This information is intended for use by health professionals

1. Name of the medicinal product

Frusene Tablets

2. Qualitative and quantitative composition

Furosemide 40.0 mg

Triamterene 50.0 mg

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet.

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

4. Clinical particulars
4.1 Therapeutic indications

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.

4.2 Posology and method of administration

Posology

The dosage depends on individual requirements.

Adults:

The usual adult dose is ½ to 2 tablets, taken in the morning. Maximum daily dose is 6 tablets (300 mg of triamterene).

Paediatric population:

Not recommended for use in children.

Older people:

In older people there is normally no requirement for dosage adjustments unless a clinically significant impairment of renal or hepatic function also exists. Triamterene may accumulate and dosage may need to be reduced. Creatinine and serum electrolytes should be monitored.

Patients with renal insufficiency

Treatment must be avoided in patients with moderate to severe renal insufficiency due to the risk of accumulation of triamterene and hyperkalaemia.

Patients with hepatic insufficiency:

Treatment must be initiated using a small dose with careful monitoring of the serum electrolyte concentrations (see section 4.4). 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.

Method of administration

The tablets should be taken with a sufficient quantity of liquid, usually in the morning. Concomitant intake of food can reduce the absorption of furosemide by 30%, so the tablets should not be taken with meals.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

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 sulfonamides (because of cross-sensitivity between sulfonamides and furosemide).

4.4 Special warnings and precautions for use

Electrolyte imbalance monitoring

Electrolyte balance and blood creatinine of the patients receiving furosemide and triamterene must be monitored. More frequent and careful monitoring is required for the following patient groups: diabetics, patients with cardiac, renal or hepatic impairment and older people. 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. See section 4.8 for details of electrolyte and metabolic abnormalities.

Pulmonary oedema

Treatment should be stopped gradually to avoid deterioration of cardiac insufficiency. Diuretics must be administered carefully to avoid hypotension and circulatory collapse in patients with pulmonary oedema caused by acute myocardial infarction.

Hepatic failure

Daily weight loss should not exceed 1 kg 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.

When treating patients with hepatic failure and ascites, the electrolyte balance must be carefully monitored and care taken that the daily weight loss due to diuresis does not exceed 900-1000 g/day. Hypotension must be avoided in these patients (risk of precipitating hepatic encephalopathy).

Folic acid deficiency

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.

Uric acid

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

Diabetes

Furosemide may worsen the glucose balance in diabetic patients.

Cholesterol Levels

Furosemide may alter HDL, LDL cholesterol and triglyceride values.

Urinary output

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

Particularly careful monitoring is necessary when treating premature infants (possible development of nephrocalcinosis/nephrolithiasis; renal function must be monitored and renal ultrasonography performed) (see section 4.8).

In the RISPERDAL placebo-controlled trials in older people with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3 %; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1 %; mean age 84 years, range 70-96) or furosemide alone (4.1 %; mean age 80 years, range 67-90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials.

Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in older people with dementia.

NSAIDs

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 (see section 4.5).

Urine

Triamterene may cause blue discolouration of the urine.

Galactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Particular Caution and/or Dose Reduction Required

Symptomatic hypotension leading to dizziness, fainting or loss of consciousness can occur in patients treated with furosemide, particularly in the elderly, patients on other medications which can cause hypotension and patients with other medical conditions that are risks for hypotension.

4.5 Interaction with other medicinal products and other forms of interaction

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

Furosemide

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, glycyrrhizin (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 (decreases the diuretic effect of furosemide by 30-50%), 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. Also concomitant intake of food may reduce the absorption of furosemide by approximately 30%.

Drugs likely to exacerbate nephrotoxicity:

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

Drugs likely to exacerbate ototoxicity:

Aminoglycoside antibiotics, cisplatin.

Effect of Frusene on other drugs

Furosemide

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 (e.g. sotalol). Effect of competitive muscle relaxants may also be enhanced or reduced.

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.

Furosemide potentiates the effect of antihypertensive agents and counteracts the effect of antihypotensive agents. This should be taken into account especially, if furosemide is administered concomitantly with diuretics (thiazide or osmotic diuretics) (risk of uncontrolled diuresis and electrolyte disturbances), angiotensin converting enzyme (ACE) inhibitors or angiotensin (AT) receptor antagonists (sudden weakening of the furosemide-induced elevated renin effect may predispose the patient to hypotension).

Clofibrate competes 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 may alter theophylline concentration.

See section 4.4 regarding increased mortality in older people with dementia concomitantly receiving furosemide and risperidone.

Triamterene:

Triamterene decreases the risk of hypokalaemia induced by furosemide.

Concomitant use of triamterene and potassium supplements (potassium salts, a high potassium diet, etc.) and other potassium sparing diuretics (e.g. amiloride, spironolactone) may increase the risk of hyperkalaemia. The risk of hyperkalaemia is also increased, if triamterene is used concomitantly with ACE inhibitors or angiotensin receptor antagonists.

Triamterene may reduce the renal clearance of amantadine, resulting in increased plasma concentrations and toxicity of amantadine. Triamterene used concomitantly with trimethoprim has resulted in the development of severe hyponatraemia. NSAIDs may reduce the antihypertensive effect of triamterene and increase the risk of renal insufficiency.

4.6 Fertility, pregnancy and lactation

Pregnancy

Furosemide crosses the placenta but has not been associated with birth defects. It may compromise placental perfusion by reducing maternal blood volume. Diuretics should not be used in a pregnancy in which uteroplacental perfusion is markedly reduced (e.g. preeclampsia).

Use of furosemide during pregnancy may predispose the foetus to hypercalciuria, nephrocalcinosis and secondary hyperparathyroidism. Infants born to mothers who have recently taken furosemide may be at risk of developing electrolyte disturbances. 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 birth defects.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Breast-feeding

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

Furosemide is excreted in human milk to such an extent that effects on the breastfed new-borns/infants are likely.

There is insufficient information on the excretion of triamterene/metabolites in human milk.

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

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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:

Blood and lymphatic system disorders

Rare or very rare (<1/1000, including case reports)

Bone marrow depression, aplastic anaemia, agranulocytosis, thrombocytopenia and haemolytic anaemia

Frequency not known

Leucopenia

Metabolism and nutrition disorders

Very common or common (>1/100)

Dehydration*, hyponatraemia*, hypochloremic metabolic alkalosis*, hypokalaemia*, hypocalcaemia*, hypomagnesemia* (incidences of the last three are reduced by triamterene)

Uncommon (>1/1,000, <1/100)

Impaired glucose tolerance (by hypokalaemia)*, hyperuricaemia, gout, reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol, elevation of serum triglycerides

Frequency not known

Hypercalciuria

Nervous system disorders

Uncommon (>1/1,000, <1/100)

Tiredness*, dizziness*, headache*, paresthesias*, restlessness*

Frequency not known

Dizziness, fainting and loss of consciousness (caused by symptomatic hypotension)

Eye disorders

Uncommon (>1/1,000, <1/100)

Visual disturbance*

Ear and labyrinth disorders

Uncommon (>1/1,000, <1/100)

Deafness (sometimes irreversible)

Rare or very rare (<1/1000, including case reports)

Tinnitus, reversible or irreversible loss of hearing (after large doses or prolonged use of furosemide).

Frequency not known

The use of furosemide may also lead to the development of sensorineural hearing loss.

Cardiac disorders

Uncommon (>1/1,000, <1/100)

Cardiac arrhythmias*

Frequency not known

Closure of the patent arterial duct may be hindered after birth, especially if administered in premature infants in the first week of life.

Vascular disorders

Very common or common (>1/100)

Decreased blood pressure*

Uncommon (>1/1,000, <1/100)

Hypotension*, hypovolaemia

Rare or very rare (<1/1000, including case reports)

Vasculitis

Gastrointestinal disorders

Uncommon (>1/1,000, <1/100)

Dry mouth*, thirst*, nausea*, bowel motility disturbances*

Rare or very rare (<1/1000, including case reports)

Pancreatitis

Hepato-biliary disorders

Rare or very rare (<1/1000, including case reports)

Cholestasis

Skin and subcutaneous tissue disorders

Rare or very rare (<1/1000, including case reports)

Urticaria, purpura, erythema multiforme, exfoliative dermatitis, photosensitivity reactions

Frequency not known

Bullous pemphigoid, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalised exanthematous pustulosis (AGEP)

Musculoskeletal, connective tissue and bone disorders

Uncommon (>1/1,000, <1/100)

Muscle cramps*

Renal and urinary disorders

Uncommon (>1/1,000, <1/100)

Reduced diuresis*, urinary incontinence, urinary obstruction (in patients with hyperplasia of the prostate)

Rare or very rare (<1/1000, including case reports)

Nephrocalcinosis (in pre-term infants treated with furosemide secondary to hyperparathyroidism), interstitial nephritisacute renal failure

General disorders and administration site conditions

Uncommon (>1/1,000, <1/100)

Fatigue*

Rare or very rare (<1/1000, including case reports)

Fever

*= an undesirable effect attributable to fluid or electrolyte imbalance induced by furosemide

Triamterene:

Blood and lymphatic system disorders

Rare or very rare (<1/1000, including case reports)

Megaloblastic anaemia, pancytopenia

Metabolism and nutrition disorders

Very common or common (>1/100)

Hyperkalaemia (incidence is reduced by furosemide)

Uncommon (>1/1,000, <1/100)

Hyperuricaemia

Nervous system disorders

Uncommon (>1/1,000, <1/100)

Headache

Vascular disorders

Uncommon (>1/1,000, <1/100)

Hypovolaemia

Gastrointestinal disorders

Very common or common (>1/100)

Nausea, vomiting, diarrhoea

Uncommon (>1/1,000, <1/100)

Dry mouth

Skin and subcutaneous tissue disorders

Uncommon (>1/1,000, <1/100)

Rashes

Rare or very rare (<1/1000, including case reports)

Photosensitivity reactions, pseudoporphyria

Renal and urinary disorders

Uncommon (>1/1,000, <1/100)

Elevation of s-creatinine, transient renal insufficiency

Rare or very rare (<1/1000, including case reports)

Interstitial nephritis, urinary stones

General disorders and administration site conditions

Rare or very rare (<1/1000, including case reports)

Serum sickness, weakness

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdose include increased diuresis, natriuresis, hypovolaemia and decrease of blood pressure (see section 4.8). 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: furosemide and potassium-sparing agents, ATC code: C03EB01.

Furosemide:

Its effects are evident within 1 hour after a dose by mouth and lasts for about 4 to 6 hours.

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 furosemide to conserve potassium, in the treatment of refractory oedema associated with hepatic cirrhosis, congestive heart failure and the nephrotic syndrome.

5.2 Pharmacokinetic properties

Furosemide:

Absorption of furosemide is variable and affected by many factors, such as concomitant ingestion of food (which slows down and may reduce the absorption) and the comorbidity of the patient (absorption is reduced in patients with uncompensated cardiac failure and oedematous conditions). The mean time to peak concentration of furosemide in plasma after administration of oral tablet is around 1.5 h. Bioavailability of oral formulations varies between 20 and 80 %. No direct correlation exists between the absorbed dose and diuresis. Some enterohepatic recirculation exists. First-pass metabolism takes place in the intestinal wall and only 10 % of metabolism occurs in the liver. Furosemide binds variably to plasma proteins, mainly albumin and the free fraction varies between 1 and 4 %. The volume of distribution is 0.1 to 0.2 l/kg. Furosemide is metabolised in the kidney by glucuronic acid conjugation and excreted in the urine and faeces as conjugates. A very small fraction is metabolised to saluamine. Most of the parent drug is excreted unchanged into the glomerular fluid and urine by an active transport mechanism in the proximal tubule. Furosemide clearance is 2 mL/min/kg in normal patients. Clearance is influenced by age (reduces in neonates, premature infants and geriatrics), underlying disease state (reduces with cardiac disease, uremia or renal impairment) and drug interactions. Elimination half-life of healthy subjects is ½ to 2 hours, which is considerably extended in renal failure. The half-life may be slightly longer in patients with hepatic dysfunction or heart failure. In the elderly, the elimination depends on the renal function, which is usually lowered.

Triamterene:

Absorption of triamterene is variable and the bioavailability varies between 30 and 80 %. First-pass metabolism is quite extensive, up to 40 %. Peak concentration in plasma is reached in 1.5 to 2.4 hours.

45 to 70 % of the compound is bound to plasma proteins. Estimates of the volume of distribution vary considerably, from 2 to 13 l/kg. Triamterene is metabolised in the liver to hydroxytriamterene and sulfate-conjugated to give a pharmacologically active metabolite. Elimination half-life of the parent compound and metabolite is the same, 2 to 4 hours. 50 to 70 % is excreted in the urine (1 to 10 % as unchanged triamterene). Hepatic failure and renal failure both slow the elimination of 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.

5.3 Preclinical safety data

None stated.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Corn starch

Starch, pregelatinised

Polysorbate 80

Gelatin

Sodium starch glycolate

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25 °C. Store in the original container.

6.5 Nature and contents of container

Not all pack sizes may be marketed

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.

6.6 Special precautions for disposal and other handling

No special instructions.

7. Marketing authorisation holder

Orion Corporation

Orionintie 1

FIN-02200 Espoo

Finland

8. Marketing authorisation number(s)

PL 27925/0007

9. Date of first authorisation/renewal of the authorisation

20 December 1996

10. Date of revision of the text

06/2018