic reactions (even shock, skin eruptions, interstitial nephritis). Various other forms of hypersensitivity include vasculitis; fever; intestinal nephritis and photo sensitivity.
3.	Anaemia, leucopenia, aplastic anaemia and thrombocytopenia (with purpura) may occur. Rare cases of agranulocytosis, which responded to treatment, have occurred.
4.	Asympotomatic hyperuricaemia may occur and gout may be precipitated.
5.	Alterations in glucose tolerance test with abnormalities of the fasting and 2 hour postprandial sugar levels have been observed and cases of precipitation of diabetes mellitus have been reported. The fluid balance should be carefully supervised during treatment with LASIX®.
6.	LASIX® may lower serum calcium levels and cases of tetany have been reported. In premature infants, calcium salts may be deposited in renal tissue (nephrocalcinosis).
7.	Excessive diuresis may result in dehydration and reduction in blood volume, with circulatory collapse and with the possibility of vascular thrombosis and embolism, particularly in elderly patients.
	Excessive loss of potassium in patients receiving cardiac glycosides may precipitate digitalis toxicity.
	Care should also be taken in patients receiving potassium depleting steroids.
8.	Electrolyte disturbances:
	Hypokalaemia may be counteracted with a potassium rich diet. If a deficiency state exists - especially in cirrhosis - the serum potassium must first be restored by potassium supplementation, and if necessary, sodium and chloride. Because of the strong natruretic effect of LASIX® the sodium levels could be reduced especially if the oedema is reduced quickly. Electrolyte depletion presents itself as weakness, dizziness, lethargy, cramps in the legs, loss of appetite, vomiting and/or mental confusion, dryness of mouth, visual impairment, dehydration, fall in blood pressure, circulatory disturbances (or collapse), thrombophilia and feeling of pressure in the head.
	A markedly reduced sodium intake may impair the diuretic effect of saluretics. Conversely diuresis is sometimes increased by administration of sodium chloride during medication with LASIX®. Another important point is that glomerular filtration is reduced by a very low salt diet.
9.	Animal experiments show no teratogenic effects, but the safety of furosemide in pregnancy in humans has not been established. LASIX® is therefore not recommended for use during the first and last 3 months of pregnancy. It may be used in pregnancy only if strictly indicated and only for a short term treatment. LASIX® passes into breast milk.
10.	Anaphylactic shock is rare, but is acutely life-threatening. In this case the medicine must be discontinued and the patient treated with the usual agents adrenaline, corticosteroids and antihistamines.
11.	Serum cholesterol and triglyceride levels may rise under furosemide treatment, but will usually return to normal under long term treatment within six months.
12.	In premature infants, calcium salts may be deposited in the renal tissue (nephrocalcinosis).
13.	Gastrointestinal disorders (eg. nausea, vomiting, diarrhoea) and acute pancreatitis have been observed.
14.	As with any diuretic therapy there may be a transient rise in creatinine, urea and uric acid in the blood.
15.	Any pre-existing metabolic alkalosis may be aggravated.
16.	The ability to drive or operate machinery may be impaired in certain patients.
17.	Symptoms of obstructed micturition (eg. in hydronephrosis, prostatic hypertrophy, urethral stricture) may become manifest or may be aggravated by diuretics.
18.	Isolated cases of acute Pancreatitis have been reported.
19.	Reduced glucose tolerance.

Drug Interaction:

i)	Nephrotoxicity associated with the use of cephalosporins may be potentiated when LASIX® is used in conjunction with cephalosporins. These medicines should thus not be used together.
ii)	It should be noted that LASIX® may increase the ototoxicity of aminoglycoside antibiotics (eg. kanamycin, gentamycin, tobramycin); irreversible disorders of hearing may result.
iii)	When a cardiac glycoside is administered concomitantly it should be remembered that potassium deficiency increases the sensitivity of the myocardium to digitalis. When a glucocorticoid is administered during diuretic treatment, the potassium lowering effect of the steroid must be borne in mind.
iv)	As there is a risk of hearing damage after concomitant use of cisplatin and furosemide, these two drugs should not be administered simultaneously.
v)	Furosemide may sometimes attenuate the effects of other drugs (eg of antidiabetics and of pressor amines) and potentiate them (eg. the effect of salicylates, theophylline, lithium and curare type muscle relaxants).
vi)	Non-steroidal anti-inflammatory drugs (eg. indomethacin) may potentiate the effect of LASIX® and may cause renal failure in case of pre-existing hypovolaemia.
vii)	The effect of other antihypertensive agents may be potentiated by furosemide especially in combination with ACE-inhibitors; a marked fall in blood pressure may be seen.
viii)	In the case of laxative abuse the risk of increased potassium loss should be borne in mind.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
After the ingestion of an overdosage there is some danger of dehydration and electrolyte depletion due to excessive diuresis.
The guiding principle of treatment is water and electrolyte replacement in accordance with urine output (with monitoring of carbohydrate metabolism if necessary).

IDENTIFICATION:

LASIX® Ampoule 250 mg:	A clear, colourless solution in a 25 mL amber glass ampoule, coded with a yellow ring.
LASIX® 500 mg Tablets:	Light yellow, biconvex, oblong tablet with three score-lines on either side. The four segments of the oblong tablet are marked with the letters PDLX respectively. On each segment the Hoechst logo appears on the reverse side.

PRESENTATION:

LASIX® Ampoule 250 mg:	Carton of 5 ampoules.
LASIX® 500 mg Tablets:	Amber glass bottles containing 30 to 100 tablets.

STORAGE INSTRUCTIONS:
Store below 25°C and protect from light.
Exposure to light may cause a discolouration of the tablets.
Keep out of reach of children.

REGISTRATION NUMBER (OR REFERENCE NUMBERS) (ACT 101/1965):

LASIX® 250 mg Ampoule:	H1920 (Act 101/1965)
LASIX® 500 mg Tablets:	D/18.1/266

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Noristan Limited
326 Marks Street, Waltloo, Pretoria.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
May 1991

Hoechst Pharmaceuticals
Division of
Noristan Limited

        H 43/05
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