SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

MODURETIC® 50 mg/5 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains amiloride hydrochloride equivalent to 5 mg anhydrous amiloride hydrochloride and 50 mg hydrochlorothiazide.

Excipient(s) with known effect:

Each tablet contains 71.0 mg lactose hydrous.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Tablets.

Peach-coloured, half-scored, diamond shaped tablets, marked ‘MSD 917’.

4.    CLINICAL PARTICULARS

4.1. Therapeutic indications

Potassium-conserving diuretic and antihypertensive.

‘Moduretic’ is indicated in patients with: hypertension, congestive heart failure, hepatic cirrhosis with ascites and oedema. In hypertension, ‘Moduretic’ may be used alone or in conjunction with other antihypertensive agents.

‘Moduretic’ is intended for the treatment of patients in whom potassium depletion might be suspected or anticipated. The presence of amiloride hydrochloride minimises the likelihood of potassium loss during vigorous diuresis for long-term maintenance therapy. The combination is thus indicated especially in conditions where potassium balance is particularly important.

4.2 Posology and method of administration

Posology

Hypertension

Initially half a ‘Moduretic’ tablet given once a day. If necessary, increase to one ‘Moduretic’ tablet given once a day or in divided doses.

Congestive heart failure

Initially half a ‘Moduretic’ tablet a day, subsequently adjusted if required, but not exceeding two ‘Moduretic’ tablets a day. Optimal dosage is determined by the diuretic response and the plasma potassium level. Once an initial diuresis has been achieved, reduction in dosage may be attempted for maintenance therapy. Maintenance therapy may be on an intermittent basis.

Patients with hepatic cirrhosis with ascites

Initiate therapy with a low dose. A single daily dose of one ‘Moduretic’ tablet may be increased gradually until there is an effective diuresis. Dosage should not exceed two ‘Moduretic’ tablets a day. Maintenance dosages may be lower than those required to initiate diuresis; dosage reduction should therefore be attempted when the patient’s weight is stabilised. A gradual weight reduction is especially desirable in cirrhotic patients to reduce the likelihood of untoward reactions associated with diuretic therapy.

Paediatric population

Moduretic is contraindicated in children under 18 years because safety and efficacy have not been established (see section 4.3).

Elderly patients

Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance; the dosage should be carefully adjusted to renal function and clinical response.

Method of administration Oral use

4.3 Contraindications

Hyperkalaemia (plasma potassium over 5.5 mmol/l); other potassium-conserving diuretics. Potassium supplements or potassium-rich food (except in severe and/or refractory cases of hypokalaemia under careful monitoring); concomitant use with spironolactone or triamterene; anuria; acute renal failure, severe progressive renal disease, severe hepatic failure, precoma associated with hepatic cirrhosis, Addison’s disease, hypercalcaemia, concurrent lithium therapy, diabetic nephropathy; patients with blood urea over 10 mmol/l, patients with diabetes mellitus, or those with serum creatinine over 130 pmol/l in whom serum electrolyte and blood urea levels cannot be monitored carefully and frequently. Because the safety of amiloride hydrochloride for use in children has not been established, ‘Moduretic’ is not recommended for children under 18 years of age. For use in pregnancy and breast-feeding mothers, see 4.6 ‘Pregnancy and lactation’.

Hypersensitivity to the active substance(s), to any sulfonamide-derived drugs or to any of the excipients listed in section 6.1

4.4. Special warnings and precautions for use

Hyperkalaemia has been observed in patients receiving amiloride hydrochloride, either alone or with other diuretics, particularly in the aged or in hospital patients with hepatic cirrhosis or congestive heart failure with renal involvement, who were seriously ill, or were undergoing vigorous diuretic therapy. Such patients should be carefully observed for clinical, laboratory, and ECG evidence of hyperkalaemia (not always associated with an abnormal ECG).

Neither potassium supplements nor a potassium-rich diet should be used with ‘Moduretic’ except under careful monitoring in severe and/or refractory cases of hypokalaemia.

Some deaths have been reported in this group of patients.

Treatment of hyperkalaemia: Should hyperkalaemia develop, discontinue treatment immediately and, if necessary, take active measures to reduce the plasma potassium to normal.

Impaired renal function: Renal function should be monitored because the use of ‘Moduretic’ in impaired renal function may result in the rapid development of hyperkalaemia. Thiazide diuretics become ineffective when creatinine levels fall below 30 ml/min.

Electrolyte imbalance: Although the likelihood of electrolyte imbalance is reduced by ‘Moduretic’, careful check should be kept for such signs of fluid and electrolyte imbalance as hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. It is particularly important to make serum and urine electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid or electrolyte imbalance include: dryness of the mouth, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalaemia may develop, especially as a result of brisk diuresis, after prolonged therapy or when severe cirrhosis is present. Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability).

Diuretic-induced hyponatraemia is usually mild and asymptomatic. It may become severe and symptomatic in a few patients who will then require immediate attention and appropriate treatment.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Therapy should be discontinued before carrying out tests for parathyroid function.

Azotaemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotaemia and oliguria develop during treatment of renal disease, ‘Moduretic’ should be discontinued.

Hepatic disease: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease (see 4.3 ‘Contraindications’), since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Metabolic: Hyperuricaemia may occur, or gout may be precipitated or aggravated, in certain patients receiving thiazides. Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by therapy with ‘Moduretic’ (see 4.3 ‘Contra-indications’). Dosage adjustment of antidiabetic agents, including insulin, may be required.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

To minimise the risk of hyperkalaemia in diabetic or suspected diabetic patients, the status of renal function should be determined before initiating therapy with ‘Moduretic’. Therapy should be discontinued at least three days before giving a glucose tolerance test. Potassium-conserving therapy should be initiated only with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, e.g. patients with cardiopulmonary disease or patients with inadequately controlled diabetes.

Shifts in acid-base balance alter the balance of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in plasma potassium.

Sensitivity reactions: The possibility that thiazides may activate or exacerbate systemic lupus erythematosus has been reported.

4.5 Interaction with other medicinal products and other forms of interaction

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the prescribing information for lithium preparations before use of such preparations.

Non-Steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: Non-steroidal anti-inflammatory

drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of antihypertensive drugs, including the diuretic, natriuretic and antihypertensive effects of diuretics.

In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.

Concomitant administration of NSAIDs and potassium-sparing agents, including amiloride HCl, may cause hyperkalemia, particularly in elderly patients. Therefore, when amiloride HCl is used concomitantly with NSAIDs, serum potassium levels should be carefully monitored.

Amiloride Hydrochloride

When amiloride hydrochloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, trilostane, ciclosporin or tacrolimus, the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Hydrochlorothiazide

When given concurrently, the following drugs may interact with thaizide diuretics:

Alcohol, barbiturates or narcotics: Co-administration may potentiate orthostatic hypotension. Oral and parenteral antidiabetic drugs may

require adjustment of dosage with concurrent use. ‘Moduretic’ can act synergistically with chlorpropamide to increase the risk of hyponatraemia. Other antihypertensive drugs may have an additive effect. Therefore the dosage of these agents, especially adrenergic-blockers, may need to be reduced when ‘Moduretic’ is added to the regimen. Diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with an ACE inhibitor to reduce the likelihood of first dose hypotension. Cholestyramine and colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. When cholestyramine is given 4 hours after the hydrochlorothiazide, the absorption of hydrochlorothiazide is reduced by 30 to 35 percent. Corticosteroids or ACTH may intensify any thiazide-induced electrolyte depletion, particularly hypokalaemia. Pressor amines such as epinephrine (adrenaline) may show decreased arterial responsiveness when used with ‘Moduretic’ but this reaction is not enough to preclude their therapeutic usefulness. Non-depolarising muscle relaxants such as tubocurarine may possibly interact with ‘Moduretic’ to increase muscle relaxation.

Drug/laboratory tests: Because thiazides may affect calcium metabolism, ‘Moduretic’ may interfere with tests for parathyroid function.

4.6 Fertility, pregnancy and lactation

Pregnancy

Diuretics

The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated, because they may be associated with hypovolaemia, increased blood viscosity, and decreased placental perfusion. Diuretics do not prevent the development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful for its treatment.

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance, bone marrow depression and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breast-feeding

Although it is not known whether amiloride hydrochloride is excreted in human milk, it is known that hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Moduretic during breast feeding is not recommended. If Moduretic is used during breast-feeding, doses should be kept as low as possible.

4.7. Effects on ability to drive and use machines

Infrequently, patients may experience weakness, fatigue, dizziness, stupor and vertigo. Should any of these occur, the patient should be cautioned not to drive or operate machinery.

4.8 Undesirable effects

Although minor side effects are relatively common, significant side effects are infrequent.

Reported side effects are generally associated with diuresis, thiazide therapy, or with the underlying disease.

No increase in the risk of adverse reactions has been seen over those of the individual components.

The following side effects have been reported with ‘Moduretic’:

* *

Body as a whole: anaphylactic reaction, headache , weakness , fatigue, malaise, chest pain, back pain, syncope.

Cardiovascular: arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris.

Digestive: anorexia , nausea , vomiting, diarrhoea, constipation, abdominal pain, GI bleeding, appetite changes, abdominal fullness, flatulence, thirst, hiccups.

Metabolic: elevated plasma potassium levels (above 5.5 mmol/l), electrolyte imbalance, hyponatraemia (see 4.4 ‘Special warnings and precautions for use’), gout, dehydration, symptomatic hyponatraemia.

_*

Integumentary: rash , pruritus, flushing, diaphoresis.

Musculoskeletal: leg ache, muscle cramps, joint pain.

Nervous: dizziness*, vertigo, paraesthesiae, stupor.

Psychiatric: insomnia, nervousness, mental confusion, depression, sleepiness. Respiratory: dyspnoea.

Special senses: bad taste, visual disturbance, nasal congestion.

Urogenital: impotence, dysuria, nocturia, incontinence, renal dysfunction including renal failure.

Additional side effects that have been reported with the individual components and may be potential side effects of ‘Moduretic’ are listed below:

Amiloride:

Side effects that have been reported most frequently during controlled clinical trials with Moduretic

Body as a whole: neck/shoulder ache, pain in extremities.

Digestive: abnormal liver function, activation of probable pre-existing peptic ulcer, dyspepsia, jaundice.

Integumentary: dry mouth, alopecia.

Nervous: tremors, encephalopathy.

Haematological: aplastic anaemia, neutropenia.

Cardiovascular: one patient with partial heart block developed complete heart block, palpitation.

Psychiatric: decreased libido, somnolence.

Respiratory: cough.

Special senses: tinnitus, increased intra-ocular pressure.

Urogenital: polyuria, urinary frequency, bladder spasm. Hydrochlorothiazide:

Body as a whole: fever.

Cardiovascular: necrotising angiitis (vasculitis, cutaneous vasculitis.)

Digestive: jaundice (intrahepatic cholestatic jaundice), pancreatitis, cramping, gastric irritation.

Endocrine/Metabolic:    glycoscuria, hyperglycaemia, hyperuricaemia,

hypokalaemia.

Integumentary: photosensitivity, sialadenitis, urticaria, toxic epidermal necrolysis.

Haematological: agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia.

Psychiatric: restlessness.

Renal: interstitial nephritis.

Respiratory: respiratory distress, including pneumonitis, pulmonary oedema. Special senses: transient blurred vision, xanthopsia.

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.

4.9. Overdose

No specific data are available on overdosage with ‘Moduretic’. No specific antidote is available, and it is not known whether the drug is dialysable.

Treatment should be symptomatic and supportive. Therapy should be discontinued and the patient watched closely. Emesis should be induced and/or gastric lavage performed. The most common signs and symptoms of overdosage with amiloride hydrochloride are dehydration and electrolyte imbalance. Blood pressure should be monitored and corrected where necessary. If hyperkalaemia occurs, active measures should be taken to reduce the plasma potassium levels.

Electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration are the most common signs and symptoms of hydrochlorothiazide overdosage. If digitalis has been administered, hypokalaemia may accentuate cardiac arrhythmias.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Diuretic and potassium-soaring agent, ATC code: C03EA01

Mechanism of action

Hydrochlorothiazide is a diuretic with antihypertensive properties. It acts by inhibiting the renal tubular reabsorption of sodium and chloride ions, which are excreted with an accompanying volume of water. Potassium excretion is also promoted.

Amiloride hydrochloride is a potassium-sparing diuretic. It also promotes the excretion of sodium and chloride, but it reduces the excretion of potassium.

5.2. Pharmacokinetic properties

About 70% of an oral dose of hydrochlorothiazide is absorbed. It has a plasma half life of 5.6 to 14.8 hours. It is excreted unchanged in the urine. It crosses the placental barrier and is secreted in breast milk.

About 50% of an oral dose of amiloride hydrochloride is absorbed. It has a plasma half life of about 6 to 9 hours, but its effects may persist for up to 48 hours after a single dose. It is excreted unchanged in the urine and faeces.

5.3.    Preclinical safety data

No relevant data.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Calcium hydrogen phosphate E341 Guar gum Lactose hydrous Magnesium stearate E572 Maize starch

Pregelatinised maize starch Sunset yellow aluminium lake E110

6.2    Incompatibilities

Not applicable.

6.3.    Shelf life

3 years.

6.4    Special precautions for storage

Store below 25°C. Protect from moisture

6.5    Nature and contents of container

White opaque polypropylene HDPE or glass bottles containing 30, 50, 100 or 500 tablets.

PVC blister packs, lidded with aluminium foil containing 28 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

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

7.    MARKETING AUTHORISATION HOLDER:

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

8.    MARKETING AUTHORISATION NUMBER

PL 00025/5016R

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION:

Date of first authorisation: 6 November 1989

Date of latest renewal: 23 March 2005

10 DATE OF REVISION OF THE TEXT

10/09/2015