SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

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1 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Co-Amilozide 5/50 Tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains Amiloride Hydrochloride 5 mg and Hydrochlorothiazide 50 mg. For excipients, see PHARMACEUTICAL FORM Tablet A flat, pale peach bevelled edged tablet, engraved CO breakline AM on one side and plain on the other side. 4. CLINICAL PARTICULARS 4.1. Therapeutic Indications 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 antihypertensive agents. This product is intended for patients where potassium depletion is anticipated or might be suspected Posology and Method of Administration Route of administration Oral Adults: Hypertension: Initially half a tablet daily, increased to a maximum of one tablet daily if necessary. Congestive heart failure: Initially half a tablet daily, increased to a maximum of two tablets daily if necessary. The optimal dose is determined by the

2 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 intermittant basis Hepatic cirrhosis with oedema and ascites: Initially one tablet daily, increased if necessary to a maximum of two tablets daily. 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 should be reduced for maintenance if possible Children: Co-amilozide tablets are not recommended for children under 18 years of age as safety and efficacy have not been established (see section 4.3 Contraindications). Elderly: The dosage in elderly patients should be adjusted to reflect the clinical response and renal function Contraindications Hyperkalaemia (plasma potassium over 5.5 mmol/l); other potassium conserving diuretics or potassium supplements; concomitant treatment 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; 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. Prior hypersensitivity to amiloride hydrochloride, hydrochlorothiazide or other sulphonamide - derived drugs. Contraindicated in children under 18 years of age (see section 4.2 posology) 4.4 Special warnings and precautions for use 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.

3 Potassium supplements and potassium-rich foods should be avoided, except in cases of severe or refractory hypokalaemia where careful monitoring of serum potassium levels is required (see section 4.3). 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 plasma potassium to normal levels. Electrolyte imbalance Patients should be monitored for fluid and electrolyte imbalance; hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. Warning signs and symptoms include dry mouth, weakness, lethargy, drowsiness, restlessness, seizures, muscle cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. If the patient is vomiting excessively or receiving parenteral fluids, serum and urine electrolytes should be determined. 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 (see section 4.5). Diuretic-induced hyponatraemia is usually mild and asymptomatic, although it may become severe and symptomatic. If this occurs, the patient requires prompt treatment. 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. Co-amilozide therapy should be discontinued before carrying out tests for parathyroid function. Impaired renal function Renal function should be monitored because the use of co-amilozide in impaired renal function may result in the rapid development of hyperkalaemia. Thiazide diuretics are ineffective when creatinine clearance falls below 30 ml/min. Uraemia 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 uraemia and oliguria develop. Hepatic dysfunction 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.

4 Metabolic effects Hyperuricaemia may occur, or gout may be aggravated or precipitated in certain patients. Hypersensitivity reactions to allopurinol have been reported to occur more frequently in patients receiving thiazide diuretics (see section 4.5). 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. 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. Increases in plasma cholesterol and triglyceride levels may be seen. Systemic lupus erythematosus It has been reported that thiazides may activate or exacerbate systemic lupus erythematosus. Concurrent use of NSAIDs If NSAIDs and co-amilozide are used concurrently, renal function and serum potassium should be closely monitored (see section 4.5). Excipients Co-amilozide contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Co-amilozide contains Sunset yellow (E110) which can cause allergic reactions including asthma. Allergy is more common in those people who are allergic to aspirin. 4.5 Interaction with other medicinal products and other forms of interaction Interactions affecting the use of co-amilozide Anion exchange resins Single doses of either colestyramine or colestipol resins reduce the absorption of hydrochlorothiazide from the gastrointestinal tract by up to 85 and 43 percent respectively. When colestyramine is given 4 hours after the

5 hydrochlorothiazide, the absorption of hydrochlorothiazide is reduced by 30 to 35 percent. NSAIDs NSAIDs may attenuate the diuretic and antihypertensive effects of thiazide diuretics. Concomitant administration of NSAIDs and potassium sparing diuretics may cause hyperkalaemia and renal failure, particularly in the elderly. Therefore when co-amilozide is used concurrently with NSAIDs, renal function and serum potassium should be carefully monitored. CNS depressant agents Co-administration of alcohol, barbiturates or narcotics may potentiate orthostatic hypotension. Interactions affecting the use of other medications Lithium Concurrent use of lithium and co-amilozide is contraindicated (see section 4.3). There is an increased risk of lithium toxicity, due to reduced renal clearance of lithium, and of sodium depletion occurring as a consequence of diuresis. Antihypertensive agents Close supervision and observation is recommended after the first dose of an Angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist due to the risk of first dose hypotension. Consideration should be given to reducing the dose or temporarily withdrawing treatment, two to three days before an ACE inhibitor is introduced. There is an increased risk of hyperkalaemia when potassium-sparing diuretics are administered with ACE inhibitors or angiotensin II receptor antagonists. The dose of concurrently administered antihypertensives (especially alphaadrenergic blockers) or other drugs with blood pressure lowering potential may require adjustment when co-amilozide is added to existing therapy as additive hypotensive effects may occur. Medications affected by electrolyte disturbances Consideration should be given to the possibility of electrolyte disturbances when co-amilozide is administered concurrently with other drugs that also have this effect. Appropriate monitoring is recommended (section 4.4). Electrolyte disturbances such as hypokalaemia may increase the toxicity and the risk of arrythmias associated with certain drugs (e.g. cardiac glycosides, amisulpride, atomoxetine, pimozide, sotalol, sertindole). There is increased risk of hypokalaemia with concurrent use of thiazide diuretics and corticosteroids, ACTH, theophylline, amphotericin, reboxetine or loop diuretics.

6 Potentially serious hypokalaemia may result from beta 2 -adrenoreceptor stimulant therapy, and caution is advised if initiating co-amilozide therapy in severely asthmatic patients. Monitoring of serum potassium is recommended. Increased risk of hyperkalaemia occurs when amiloride is taken with potassium salts or drugs which reduce potassium excretion or elevate serum potassium levels, e.g. ACE Inhibitors, angiotensin II receptor antagonists, NSAIDs, aliskiren, ciclosporin, drospirenone, tacrolimus, trilostane. There is an increased risk of hypercalcaemia if thiazide diuretics are administered with vitamin D, calcium salts or toremifene. Concomitant use with carbamazepine may increase the risk of hyponatraemia. Catecholamines Pressor amines, such as adrenaline, may show decreased responsiveness when used with co-amilozide, but the therapeutic effect may still be of use. Neuromuscular blocking agents Non-depolarising muscle relaxants may possibly interact with co-amilozide to cause increased muscle relaxation. Allopurinol Thiazide diuretics may cause predisposition to allopurinol hypersensitivity reactions. Fluconazole Hydrochlorothiazide increases plasma levels of fluconazole Although no dose adjustment of fluconazole is generally required the prescriber should be aware of this interaction. Anti-diabetic agents Co-amilozide may antagonise the effects of oral and parenteral hypoglycaemic agents. Co-amilozide and chlorpropamide can act in synergy to increase the risk of hyponatraemia. 4.6 Pregnancy and lactation Pregnancy 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. There are no adequate and well-controlled studies in pregnant women, therefore Coamilozide should not be used in pregnancy unless it is considered that the benefits to the mother outweigh the risks to the foetus.

7 Thiazides cross the placental barrier and are detectable in cord blood. The possible risks to the foetus include foetal or neonatal jaundice, thrombocytopenia, disturbance of electrolyte balance and bone marrow depression. Lactation Thiazides are detectable in breast milk; although it is not known whether amiloride hydrochloride is excreted into breast milk. If the use of co-amilozide is considered essential, the mother should stop breast-feeding. Thiazides in high doses causing intense diuresis can inhibit the milk production Effects on Ability to Drive and Use Machines Infrequently, patients may experience weakness, fatigue, dizziness, vertigo and stupor. The patient should be cautioned not to drive or operate machinery should any of these effects occur. 4.8 Undesirable effects The following undesirable effects have been reported with Co-amilozide or either of the individual components. Their frequency cannot be estimated from the available data. 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. Co-amilozide Metabolism and nutrition disorders: Elevated plasma potassium levels, electrolyte imbalance, hyponatraemia (possibly symptomatic), increased blood uric acid levels possibly leading to gout, dehydration, increased blood cholesterol, increased blood triglycerides Psychiatric disorders: Insomnia, nervousness, mental confusion, depression Nervous system disorders: Headache, dizziness, stupor, somnolence, paraesthesia, syncope, dysgeusia Eye disorders: Visual disturbances Ear and labyrinth disorders: Vertigo Cardiac disorders: Arrhythmias, tachycardia, angina pectoris Vascular disorders: Orthostatic hypotension, flushing Respiratory disorders: Dyspnoea, nasal congestion, hiccups

8 Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, abdominal pain, gastrointestinal haemorrhage, anorexia, changes in appetite, abdominal distension, flatulence Skin and subcutaneous tissue disorders: Rash, pruritus, hyperhidrosis Musculoskeletal, connective tissue and bone disorders: Myalgia, muscle spasms, joint pain Renal and urinary disorders: Dysuria, nocturia, incontinence, renal dysfunction including renal failure, especially during concomitant treatment with NSAIDs. Reproductive disorders: Erectile dysfunction General disorders: Thirst, asthenia, fatigue, malaise, chest pain, back pain Additional side effects have been reported with the individual components of Coamilozide and may also occur with the combination product. Amiloride Blood and lymphatic system disorders: Aplastic anaemia, neutropenia Psychiatric disorders: Decreased libido Nervous system disorders: Tremor, encephalopathy Eye disorders: Increased intraocular pressure Ear and labyrinth disorders: Tinnitus Cardiac disorders: Aggravation of partial heart block, palpitations Respiratory disorders: Cough Gastrointestinal disorders: Dyspepsia, dry mouth, activation of pre-existing peptic ulcers Hepato-biliary disorders: Hepatic function abnormal, jaundice Musculoskeletal disorders: Neck pain, musculoskeletal pain, pain in extremity Skin and subcutaneous tissue disorders: Alopecia Renal and urinary disorders: Polyuria, pollakiuria, bladder spasm Hydrochlorothiazide Blood and lymphatic system disorders: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, thrombocytopenia, thrombocytopenic purpura Immune system disorders: Anaphylaxis Metabolism and nutrition disorders: Glycosuria, hyperglycaemia

9 Psychiatric disorders: Restlessness Eye disorders: Transient blurred vision, xanthopsia Vascular: Vasculitis, vasculitis necrotising Respiratory, thoracic and mediastinal: Respiratory distress, pneumonitis, pulmonary oedema Gastrointestinal disorders: Stomach discomfort, sialoadenitis, pancreatitis Hepatobiliary disorders: Cholestatic jaundice Skin and subcutaneous tissue disorders: Urticaria, photosensitivity, cutaneous vasculitis, toxic epidermal necrolysis Renal and urinary disorders: Interstitial nephritis General disorders: Pyrexia Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: Overdose Symptoms The most common signs of overdosage are dehydration and electrolyte imbalance, including hyperkalaemia or hypokalaemia. If digitalis has been administered, hypokalaemia may exaggerate cardiac arrhythmias. Management No specific data is available on overdose with co-amilozide. No specific antidote is available and it is not known whether either component of coamilozide is dialysable. Therapy should be discontinued and the patient observed. Consider gastric lavage if the patient presents within one hour of ingestion of a significant overdose. Treatment should be symptomatic and supportive and aimed at fluid replacement, correction of electrolyte imbalance and maintenance of blood pressure. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic Properties Pharmacotherapeutic group: Low ceiling diuretics and potassium-sparing agents. ATC code: C03E A0l.

10 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 kaliuretic effects of other diuretics, i.e. hydrochlorothiazide in this combination. Hydrochlorothiazide slightly increases the bicarbonate excretion without appreciable alteration 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 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 Pre-clinical Safety Data There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC. 6. PHARMACEUTICALS PARTICULARS 6.1 List of Excipients Lactose Monohydrate Microcrystalline Cellulose Maize Starch Magnesium Stearate Purified Talc Sodium Starch Glycollate

11 Sunset Yellow Aluminium Lake (E110) 6.2 Incompatibilities Not applicable. 6.3 Shelf life Blisters: 4 years 6.4 Special Precautions for Storage Store below 25 ο C. Protect from moisture and light. 6.5 Nature and contents of container Al/PVC blisters, packs sizes of 28, 50 or 100 tablets Not all packs may be marketed 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER Strides Pharma UK Ltd Unit 4 Metro Centre Tolpits Lane Watford Hertfordshire WD18 9SS Trading as: Co-pharma 8. MARKETING AUTHORISATION NUMBER(S) PL 13606/ DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

12 21 February DATE OF REVISION OF THE TEXT 27/04/2017