MODURETIC TABLETS

Active substance: HYDROCHLOROTHIAZIDE

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1.

NAME OF THE MEDICINAL PRODUCT

®

MODURETIC Tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Amiloride hydrochloride equivalent to 5
hydrochlorothiazide.

3.

mg anhydrous amiloride hydrochloride and 50 mg

PHARMACEUTICAL FORM
Tablets.
Peach-coloured, half-scored, diamond shaped tablet, 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
Hypertension. Usually 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.
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 use: ‘Moduretic’ is not recommended for children under 18 years as safety and efficacy have not
been established (see 4.3 ‘Contraindications’).
Use in the elderly: 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.

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. Prior hypersensitivity to amiloride
hydrochloride, hydrochlorothiazide or other sulphonamide-derived drugs. Because the safety and efficacy 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’.

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 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.
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 ‘Contra-indications’), 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 thiazideinduced 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.

Pregnancy and lactation
Use in pregnancy: 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.
Since thiazides cross the placental barrier and appear in cord blood, use where pregnancy is present or
suspected requires that the benefits of the drug be weighed against possible hazards to the foetus. These
hazards include foetal or neonatal jaundice, thrombocytopenia, bone marrow depression, and possibly other
side effects that have occurred in the adult.
Use in breast-feeding mothers: Although it is not known whether amiloride hydrochloride is excreted in
human milk, it is known that thiazides do appear in breast milk. If use of the drug combination is deemed
essential, the patient should stop breast-feeding.

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:
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,
thrombocytopenia.

aplastic

anaemia,

haemolytic

anaemia,

leucopenia,

Psychiatric: restlessness.
Renal: interstitial nephritis.
Respiratory: respiratory distress, including pneumonitis, pulmonary oedema.
Special senses: transient blurred vision, xanthopsia.


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

purpura,

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
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.
chloride, but it reduces the excretion of potassium.

5.2.

It also promotes the excretion of sodium and

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
Guar gum
Lactose
Magnesium stearate
Maize starch
Pregelatinised maize starch
Sunset yellow aluminium lake E110

6.2.

Incompatibilities
None known.

6.3.

Shelf life
3 years.

6.4.

Special precautions for storage
Store in a dry place below 25°C.

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.

6.6.

Instruction for use/handling
None

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 AUTHORISATION
6th November 1989

10

DATE OF REVISION OF THE TEXT
30/12/2009

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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