This information is intended for use by health professionals

1. Name of the medicinal product

MODURET 25®

2. Qualitative and quantitative composition

Each tablet of 'Moduret 25' contains amiloride hydrochloride equivalent to 2.5 mg anhydrous amiloride hydrochloride and 25 mg hydrochlorothiazide.

Excipient(s) with known effect:

Each tablet contains 35.5 mg lactose hydrous.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Off-white, diamond-shaped tablets, with a break-line and marked with identification number '923'.

4. Clinical particulars
4.1 Therapeutic indications

Potassium-conserving diuretic and anti-hypertensive for the treatment of patients with congestive heart failure, hypertension, or hepatic cirrhosis with ascites and oedema, in whom potassium depletion might be anticipated.

4.2 Posology and method of administration

Posology

Hypertension:

Initially one 'Moduret 25' tablet given once a day. If necessary increase to two 'Moduret 25' tablets given once a day or in divided doses.

Congestive heart failure:

Initially one tablet of 'Moduret 25' a day, subsequently adjusted if required, but not exceeding four 'Moduret 25' 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 two 'Moduret 25' tablets may be increased gradually until there is an effective diuresis. Dosage should not exceed four 'Moduret 25' 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:

'Moduret 25' 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 μmol/l in whom serum electrolyte and blood urea levels cannot be monitored carefully and frequently. In renal impairment, use of a potassium - conserving agent may result in rapid development of hyperkalaemia. Because the safety of amiloride hydrochloride for use in children has not been established, 'Moduret 25' is not recommended for children. For 'Use in pregnancy' and 'Use in breast-feeding mothers', see 'Pregnancy and Lactation'.

Hypersensitivity to the amiloride hydrochloride, hydrochlorothiazide, acetazolamide or other thiazide or sulfonamide-derived drugs.

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 'Moduret 25' 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 'Moduret 25' in impaired renal function may result in the rapid development of hyperkalaemia. Thiazide diuretics become ineffective when creatinine clearance falls below 30 ml/min.

Electrolyte imbalance: Although the likelihood of electrolyte imbalance is reduced by 'Moduret 25', careful check should be kept for such signs of fluid and electrolyte imbalance as hyponatraemia, hypochloremic 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 gastro-intestinal 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.

Uraemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing uraemia and oliguria develop during treatment of renal disease, 'Moduret 25' 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 'Moduret 25' (see 4.3 'Contraindications'). 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 'Moduret 25'. 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.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC. (See also section 4.8).

Lactose hydrous: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 hyperkalaemia, 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 ACE inhibitor, angiotensin II receptor antagonist, 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 thiazide diuretics:

Alcohol, barbiturates or narcotics: Co-administration may potentiate orthostatic hypotension. Oral and parenteral antidiabetic drugs may require adjustment of dosage with concurrent use. 'Moduret 25' 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 'Moduret 25' 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 gastro-intestinal tract by up to 85 and 43%, respectively. When cholestyramine is given 4 hours after the hydrochlorothiazide, the absorption of hydrochlorothiazide is reduced by 30 to 35%. 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 'Moduret 25' but this reaction is not enough to preclude their therapeutic usefulness. Non-depolarising muscle relaxants such as tubocurarine may possibly interact with 'Moduret 25' to increase muscle relaxation. Drug/laboratory tests: Because thiazides may affect calcium metabolism, 'Moduret 25' 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 oedema, 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 'Moduret 25' during breast feeding is not recommended. If 'Moduret 25' 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 'Moduret 25':

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*, pruritis, flushing, diaphoresis.

Musculoskeletal: leg ache, muscle cramps, joint pain.

Nervous: dizziness*, vertigo, paraesthesia, 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 'Moduret 25' are listed below:

Amiloride:

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: glycosuria, 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.

Neoplasms Benign, malignant and unspecified (incl cysts and polyps): Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma).

Description of Selected Adverse Reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. (See also sections 4.4 and 5.1).

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.

* Side effects that have been reported most frequently during controlled clinical trials with 'Moduret 25'

4.9 Overdose

No specific data are available on overdosage with 'Moduret 25'. 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, hypochloremia, hyponatraemia) and dehydration are the most common signs and symptoms of hydrochlorothiazide overdosage. If digitalis has been administered, hypokalaemia may accentuate cardiac arrhythmias.

The plasma half-life of hydrochlorothiazide is 5.6 hours with a subsequent longer terminal half-life; the plasma half-life of amiloride is about six hours.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Mechanism of action

'Moduret 25' provides diuretic and antihypertensive activity (principally due to the hydrochlorothiazide component), while acting through the amiloride components to prevent excessive potassium loss that may occur in patients receiving a thiazide diuretic. Due to this latter component, the urinary excretion of magnesium is less with 'Moduret 25' than with a thiazide or loop diuretic used alone. The onset of the diuretic action of 'Moduret 25' is within 1 to 2 hours and this action appears to be sustained for approximately 24 hours.

Non-melanoma skin cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg). (See also section 4.4).

5.2 Pharmacokinetic properties

Amiloride hydrochloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. Effects on electrolytes increase with single doses of amiloride hydrochloride up to approximately 15 mg.

Amiloride hydrochloride is not metabolised by the liver but is excreted unchanged by the kidneys. About 50% of a 20 mg dose of amiloride hydrochloride is excreted in the urine and 40% in the stool within 72 hours. Amiloride hydrochloride has little effect on glomerular filtration rate or renal blood flow. Because amiloride hydrochloride is not metabolised by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome develops.

The onset of the diuretic action of hydrochlorothiazide occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours. Hydrochlorothiazide is eliminated rapidly by the kidney.

The mechanism of the antihypertensive effect of thiazides may be related to the excretion and redistribution of body sodium. Hydrochlorothiazide usually does not cause clinically important changes in normal blood pressure.

5.3 Preclinical safety data

No further information.

6. Pharmaceutical particulars
6.1 List of excipients

Calcium Hydrogen Phosphate E341

Guar Gum

Lactose hydrous

Magnesium Stearate E572

Maize Starch

Pregelatinised Maize Starch

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 Years.

6.4 Special precautions for storage

Store below 25°C. Protect from light.

6.5 Nature and contents of container

Calendar pack of 28 tablets or bottles of 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

United Kingdom

8. Marketing authorisation number(s)

PL 00025/0178

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 10 December 1982

Date of latest renewal: 23 March 2005

10. Date of revision of the text

04 April 2019

LEGAL CATEGORY

POM

© Merck Sharp & Dohme Limited 2019. All rights reserved.

SPC.MUE.18.UK.6637.IB-PRAC