Spironolactone Actavis

- Oedema associated with congestive heart failure

- Severe heart failure, (NYHA III-IV)

- As an adjuvant in treatment of resistant hypertension

- Nephrotic syndrome

- Liver cirrhosis with ascites and oedema

- Diagnosis and treatment of primary hyperaldosteronism (Conn's syndrome)

Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available

- Congestive cardiac failure

- Hepatic cirrhosis with ascites and oedema

- Malignant ascites

- Nephrotic syndrome

- Diagnosis and treatment of primary aldosteronism.

Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available.

Posology

Adults

The dosage should be determined individually depending on the condition and the degree of diuresis required. Dosage up to100 mg daily may be administered as a single dose or in divided doses.

Oedema associated with congestive heart failure

For management of oedema an initial daily dose of 100 mg of Spironolactone Actavis administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. Maintenance dose should be individually determined.

Severe heart failure (NYHA Class III-IV)

Treatment in conjunction with standard therapy should be initiated at a dose of Spironolactone Actavis 25 mg once daily if serum potassium is ≤ 5.0 mEq/L and serum creatinine is ≤ 2.5 mg/dL (221 µmol/L).

Resistent Hypertension

The starting dose for Spironolactone Actavis should be 25mg daily in a single dose; the lowest effective dose should be found, very gradually titrating upwards to a dose of 100mg daily or more.

Nephrotic syndrome

Usual dose is 100-200mg/day. Spironolactone Actavis has not been shown to be anti-inflammatory, nor to affect the basic pathological process. Its use is only advised if glucocorticoids by themselves are insufficiently effective.

Hepatic cirrhosis with ascites and oedema

The starting dose is 100-200 mg per day, e.g. based on Na+/K+ ratio. If the response to 200 mg Spironolactone Actavis within the first two weeks is not sufficient, furosemide is added and if necessary, the Spironolactone Actavis dose is increased stepwise up to 400 mg per day. Maintenance dosage should be individually determined.

Diagnosis and treatment of primary aldosteronism

If primary hyperaldosteronism is suspected, Spironolactone Actavis is given at a dose of 100 - 150 mg, or up to 400 mg daily. In the event of rapid onset of a strong diuretic and antihypertensive effect, this is a clear indication of elevated aldosterone production. In this case, 100 - 150 mg daily is administered for 3 - 5 weeks prior to surgery. If surgery is not an option, this dose is often sufficient to maintain blood pressure and potassium concentration at normal levels. In exceptional cases, higher doses are necessary, but the lowest possible dosage should be found.

Paediatric population

Initial daily dosage should provide 1-3 mg of Spironolactone Actavis per kilogram body weight, given in divided doses. Dosage should be adjusted on the basis of response and tolerance. The tablet may be ground or crushed and then suspended in water to make it easier to take.

Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available.

The Elderly

It is recommended that treatment is started at the lowest possible dose, then titrated with higher doses until the optimum effect is achieved. Caution is required, in particular in renal dysfunction.

Method of administration

The tablets should be taken with meals. Daily dosages in excess of 100 mg should be given in several divided doses.

Posology

Adults

Congestive cardiac failure with oedema

For management of oedema an initial daily dose of 100 mg of spironolactone administered in either single or divided doses is recommended, but may range from 25 mg to 200 mg daily. Maintenance dose should be individually determined.

Severe heart failure (New York Heart Association Class III-IV)

Hepatic cirrhosis with ascites and oedema

If urinary Na⁺/K⁺ ratio is greater than 1.0, 100 mg/day. If the ratio is less than 1.0, 200 mg/day to 400 mg/day. Maintenance dosage should be individually determined.

Malignant ascites

Initial dose usually 100 mg/day to 200 mg/day. In severe cases the dosage may be gradually increased up to 400 mg/day. When oedema is controlled, maintenance dosage should be individually determined.

Nephrotic syndrome

Usual dose 100 mg/day to 200 mg/day. Spironolactone has not been shown to be anti-inflammatory, or to affect the basic pathological process. Its use is only advised if glucocorticoids by themselves are insufficiently effective.

Diagnosis and treatment of primary aldosteronism

Aldactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets.

Long test: Aldactone is administered at a daily dosage of 400 mg for 3 to 4 weeks. Correction of hypokalaemia and hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism.

Short test: Aldactone is administered at a daily dosage of 400 mg for 4 days. If serum potassium increases during Aldactone administration but drops when Aldactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered.

After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, Aldactone may be administered at doses of 100 mg to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Aldactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

Elderly

It is recommended that treatment is started with the lowest dose and titrated upwards as required to achieve maximum benefit. Care should be taken with severe hepatic and renal impairment which may alter drug metabolism and excretion.

Paediatric population

Initial daily dosage should provide 1-3 mg of spironolactone per kilogram body weight given in divided doses. Dosage should be adjusted on the basis of response and tolerance.

Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available.

Method of administration

Administration of Aldactone once daily with a meal is recommended.

- Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m²), acute or progressive kidney disease (whether or not this is accompanied by anuria)

- Hyponatraemia

- Hyperkalaemia (serum potassium level > 5.0 mmol/L) at initiation

- Concomitant use of potassium-sparing diuretics (including eplerenone) or potassium-supplements, or dual-RAAS blockade with the combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB)

Spironolactone Actavis is contraindicated in paediatric patients with moderate to severe renal impairment.

Spironolactone is contraindicated in adult and paediatric patients with the following:

- acute renal insufficiency, significant renal compromise, anuria

- Addison's disease

- hyperkalaemia

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- concomitant use of eplerenone or other potassium sparing diuretics.

Spironolactone is contraindicated in paediatric patients with moderate to severe renal impairment.

Aldactone should not be administered concurrently with other potassium conserving diuretics and potassium supplements should not be given routinely with Aldactone as hyperkalaemia may be induced.

Fluid and electrolyte balance

During long-term therapy with Spironolactone Actavis, fluid and and electrolyte status should be regularly monitored, especially in elderly patients. Administration of Spironolactone Actavis is not recommended if plasma potassium levels are elevated and contra-indicated in severe renal insufficiency During treatment with Spironolactone Actavis, severe hyperkalaemia can occur, which may result in cardiac arrest (sometimes fatal) in patients with severe renal dysfunction who are receiving concomitant treatment with potassium supplements.

Hyperkalaemia may be accompanied by paraesthesia, weakness, mild paralysis or muscle spasms and is difficult to distinguish clinically from hypokalaemia. ECG changes may be the first sign of disturbed potassium balance, although hyperkalaemia is not always accompanied by an abnormal ECG.

Combination with potent potassium-sparing diuretics such as triamterene and amiloride is contra-indicated in order to prevent hyperkalaemia and care should be taken to avoid administration of extra potassium

Impaired renal function

Potassium levels should be monitored regularly in patients with impaired renal function, including diabetic microalbuminuria. The risk of hyperkalaemia increases with decreasing renal function. Therefore, these patients should be treated with caution.

Severe hepatic insufficiency

Caution is required in patients with hepatic disorders due to the risk of hepatic coma.

Carcinogenicity

Animal studies have shown that at high doses and after long-term use, Spironolactone Actavis induces tumours. The significance of these data for clinical application is unclear. However, the benefits of therapy should be weighed against the possible long-term harm before initiating long-term use of Spironolactone Actavis in young patients.

Lactose

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

Paediatric population

Potassium-sparing diuretics should be used with caution in hypertensive paediatric patients with mild renal insufficiency because of the risk of hyperkalaemia..

Concomitant use of medicinal products known to cause hyperkalaemia with Spironolactone Actavis may result in severe hyperkalaemia.

Fluid and electrolyte balance

Fluid and electrolyte status should be regularly monitored particularly in the elderly, in those with significant renal and hepatic impairment.

Hyperkalaemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities which may be fatal. Should hyperkalaemia develop Aldactone should be discontinued, and if necessary, active measures taken to reduce the serum potassium to normal.

Reversible hyperchloraemic metabolic acidosis, usually in association with hyperkalaemia has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.

Concomitant use of Aldactone with other potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs, angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin or other drugs or conditions known to cause hyperkalaemia, potassium supplements, a diet rich in potassium or salt substitutes containing potassium, may lead to severe hyperkalaemia.

Urea

Reversible increases in blood urea have been reported in association with Aldactone therapy, particularly in the presence of impaired renal function.

Hyperkalaemia in Patients with Severe Heart Failure

Hyperkalaemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving spironolactone. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium >3.5 mEq/L. The recommended monitoring for potassium and creatinine is 1 week after initiation or increase in dose of spironolactone, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium >5 mEq/L or for serum creatinine >4 mg/dL.

Paediatric population

Potassium-sparing diuretics should be used with caution in hypertensive paediatric patients with mild renal insufficiency because of the risk of hyperkalaemia..

No data are available on the ability to drive. Undesirable effects such as dizziness, confusion and headache may occur. The possible occurrence of these undesirable effects should be taken into account when driving or using machines.

Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

The undesirable effects are dependent on dose and duration of treatment.

The most common adverse effects are hyperkalaemia (9%), disorders of the reproductive system and breasts, including gynaecomastia, reported in 13% of patients (at a dose of less than 100 mg).)

Common: hyponatraemia (in particular during combined intensive therapy with thiazide diuretics), hyperkalaemia in (1) patients with severe renal dysfunction, (2) patients receiving treatment with ACE inhibitors or potassium chloride, (3) the elderly, and (4) diabetic patients

Uncommon: acidity of the blood (acidosis) in patients with liver problems

Rare: insufficient fluid in the tissues (dehydration), porphyria, temporary increase in nitrogen levels in the blood and urine, hyperuricemia (may lead to gout in predisposed patients)

Not known: reversible hyperchloraemic metabolic acidosis - usually accompanied by hyperkalaemia has been reported in some patients with decompensated hepatic cirrhosis, even where renal function was normal.

Psychiatric disorders

Uncommon: confusion

Nervous system disorders

Very common: headache

Common: weakness, lethargy in patients with cirrhosis, tingling (paraesthesia)

Rare: paralysis, paraplegia of the limbs due to hyperkalaemia

Not known: dizziness, ataxia

Vascular disorders

Very rare: inflammation of the vessel walls (vasculitis)

Not known: mild hypotension

Gastrointestinal disorders

Very common: indigestion, diarrhoea

Common: nausea and vomiting

Very rare: gastric inflammation, gastric ulcers, intestinal haemorrhage, cramps

Hepatobiliary disorders

Very rare: hepatitis

Skin and subcutaneous tissue disorders

Uncommon: skin rash, urticaria, erythema, chloasma, pruritus, exanthema

Very rare: alopecia, eczema, erythema annulare centrifugum (EAC), hypertrichosis

Not known: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), Pemihigoid

Musculoskeletal and connective tissue disorders

Uncommon: muscle spasms, leg cramps

Very rare: systemic lupus erythematosus (SLE), Osteomalacia

Renal and urinary disorders

Uncommon: elevated serum creatinine levels

Very rare: acute renal failure

Reproductive system and breast disorders

Very common: Men: reduced libido, erectile dysfunction, impotence, enlargement of the mammary glands (gynaecomastia);

Women: breast disorders, tenderness of the breasts, menstrual disorders, deepening of the voice (in many cases irreversible)

Common: Women: changes in vaginal secretions, reduced libido, absence of periods (amenorrhoea), post-menopausal bleeding

General disorders and administration site conditions

Very common: fatigue, drowsiness

common: malaise

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

Website: www.mhra.gov.uk/yellowcard.

Gynaecomastia may develop in association with the use of spironolactone. Development appears to be related to both dosage level and duration of therapy and is normally reversible when the drug is discontinued. In rare instances some breast enlargement may persist.

The following adverse events have been reported in association with spironolactone therapy:

General disorders and administration site conditions: malaise

Neoplasms benign, malignant and unspecified (including cysts and polyps): benign breast neoplasm

Gastrointestinal disorders: gastrointestinal disturbances, nausea

Blood and lymphatic system disorders: leukopenia (including agranulocytosis), thrombocytopenia

Hepatobiliary disorders: hepatic function abnormal

Metabolism and nutrition disorders: electrolyte disturbances, hyperkalaemia

Musculoskeletal disorders: leg cramps

Nervous system disorders: dizziness

Psychiatric disorders: changes in libido, confusion

Reproductive system and breast disorders: menstrual disorders, breast pain

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, hypertrichosis, pruritus, rash, urticaria, pemphigoid

Renal and urinary disorders: acute renal failure

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose can manifest itself in the form of nausea and vomiting, and (more rarely) by drowsiness, confusion, skin rash or diarrhoea.

In addition, infertility can occur at very high doses (450 mg/day).

Hyponatraemia, or hyperkalaemia may be induced , but these effects are unlikely to be associated with acute overdosage. Symptoms of hyperkalaemia may manifest as paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia. Electrocardiographic changes are the earliest specific signs of potassium disturbances. No specific antidote has been identified. Improvement may be expected after withdrawal of the drug.

If electrolyte balance disturbance and dehydration occur,treatment is symptomatic and supportive and may include replacement of fluids and electrolytes may be indicated. For hyperkalaemia, reduce potassium intake, administer potassium-excreting diuretics, intravenous glucose with regular insulin or oral ion-exchange resins.

Acute overdosage may be manifested by drowsiness, mental confusion, nausea, vomiting, dizziness or diarrhoea. Hyponatraemia, or hyperkalaemia may be induced, but these effects are unlikely to be associated with acute overdosage. Symptoms of hyperkalaemia may manifest as paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia. Electrocardiographic changes are the earliest specific signs of potassium disturbances. No specific antidote has been identified. Improvement may be expected after withdrawal of the drug. General supportive measures including replacement of fluids and electrolytes may be indicated. For hyperkalaemia, reduce potassium intake, administer potassium-excreting diuretics, intravenous glucose with regular insulin or oral ion-exchange resins.

Pharmacotherapeutic group: cardiovascular system, diuretics, potassium-sparing diuretics, aldosterone antagonist.

ATC code: C03DA01

Spironolactone Actavis affects the kidney and the adrenal gland (as an antagonist of aldosterone in the renal tubuli and an inhibitor of aldosterone synthesis in high concentrations).

Spironolactone Actavis promotes diuresis in patients with oedema or ascites by increasing excretion of sodium in the urine. Potassium loss caused by thiazide diuretics is reduced. It has a gradual and prolonged action.

The antihypertensive effect of Spironolactone Actavis is based on water and salt depletion.

Severe heart failure: RALES

The Randomized Aldactone Evaluation Study (RALES) was a multinational, double-blind study in 1663 patients with an ejection fraction of ≤ 35%, a history of New York Heart Association (NYHA) class IV heart failure within 6 months, and class III-IV heart failure at the time of randomisation. All patients were taking a loop diuretic, 97% were taking an ACE inhibitor and 78% were on digoxin (at the time this trial was conducted, beta-blockers were not widely used to treat heart failure and only 15% were treated with a beta-blocker). Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to Spironolactone Actavis 25 mg orally once daily or matching placebo. Patients who tolerated 25 mg once daily had their dose increased to 50 mg once daily as clinically indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg every other day. The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of a significant mortality benefit detected on a planned interim analysis. Spironolactone Actavis reduced the risk of death compared to placebo (mortality Spironolactone Actavis 284/841 (35%); placebo 386/822 (46%); Risk reduction 30% ; 95% confidence interval 18% to 40%; p<0.001). Spironolactone Actavis also significantly reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure as well as the risk of hospitalization for cardiac causes.

Paediatric population

There is a lack of substantive information from clinical studies on Spironolactone Actavis in children. This is a result of several factors: the few trials that have been performed in the paediatric population, the use of Spironolactone Actavis in combination with other agents, the small numbers of patients evaluated in each trial and the different indications studied. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in scientific literature.

Pharmacotherapeutic group: potassium-sparing agents, ATC code C03DA01

Mechanism of action

Spironolactone, as a competitive aldosterone antagonist, increases sodium excretion whilst reducing potassium loss at the distal renal tubule. It has a gradual and prolonged action.

Clinical efficacy and safety

Severe Heart Failure

RALES was a multinational, double-blind study in 1663 patients with an ejection fraction of ≤35%, a history of NYHA Class IV heart failure within 6 months, and Class III-IV heart failure at the time of randomization. All patients were taking a loop diuretic, 97% were taking an ACE inhibitor and 78% were on digoxin (at the time this trial was conducted, b-blockers were not widely used to treat heart failure and only 15% were treated with a b-blocker). Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Patients who tolerated 25 mg once daily had their dose increased to 50 mg once daily as clinically indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg every other day. The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18% - 40%). Spironolactone also significantly reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure as well as the risk of hospitalization for cardiac causes. Changes in NYHA class were more favourable with spironolactone. Gynaecomastia or breast pain was reported in 10% of men who were treated with spironolactone, as compared with 1% of men in the placebo group (p<0.001). The incidence of serious hyperkalaemia was low in both groups of patients.

Paediatric population

There is a lack of substantive information from clinical studies on spironolactone in children. This is a result of several factors: the few trials that have been performed in the paediatric population, the use of spironolactone in combination with other agents, the small numbers of patients evaluated in each trial and the different indications studied. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.

Absorption

Approximately 70% of Spironolactone Actavis is absorbed after oral administration. The bioavailability of Spironolactone Actavis can be increased if it is taken with food. The clinical relevance of this effect is however not entirely clear. Following the administration of 100 mg of Spironolactone Actavis daily for 15 days in non-fasted healthy volunteers, time to peak plasma concentration (tmax), peak plasma concentration (Cmax), and elimination half-life (t1/2) for Spironolactone Actavis is 2.6 hr., 80ng/ml, and approximately 1.4hr., respectively. For the 7-alpha- (thiomethyl) Spironolactone Actavis and canrenone metabolites, tmax was 3.2 hr. and 4.3 hr., Cmax was 391 ng/ml and 181 ng/ml, and t1/2 was 13.8 hr. and 16.5 hr, respectively.

Distribution

Both Spironolactone Actavis and canrenone are over 90% bound to plasma proteins.

Biotransformation

Spironolactone Actavis is extensively metabolised to active metabolites: including thiomethyl- Spironolactone Actavis and canrenone.

Elimination

The plasma half-life of Spironolactone Actavis is approximately 1.5 hours, that of 7-thiomethyl- Spironolactone Actavis approximately 9-12 hours and that of canrenone 10-35 hours. Elimination of metabolites occurs primarily in the urine and secondarily through biliary excretion in the faeces. The renal action of a single dose of Spironolactone Actavis reaches its peak after 7 hours, and activity persists for at least 24 hours

Paediatric population

There are no pharmacokinetic data available in respect of use in paediatric population. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.

Spironolactone is well absorbed orally and is principally metabolised to active metabolites: sulfur containing metabolites (80%) and partly canrenone (20%). Although the plasma half-life of spironolactone itself is short (1.3 hours) the half-lives of the active metabolites are longer (ranging from 2.8 to 11.2 hours). Elimination of metabolites occurs primarily in the urine and secondarily through biliary excretion in the faeces.

Following the administration of 100 mg of spironolactone daily for 15 days in non-fasted healthy volunteers, time to peak plasma concentration (t_max), peak plasma concentration (C_max), and elimination half-life (t_1/2) for spironolactone is 2.6 hr., 80 ng/ml, and approximately 1.4 hr., respectively. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, t_max was 3.2 hr. and 4.3 hr., C_max was 391 ng/ml and 181 ng/ml, and t_1/2 was 13.8 hr. and 16.5 hr., respectively.

The renal action of a single dose of spironolactone reaches its peak after 7 hours, and activity persists for at least 24 hours.

Paediatric population

There are no pharmacokinetic data available in respect of use in paediatric population. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.

Preclinical data do not add relevant information to that already mentioned in other sections of this SmPC.

Spironolactone Actavis has been shown to be tumourigenic in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not known.

Studies on reproduction toxicity have not shown an increased risk of congenital anomalies, but an anti-androgenic effect in rat offspring has raised concern about possible adverse effects on male genital development. There is no confirmation in humans of these possible adverse effects.

Carcinogenicity

Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain. However the long term use of spironolactone in young patients requires careful consideration of the benefits and the potential hazard involved. Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses. The use of Aldactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and foetus.

Not applicable.

Not applicable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.