Frusene Tablets

Furosemide 40.0 mg

Triamterene 50.0 mg

For excipients, refer to 6.1.

Tablet.

Pale-yellowish, convex, scored, uncoated tablet, diameter 9 mm.

For the treatment of oedematous conditions, where a prompt diuresis is required and where potassium conservation is important: congestive heart failure, pulmonary oedema, cardiac oedema, hepatic oedema, and ascites.

A fixed ratio combination should only be used if titration with component drugs separately indicates that this product is appropriate.

The dosage depends on individual requirements.

Tablets should be taken with a sufficient quantity of liquid, preferably one hour before food because concomitant intake of food can reduce the absorption of furosemide by 30%.

Adults:

The usual adult dose is ½ to 2 tablets, taken in the morning. Maximum daily dose is 6 tablets.

Children:

Not recommended for use in children.

Hepatic insufficiency:

Treatment must be initiated using a small dose with careful monitoring of the serum electrolyte concentrations (refer to section 4.4. Special warnings and precautions for use). The natriuretic potency of Furosemide may be weakened in patients with hepatic insufficiency but the kaliuretic potency usually remains. Elimination of triamterene is slowed down and its efficacy is increased in severe hepatic insufficiency.

Moderate or severe renal impairment (Creatinine Clearance < 25 ml/min). Hepatic coma and severe hepatic insufficiency. Anuria. Hyperkalaemia. Sodium depletion and accompanying hypovolemia. Hypersensitivity to Furosemide, triamterene or to the excipients of the preparation. Hypersensitivity to sulphonamides (because of cross-sensitivity between sulphonamides and furosemide.

Electrolyte balance of the patients receiving furosemide and triamterene must be monitored. More frequent and careful monitoring are required for the following patient groups: diabetics, patients with cardiac, renal or hepatic impairment and elderly patients. Of note, the risk of electrolyte disturbances can be increased even in mild renal failure. Hepatic failure and alcoholic cirrhosis particularly predispose to hypokalaemia and hypomagnesaemia. Refer to section 4.8 for details of electrolyte and metabolic abnormalities.

In elderly patients there is no requirement for dosage adjustments unless a clinically significant impairment of renal or hepatic function also exists. Creatinine and serum electrolytes should be monitored.

Diuretics must be administered carefully to avoid hypotension and circulatory collapse in patients with pulmonary oedema caused by acute myocardial infarction.

Daily weight loss should not exceed 1 kg daily to avoid relative intravascular dehydration; particular care is required in hepatic failure and ascites. Caution should also be exercised in the presence of liver disease as hepatic coma may be precipitated in susceptible cases.

Development of megaloblastic anaemia is possible in patients having folic acid deficiency (e.g. in hepatic cirrhosis). Triamterene may worsen this condition as it is a weak folic acid antagonist. In patients considered at risk, red cell folate levels should be measured and replacement given as appropriate.

Furosemide and, to a lesser extent, triamterene may predispose the patient to the development of hyperuricaemia and precipitate gout attacks (refer to section 4.8).

Acute diuresis may cause urinary retention in patients with urinary outflow obstruction (such as prostatic hyperplasia). Urinary output must be monitored in these patients.

Co-administration with nonsteriodal anti-inflammatory analgesics (NSAIDs) should be avoided wherever possible. Where this is not possible particularly careful monitoring is required to ensure that the diuretic effect is not attenuated (Refer to section 4.5)

Triamterene may cause blue discolouration of the urine.

Triamterene reduces the risk of hypokalaemia induced by use of furosemide. This is the rationale for using the two medications in a combination product.

Effect of drugs and other substances on Frusene

Drugs likely to increase the hypotensive effect:

ACE inhibitors, angiotensin receptor antagonists, beta-blockers, calcium-channel blockers, diuretics, nitrates, other antihypertensive drugs and other drugs such as dipyridamole, moxisylate, tizanidine, alprostadil.

Drugs likely to exacerbate hyponatraemia:

Diuretics, carbamazepine, aminoglutethamide, trimethoprim.

Drugs and other substances likely to exacerbate hypokalaemia:

Thiazide and loop diuretics, corticosteroids, glychyrrizin (contained in liquorice), amphotericin B.

Drugs and other substances likely to exacerbate hyperkalaemia:

Potassium salts or supplements, potassium-sparing diuretics (such as amiloride and spironolactone), ACE inhibitors, angiotensin receptor antagonists, ciclosporin, tacrolimus, trilostane and drosperinone.

Drugs and other substances likely to decrease the hypotensive and natriuretic effect:

Nonsteroidal anti-inflammatory analgesics (NSAIDs), probenecid, phenytoin, tobacco smoking. Cholestyramine and cholestipol prevent the absorption of Frusene, so they should be taken at different times, preferably 4 to 6 hours after Frusene administration.

Drugs likely to exacerbate nephrotoxicity:

Aminoglycoside and cephalosporin antibiotics, amphotericin B. Concomitant use of NSAIDs and Frusene increases the risk of acute renal failure (refer to section 4.4).

Drugs likely to exacerbate ototoxicity:

Aminoglycoside antibiotics, cisplatin.

Concomitant intake of food may reduce the absorption of furosemide by approximately 30%.

Effect of Frusene on other drugs

Frusene induced electrolyte disturbances (such as hypokalaemia) may predispose the patient to arrhythmogenic effect of other drugs (such as digoxin and drugs that prolong the QT interval). Effect of competitive muscle relaxants may also be reduced in hypokalaemia.

Frusene may reduce the elimination of lithium, phenobarbital, and amantadine causing toxic drug concentrations. Drug concentrations and/or signs of toxicity should be monitored in concomitant use and if Frusene is discontinued.

Frusene may reduce the efficacy of antihyperglycaemic medications. Adjustment of the dose of antihyperglycaemic medications may be needed in concomitant use.

Warfarin and clofibrate compete with Furosemide in the binding to serum albumin. This may have clinical significance in patients with low serum albumin levels (e.g. in nephrotic syndrome). Furosemide does not change the pharmacokinetics of warfarin to a significant extent, but the strong diuresis with associated dehydration may weaken the antithrombotic effect of warfarin.

Furosemide crosses the placenta and has been shown to reduce placental circulation. It may predispose the foetus to hypercalciuria, nephrocalcinosis, and secondary hyperparathyroidism. Closure of the patent arterial duct can also be hindered after birth. Use of Furosemide in premature infants has led to development of sensorineural hearing loss. Triamterene crosses the placenta, but has not been associated with causing birth defects.

Furosemide and triamterene are excreted in the breast milk in small quantities and Furosemide may impair lactation.

Frusene Tablets should be used during pregnancy or lactation only if clearly needed.

Occasionally Frusene may cause hypotension, especially at the start of therapy. This may manifest itself as dizziness or faintness. If affected, avoid driving or the use of machinery.

Of the adverse events caused by Furosemide and triamterene, most are linked to the pharmacological effects of the compounds, and they are more common in patients with multiple illnesses or compromised physical condition.

Furosemide:

Triamterene:

Symptoms of overdose include increased diuresis, natriuresis, hypovolaemia, and decrease of blood pressure (refer to section 4.8. Undesirable effects). After an overdose, activated charcoal should be administered as soon as possible to decrease absorption of the drug.. Fluid and electrolyte balance must be monitored. Sodium chloride -infusion can be used to sustain blood pressure. Otherwise, the treatment is symptomatic.

Furosemide:

Furosemide is a potent diuretic with a rapid action. Its effects are evident within 1 hour after a dose by mouth and lasts for about 4 to 6 hours. It has been reported to exert inhibiting effects on electrolyte reabsorption in the proximal and distal renal tubules and in the ascending Loop of Henle.

Excretion of sodium, potassium and chloride ions is increased and water excretion enhanced.

Unlike thiazide diuretics where, owing to their flat dose-response curve, very little is gained by increasing the dose, furosemide has a steep dose-response curve, which gives it a wide therapeutic range.

Triamterene:

Triamterene is a mild diuretic which appears to mainly act on the distal renal tubules. It produces a diuresis in about 2 to 4 hours, reaching a maximum effect in about 6 hours. Triamterene adds to the natriuretic but diminishes the kaliuretic affects of other diuretics and is used as an adjunct to frusemide to conserve potassium, in the treatment of refractory oedema associated with hepatic cirrhosis, congestive heart failure and the nephrotic syndrome.

Furosemide:

Furosemide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. It has a biphasic half-life in the plasma with a terminal elimination phase that has been estimated to range up to about 1½ hours. It is up to 99% bound to plasma proteins and is mainly excreted in the urine, largely unchanged, but also in the form of the glucuronide and free amine metabolites. Variable amounts are also excreted in the bile, non renal elimination being considerably increased in renal failure. Furosemide crosses the placental barrier and is excreted in the breast milk.

Triamterene:

Triamterene is incompletely but fairly rapidly absorbed from the gastrointestinal tract. It has been estimated to have a plasma half-life of about 2 hours. It is extensively metabolised and is excreted in the urine in the form of metabolites with some unchanged triamterene. Variable amounts are also excreted in the bile. Animal studies have indicated that triamterene crosses the placental barrier and is excreted in the breast milk.

None stated

Lactose monohydrate

Corn starch

Starch, pregelatinised

Polysorbate 80

Gelatin

Sodium starch glycolate

Magnesium stearate

Not applicable.

5 years.

Do not store above 30 °C. Store in the original container.

PVC-Al-foil blister strip, 14 or 56 tablets.

PE-bottle with LDPE snap cap, 28, 100, or 1000 tablets.

PE-bottle with HDPE screw cap, 100 tablets.

No special instructions.

Orion Corporation

P.O.Box 65

FIN-02200, Espoo

Finland

PL 27925/0007

20 December 1996 /

July 2006