co-amilozide 5mg-50mg tablets pl-17907-0227 ukpar · co-amilozide tablets 5/50mg / zida-co 5/50 (pl...

UKPAR Co-amilozide 5mg/50mg Tablets PL 17907/0227

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Co-amilozide 5mg/50mg Tablets

(amiloride hydrochloride / hydrochlorothiazide)

PL 17907/0227

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after authorisation

Page 13

Summary of Product Characteristics

Page 14

Product Information Leaflet

Page 21

Labelling

Page 23


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PL 17907/0227

LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted Bristol Laboratories Ltd. a Marketing Authorisation (licence) for the medicinal product, Co-amilozide 5mg/50mg Tablets (PL 17907/0227), on 1st June 2011. This is a prescription-only medicine (POM). Co-amilozide 5mg/50mg Tablets belong to a group of medicines called diuretics (water tablets) which work by increasing the amount of water passed by your kidneys. This medicine is used to treat:

• High blood pressure

• Heart failure

• Cirrhosis of liver with fluid retention (swollen legs and abdomen) This application is considered to be identical to a previously granted licence for Co-amilozide Tablets 5/50mg / Zida-Co 5/50 (PL 34007/0022), authorised to Ennogen Limited on 6th February 2009. The proposed and reference products are identical. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of Co-amilozide 5mg/50mg Tablets outweigh the risk; hence a Marketing Authorisation has been granted.


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PL 17907/0227

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 6

Non-clinical assessment

Page 9

Clinical assessment

Page 10

Overall conclusion and benefit-risk assessment

Page 11


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Bristol Laboratories Ltd. a Marketing Authorisation for the medicinal product, Co-amilozide 5mg/50mg Tablets (PL 17907/0227), on 1st June 2011. The product is a prescription-only medicine (POM). This is a simple, abridged, ‘informed consent’ application submitted according to Article 10(c) of EC Directive 2001/83 (as amended), cross referencing Co-amilozide Tablets 5/50mg / Zida-Co 5/50 (PL 34007/0022), licensed to Ennogen Limited. The cross-referenced product was originally awarded a default conversion licence in January 1985 to Lennon Pharmaceuticals Ltd. (PL 5723/0001) and subsequently underwent a Change of Ownership (CoA) to Sandoz Ltd. in January 2000, before undergoing a second CoA to the current Ennogen Limited licence in February 2009. Co-amilozide 5/50mg Tablets are indicated in patients with hypertension, congestive heart failure, hepatic cirrhosis with ascites and oedema. In hypertension, Co-amilozide may be used alone or in conjunction with other anti-hypertensive agents. This product is intended for patients where potassium depletion is anticipated or might be suspected. Hydrochlorothiazide and amiloride are both oral diuretics which act by reducing reabsorption of electrolytes from the renal tubules thereby increasing the excretion of sodium and chloride ions and consequently of water. Hydrochlorothiazide also increases the excretion of potassium ions while amiloride has the opposite effect and has been found to diminish the kaluretic effects of other diuretics, i.e. hydrochlorothiazide in this combination. Hydrochlorothiazide slightly increases the bicarbonate excretion without appreciable alterations to the acid-base balance or the pH of the urine. It has an anti-hypertensive effect and enhances the action of other hypotensive agents. Diuresis occurs in about two hours and lasts up to twenty-four hours. The MHRA considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. As the application is for a product that is identical to an already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, routine pharmacovigilance activities are proposed and a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profiles of the actives are well-established. It is not considered that this medicinal product represents any risk to the environment. There is no reason to conclude that marketing of this product will change the overall use pattern of the existing market. The availability of this medicinal product, which is identical to the cited reference product, will not lead to any increase in environmental


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exposure concentrations of the active ingredients. An Environmental Risk Assessment (ERA) is not considered necessary. No new data were submitted, nor was it necessary for this simple application, as the data are identical to that of the previously granted cross-reference product. As the cross-reference product was granted prior to the introduction of current legislation, no Public Assessment Report (PAR) was generated for it.


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PHARMACEUTICAL ASSESSMENT LICENCE NUMBER: PL 17907/0227

PROPRIETARY NAME: Co-amilozide 5mg/50mg Tablets

ACTIVE INGREDIENTS: hydrochlorothiazide / amiloride hydrochloride

COMPANY NAME: Bristol Laboratories Ltd

E.C. ARTICLE: Article 10c of Directive 2001/83/EC (as amended)

LEGAL STATUS: POM 1. INTRODUCTION

This is a simple abridged application, submitted under Article 10c of Directive 2001/83/EC (as amended) for Co-amilozide 5mg/50mg Tablets. The proposed Marketing Authorisation Holder (MAH) is Bristol Laboratories Ltd. The reference product is Co-amilozide Tablets 5mg/50mg (PL 34007/0022), authorised to Ennogen Limited on 6th February 2009. The proposed and reference products are identical. 2. MARKETING AUTHORISATION APPLICATION FORM

2.1 Name(s)

The approved name of the product is Co-amilozide 5mg/50mg Tablets. The product has been named in line with current requirements and the product name is acceptable. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes

Each Co-amilozide 5mg/50mg Tablet contains 5 mg amiloride hydrochloride and 50 mg hydrochlorothiazide. The tablets are licensed for marketing in the following containers:

i) Securitainers - pack sizes: 100 and 500 tablets

ii) polyvinylchloride (PVC) / aluminium foil blister strips, packed into cardboard outer cartons - pack sizes: 28, 50 or 100 tablets

Full details of container closure systems are provided in the Summary of Product Characteristics (SmPC). The container closure systems and pack sizes are identical to those stated for the reference product. The approved shelf-lives (securitainers – 5 years; blister packs – 4 years) and storage conditions (‘Do not store above 25°C. Store in original package to protect from light and moisture. Keep the container tightly closed’ for the securitainers; ‘Do not store above 25°C. Store in original package to protect from light and moisture, Keep the blister in the outer carton’ for the blisters) are consistent with the details registered for the cross-reference product.


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2.3 Legal status

POM - The product is available by supply through pharmacies, subject to a medical prescription. 2.4 Marketing Authorisation Holder / Contact Persons / Company

The proposed Marketing Authorisation Holder is ‘Bristol Laboratories Ltd, Unit 3, Canalside, Northbridge Road, Berkhamsted, Herts HP4 1EG’. The Qualified Person (QP) responsible for pharmacovigilance was stated and their CV included. 2.5 Manufacturers

The proposed manufacturing sites are consistent with those registered for the cross-reference product and evidence of GMP compliance has been provided. 2.6 Qualitative and quantitative composition

The proposed composition is consistent with the details registered for the cross-reference product. 2.7 Manufacturing process

The proposed manufacturing process is consistent with the details registered for the cross-reference product and the maximum batch size is stated. 2.8 Finished product / shelf-life specification

The proposed finished product specification is consistent with the details registered for the cross-reference product. 2.9 Drug substance specification

The proposed drug substance specifications are consistent with the details registered for the cross-reference product. 2.10 TSE Compliance

The magnesium stearate used has been confirmed as being of vegetable origin. The only excipient used that contains material of animal or human origin is lactose. The applicant has provided a declaration that milk used in the production of lactose is sourced from healthy animals under the same conditions as that for human consumption. None of the excipients are sourced from genetically modified organisms. 3. EXPERT REPORT

A satisfactory quality overall summary has been prepared by an appropriately qualified expert. The CV of the expert was provided. 4. PRODUCT NAME & APPEARANCE

See 2.1 for details of the proposed product name. Co-amilozide 5mg/50mg Tablets are presented as flat, pale, peach-coloured, bevelled-edged tablets bisected on one side


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and embossed ‘MP3’ on the other. The appearance of the tablets is identical to that of the cross-reference product. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC)

The approved SmPC is consistent with the details registered for the cross-reference product. 6. PATIENT INFORMATION LEAFLET (PIL) / LABELLING

PIL

The approved PIL is satisfactory and in line with the approved SmPC. It has been prepared according to the Quality Review of Documents (QRD) template and is consistent with the details registered for the cross-reference product. PIL user testing has been accepted based on a bridging report provided by the applicant making reference to the successful user-testing of the PIL for Ramipril 1.25 mg, 2.5 mg, 5 mg and 10 mg capsules, hard (PL 17907/0063-66; UK/H/0864/01-04/MR). The bridging is accepted. Labelling

Mock-ups of the labelling have been provided and are satisfactory. The approved labelling artwork complies with statutory requirements. In line with current legislation the applicant has included the name of the product in Braille on the outer packaging and has included sufficient space for a standard UK pharmacy dispensing label. The MAH has committed to submitting mock-ups for currently unmarketed packs to the UK regulatory authority for approval before those packs are commercially marketed. 7. CONCLUSIONS

The grounds for this application are considered adequate. A Marketing Authorisation was, therefore, granted.


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NON-CLINICAL ASSESSMENT This is a simple, abridged, ‘informed consent’ application made under Article 10(c) of EC Directive 2001/83 (as amended). No new non-clinical data have been supplied with this application and none are required for an application of this type. A non-clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the non-clinical expert has been supplied.


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CLINICAL ASSESSMENT This is a simple, abridged, ‘informed consent’ application made under Article 10(c) of EC Directive 2001/83 (as amended), cross-referring to the Marketing Authorisation for Co-amilozide Tablets 5/50mg / Zida-Co 5/50 (PL 34007/0022; Ennogen Limited). No new clinical data have been supplied with the application, and none are required for applications of this type. A clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the clinical expert has been supplied.


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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY

The data for this application are consistent with those previously assessed for the cross-reference product and as such have been judged to be satisfactory. NON-CLINICAL

No new non-clinical data were submitted and none are required for an application of this type. CLINICAL

This application is considered identical to the previously granted licence for Co-amilozide Tablets 5/50mg / Zida-Co 5/50 (PL 34007/0022; Ennogen Limited). No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE

The approved SmPC is satisfactory and consistent with the details registered for the cross-reference product. PIL user testing has been accepted based on a bridging report provided by the applicant making reference to the successful user-testing of the PIL for Ramipril 1.25 mg, 2.5 mg, 5 mg and 10 mg capsules, hard (PL 17907/0063-66; UK/H/0864/01-04/MR). The bridging is accepted. Mock-ups of the labelling have been provided and are satisfactory. The approved labelling artwork complies with statutory requirements. The MAH has committed to submitting mock-ups for currently unmarketed packs to the UK regulatory authority for approval before those packs are commercially marketed. BENEFIT-RISK ASSESSMENT

The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The applicant’s product is identical to the cross-reference product. The benefit: risk ratio is considered to be positive.


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PL 17907/0227

STEPS TAKEN FOR ASSESSMENT 1 The MHRA received the Marketing Authorisation application on 21st April

2006.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 14th June 2006.

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 10th July 2006, 31st July 2009, 10th November 2010, 1st February 2011 and 14th April 2011.

4 The applicant responded to the MHRA’s requests, providing further information for the quality sections on 28th March 2007, 1st April 2010, 10th December 2010, 13th April 2011 and 20th April 2011.

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The application was determined on 27th May 2011 and granted on 1st June 2011.


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PL 17907/0227

STEPS TAKEN AFTER AUTHORISATION Not applicable


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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Co-amilozide 5mg/50mg Tablets Amiloride hydrochloride / Hydrochlorothiazide

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5mg amiloride hydrochloride and 50mg hydrochlorothiazide.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablets. A flat, pale peach bevelled edged tablet bisected on one side, embossed ‘MP3’ on the other. The tablet can be divided into equal halves

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-amilozide Tablets 5/50mg are indicated in patients with hypertension, congestive heart failure, hepatic cirrhosis with ascites and oedema. In hypertension co-amilozide may be used alone or in conjunction with other anti-hypertensive agents. This product is intended for patients where potassium depletion is anticipated or might be suspected.

4.2 Posology and method of administration

Adults: Hypertension Usually half a tablet is given once a day. Dosage may be increased to one tablet a day either as a single or divided dose. Congestive heart failure Half a tablet a day, adjusted if necessary but not exceeding 2 tablets a day. The optimal dose is determined by the diuresis response and plasma potassium level. Once an initial diuresis has been attained, dosage reduction should be attempted for maintenance therapy. It may be possible to give maintenance therapy on an intermittent basis. Hepatic cirrhosis with ascites Therapy should be initiated with a low dose. A single daily dose of one tablet may be increased until effective diuresis is achieved. Doses should not exceed 2 tablets a day. Dosage reduction to a maintenance level should be attempted once the patient’s weight has stabilised. A gradual weight reduction is desirable to reduce the likelihood of unwanted effects associated with diuretic medication. Children: Not recommended for children under 18 years of age as safety and efficacy has not been established. Elderly: The dosage should be adjusted to reflect the clinical response and renal function. Route of administration Oral.


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4.3 Contraindications

Co-Amilozide Tablets 5/50mg are contraindicated if the patient • has hypersensitivity to amiloride hydrochloride, hydrochlorothiazide or other

sulphonamide-derived drugs, or to any of the other ingredients of the tablets. • has hyperkalaemia (plasma potassium over 5.5 mmol/l) • is taking other potassium conserving diuretics or potassium supplements • is having concomitant treatment with spironolactone or triamterene • has anuria • has acute renal failure or severe progressive renal disease • has severe hepatic failure or precoma associated with hepatic cirrhosis • has Addison’s disease • has hypercalcaemia • is having concurrent lithium therapy • has diabetic nephropathy • has blood urea over 10 mmol/l, diabetes mellitus, or serum creatinine over 130 μmol/l

where serum electrolyte and blood urea cannot be monitored carefully and frequently.

4.4 Special warnings and precautions for use

Risk of Hyperkalaemia: Hyperkalaemia has been observed in patients taking amiloride hydrochloride, especially in the elderly or hospitalised patients with hepatic cirrhosis or congestive heart failure with renal involvement, in seriously ill patients or in those undergoing vigorous diuretic treatment. In such cases, the patient should be carefully observed for clinical, laboratory or ECG evidence of hyperkalaemia. The ECG may not appear to be abnormal in all cases. Some deaths have been reported in patients especially at risk of hyperkalaemia. If hyperkalaemia is suspected, treatment should be discontinued immediately and active measures taken to reduce the plasma potassium to normal levels. Potassium supplements and potassium-rich foods should be avoided unless it is possible to monitor the serum potassium levels. To minimise the risk of hyperkalaemia in patients with proven or suspected diabetes, the renal function should be assessed before co-amilozide therapy. Co-amilozide should be discontinued for at least 3 days before a glucose tolerance test. Potassium sparing treatment should be started with caution in severely ill patients, where metabolic or respiratory acidosis may occur, (such as cardiopulmonary disease or inadequately controlled diabetes). Shifts in acid base balance alter the balance of potassium in and outside the cells; the development of acidosis may be associated with a rapid increase in plasma potassium. These tablets contain lactose and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine. Impaired renal function: Hyperkalaemia may develop rapidly in patients with impaired renal function, which should be monitored. At creatinine levels below 30ml/min, thiazide diuretics are ineffective. Electrolyte imbalance: Patients should be monitored for fluid and electrolyte imbalance; hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. Warnings signs and symptoms include dry mouth, weakness, lethargy, drowsiness, restlessness, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and GI disturbances such as nausea and vomiting. If the patient is vomiting excessively or receiving parenteral fluids, serum and urine electrolytes should be determined.


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Hypokalaemia: May develop due to aggressive diuretic therapy, after prolonged therapy or if there is severe liver cirrhosis. This may sensitise or exaggerate the heart's response to digitalis toxicity. Hyponatraemia: Diuretic-induced hyponatraemia is usually mild and asymptomatic, although it may become severe and symptomatic. If this occurs, the patient requires prompt treatment. Azotaemia: Azotaemia may be precipitated or increased by hydrochlorothiazide. In patients with impaired renal function, cumulative effects may be seen. Co-amilozide should be discontinued if increasing azotaemia and oliguria develop. Hepatic disease: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease. Minor alteration of electrolyte and fluid balance may precipitate hepatic coma. Hyperuricaemia may occur, or gout may be aggravated or precipitated in certain patients. Increases in cholesterol and triglyceride levels may be seen. It has been reported that thiazides may activate or exacerbate systemic lupus erythematosus.

4.5 Interaction with other medicinal products and other forms of interaction

Thiazides may decrease urinary calcium excretion, or 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. Cholestyramine and colestipol reduce the absorption of thiazides and should therefore be given at least 2 hours apart. Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by co-amilozide therapy. Dosage adjustment of antidiabetic agents including insulin may be required. NSAIDs may reduce the diuretic effects of diuretics. However diuretics increase the risk of nephrotoxicity of NSAIDs. Indomethacin and possibly other NSAIDs may increase the risk of hyperkalaemia when taken with potassium sparing diuretics. The risk of hyperkalaemia and an enhanced hypotensive effect may occur if an ACE inhibitor or angiotensin-II antagonist are administered concurrently with amiloride hydrochloride. If concomitant use of these agents is desirable, frequent monitoring of serum potassium should be carried out. There is also an increased risk of hyperkalaemia if cyclosporin, potassium salts or trilostane are used concomitantly with amiloride. Co-administration of alcohol, barbiturates or narcotics may potentiate orthostatic hypotension. There is a risk of postural hypotension when taken with tricyclic antidepressants. Other antihypertensive agents may have an additive effect; their dosages may need to be reduced (especially adrenergic blockers) when co-amilozide is added to existing therapy. Diuretic therapy should be discontinued for 2-3 days before an ACE inhibitor is introduced to minimise the risk of a first-dose hypotensive effect. There is an increase in the risk of first dose hypotensive effects when post-synaptic alphablockers, such as prazosin, are taken concomitantly with co-amilozide. Anti-hypertensives, calcium channel blockers, alprostadil, betablockers and moxisylyte can all enhance the antihypertensive effects of co-amilozide tablets. There is an increased risk of toxicity from cardiac glycosides and the following anti-arrhythmics; amiodarone, disopyramide, flecainide and quinidine, if hypokalaemia occurs with a thiazide diuretic. The actions of lidocaine and mexiletine are antagonised by hypokalaemia.


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There is an increased risk of hypokalaemia if co-amilozide tablets are taken with the following; reboxetine, amphotericin and high doses of sympathomimetics. There is also an increased risk of hypokalaemia if loop diuretics, thiazides or acetazolamide are given together. Carbenoxolone can increase the risk of hypokalaemia whilst antagonising the diuretic effect of co-amilozide. The ulcer healing effect of carbenoxolone is antagonised by amiloride. Corticosteroids or ACTH may intensify any thiazide induced electrolyte depletion, especially hypokalaemia and also antagonise the diuretic effect. Hypokalaemia and other electrolyte imbalances can lead to an increase in ventricular arrhythmia when co-amilozide is taken with terfenadine, halofantrine, pimozide and sotalol. Pressor amines, such as adrenaline, may show decreased arterial responsiveness when used with co-amilozide but the therapeutic effect may still be of use. There is an increased risk of hypercalcaemia if thiazides are given with vitamin D, toremifene or calcium salts. The diuretic effect of co-amilozide tablets is antagonised by oestrogen, combined oral contraceptives. Non-depolarising muscle relaxants, such as tubocurarine, may possibly interact with co-amilozide to cause increased muscle relaxation. Other muscle relaxants such as baclofen and tizanidine may enhance the hypotensive effects of co-amilozide. Lithium may accumulate due to reduced renal clearance. Cisplatin and co-amilozide can increase the risk of nephrotoxicity and ototoxicity. Co-amilozide combined with chlorpropamide, carbamazepine or aminoglutethimide can act in synergy to increase the risk of hyponatraemia. Hydrochlorothiazide increases plasma concentrations of fluconazole.

4.6 Pregnancy and lactation

Co-Amilozide Tablets are not recommended unless it is considered that the benefits to the mother outweigh the risks to the foetus or infant. Diuretic use in pregnant women may be associated with hypovolaemia, increased blood viscosity or decreased placental perfusion. Diuretics do not prevent toxaemia developing and there is no satisfactory evidence of their usefulness. Thiazides cross the placental barrier and are detectable in cord blood. The possible risks to the foetus include foetal or neonatal jaundice, thrombocytopenia and bone marrow depression. Thiazides are detectable in breast milk; although it is not known whether amiloride hydrochloride is excreted into breast milk, it is advisable to cease breast feeding if co-amilozide is prescribed.

4.7 Effects on ability to drive and use machines

Side effects such as headache, visual disturbances, confusion, dizziness and vertigo may occur. Should these occur the patient should be cautioned not to drive or operate machinery.

4.8 Undesirable effects

Although serious side effects are infrequent, minor side effects are common. They are generally associated with the underlying disease, diuresis or thiazide therapy. There is no known increased risk of side-effects due to the combination of amiloride with hydrochlorothiazide.


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General disorders: headache, weakness, fatigue, malaise, chest pain, back pain, syncope, dizziness, vertigo, stupor, paraesthesia, bad taste, visual disturbances, nasal congestion. Cardiac disorders: arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris. Gastrointestinal disorders: anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pains, GI bleeding, changes in appetite, abdominal fullness, flatulence, thirst, hiccups. Metabolism and Nutrition: elevated plasma potassium levels (above 5.5mmol/l), electrolyte imbalance, hyponatraemia (possibly symptomatic), gout, dehydration. Skin and subcutaneous tissue disorders: rashes, pruritus, flushing, sweating. Musculoskeletal, connective tissue and bone disorders: aching legs, muscle cramps, joint pains. Psychiatric disorders: insomnia, nervousness, mental confusion, depression, sleepiness. Respiratory, thoracic and mediastinal disorders: dyspnoea. Renal and urinary disorders: impotence, dysuria, nocturia, incontinence, renal dysfunction including renal failure. Amiloride has been reported to cause: neck or shoulder aches or pain in the extremities; abnormal liver function; activation of pre-existing peptic ulcers; dyspepsia or jaundice; dry mouth, alopecia or sweating; tremors or encephalopathy; aplastic anaemia or neutropenia; palpitations, possible aggravation of partial heart block; decreased libido; sleepiness; cough; tinnitus or increased intra-ocular pressure; polyuria, urinary frequency or bladder spasm. Hydrochlorothiazide has been reported to cause: fever, anaphylaxis, necrotising angiitis, jaundice, pancreatitis, cramps, gastric irritation; glycosuria, hyperglycaemia, hyperuricaemia; photosensitivity; inflammation of the salivary glands; urticaria; agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia; restlessness; interstitial nephritis; transient blurred or coloured vision; respiratory distress, including pneumonitis and pulmonary oedema.

4.9 Overdose

No specific antidote is available and it is not known whether either component of co-amilozide is dialysable. Treatment should be symptomatic and supportive. Therapy should be discontinued and the patient observed. If ingestion is recent, emesis should be induced and/or gastric lavage performed. The most common signs of overdosage are dehydration and electrolyte imbalance. Blood pressure should be monitored and corrected as necessary. In the event of hyperkalaemia, plasma potassium levels should be actively reduced. If digitalis has been administered, hypokalaemia may exaggerate cardiac arrhythmias. The plasma half-life of amiloride is about 6 hours, and of hydrochlorothiazide about 5½ hours with a longer terminal half-life.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: C03EA01 – Hydrochlorothiazide and potassium-sparing agents. Hydrochlorothiazide and amiloride are both oral diuretics which act by reducing reabsorption of electrolytes from the renal tubules thereby increasing the excretion of sodium and chloride ions and consequently of water. Hydrochlorothiazide also increases the excretion of potassium ions while amiloride has the opposite effect and has been found to diminish the kaluretic effects of other diuretics, i.e. hydrochlorothiazide in this combination.


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Hydrochlorothiazide slightly increases the bicarbonate excretion without appreciable alterations to the acid-base balance or the pH of the urine. It has an anti-hypertensive effect and enhances the action of other hypotensive agents. Diuresis occurs in about two hours and lasts up to twenty-four hours.

5.2 Pharmacokinetic properties

Amiloride hydrochloride is incompletely absorbed from the gastrointestinal tract bioavailability of about 50% is reported. Food reduces the absorption. It is not significantly bound to plasma proteins and has a half-life of 6-9 hours. It is excreted unchanged by the kidneys. Hydrochlorothiazide is rapidly absorbed from the gastro-intestinal tract, with a bioabsorbability of 65-70%. It has a plasma half-life of about 5 hours with a terminal half-life of up to 15 hours. It is excreted unchanged by the kidneys. Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.

5.3 Preclinical safety data

None Known

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose, Maize starch, Microcrystalline cellulose, Sodium starch glycollate, Purified talc, Magnesium stearate, Sunset yellow (E110).

6.2 Incompatibilities

Not applicable

6.3 Shelf life

5 years in Securitainers 4 years in Al/PVC blister packs.

6.4 Special precautions for storage

Do not store above 25oC. Store in original package, to protect from light and moisture. Securitaniers: Keep the container tightly closed. Blisters: Keep the blister in the outer carton.

6.5 Nature and contents of container

Securitainers stoppered with a polyurethane foam insert and sealed with a press cap. Pack size: 100 or 500 tablets. Aluminium/PVC blisters in cardboard cartons. Pack size: 28, 50 or 100 tablets.

6.6 Special precautions for disposal

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


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7 MARKETING AUTHORISATION HOLDER

Bristol Laboratories Ltd Unit 3, Canalside Northbridge Road Berkhamsted Herts HP4 1EG

8 MARKETING AUTHORISATION NUMBER(S)

PL 17907/0227

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/06/2011 10 DATE OF REVISION OF THE TEXT

01/06/2011


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PATIENT INFORMATION LEAFLET


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LABELLING

Carton for blisters

Braille


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Blister foil

Securitainer label – pack size 100 tablets

Securitainer label – pack size 500 tablets