SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-zidocapt 25/12.5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains Captopril 25mg and Hydrochlorothiazide 12.5mg

Excipient with known effect: Each tablet contains 34.350mg lactose (as lactose monohydrate)

For full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

White to off white, round with an approximate diameter of 7mm, with score notch.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of mild to moderate hypertension in patients who have been stabilised on the individual components given in the same proportions. The combination tablet of 25 mg captopril and 12.5 mg hydrochlorothiazide is particularly suitable for older patients and others requiring lower doses of the components.

4.2    Posology and method of administration

Posology

Adults: The usual dose is one tablet daily.

Elderly: The dose should be kept as low as possible to achieve adequate blood pressure control. In some patients half a tablet may be sufficient. Co-zidocapt 25/12.5mg Tablets are particularly suitable for the elderly patient.

Paediatric population: Safety and effectiveness has not been established.

Patients with renal failure: Co-zidocapt 25/12.5mg Tablets are not recommended for use in patients with significant renal impairment.

Method of administration

The tablets are for oral administration. They should be taken in the morning, independently of meals, together with a generous quantity of liquid.

4.3 Contraindications

Co-zidocapt 25/12.5mg Tablets are contraindicated in the following cases:

-    Hypersensitivity to captopril, any other ACE inhibitor, any sulphonamide-derived drug, or any of the excipients listed in section 6.1.

-    Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

-    History of angioedema associated with previous ACE inhibitor therapy

-    Hereditary/idiopathic angioneurotic oedema

-    Severe renal impairment (creatinine clearance < 30 ml/min)

-    Severe hepatic impairment

-    The concomitant use of Co-zidocapt 25/12mg tablets with aliskiren-

containing products is contraindicated in patients with diabetes

2

mellitus or renal impairment (GFR< 60mL/min/1.73m ) (see section

4.5 and 5.1).

4.4 Special warnings and precautions for use

CAPTOPRIL

Hypotension: Rarely hypotension is observed in uncomplicated hypertensive patients. Symptomatic hypotension is more likely to occur in hypertensive patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, vomiting, or haemodialysis. Volume and/or sodium depletion should be corrected before the administration of an ACE inhibitor and a lower starting dose should be considered.

As with any antihypertensive agent, excessive blood pressure lowering in patients with ischaemic cardiovascular or cerebrovascular disease may increase the risk of myocardial infarction or stroke. If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required.

Dual blockade of the renin angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increase the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see section 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Renovascular hypertension: There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration and monitoring of renal function.

Angioedema: Angioneurotic oedema/angioedema of the extremities, face, lips, mucous membranes, tongue, glottis or larynx may occur in patients treated with ACE inhibitors including captopril, particularly during the first weeks of treatment. However, in rare cases, severe angioedema may develop after longterm treatment with an ACE inhibitor. Treatment should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.

Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE

inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (see section 4.8).

Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy.

Hepatic failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitors and receive appropriate medical follow-up.

Hyperkalaemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril.

Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin).

If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.

Aortic and mitral valve stenosis / Obstructive hypertrophic cardiomyopathy /

Cardiogenic shock: ACE inhibitors should be used with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Neutropenia/Agranulocytosis: Neutropenia/agranulocytosis,thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors, including captopril. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Captopril should be used with extreme caution in patients with collagen vascular disease,immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.

If captopril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every 2 weeks during the first 3 months of captopril therapy, and periodically thereafter. During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever) when a differential white blood cell count should be performed.

Captopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia (neutrophils less than 1000/mm³) is detected or suspected.

In most patients neutrophil counts rapidly return to normal upon discontinuing captopril.

Proteinurea: proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.

Total urinary proteins greater than 1 g per day were seen in about 0.7% of patients receiving captopril. The majority of patients had evidence of prior renal disease or had received relatively high doses of captopril (in excess of 150 mg/day), or both.

Nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases,

proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.

Patients with prior renal disease should have urinary protein estimations (dip-stick on first morning urine) prior to treatment, and periodically thereafter.

Anaphylactoid reactions during desensitisation: sustained lifethreatening anaphylactoid reactions have been rarely reported for patients undergoing desensitising treatment with hymenoptera venom while receiving another ACE inhibitor. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.

Anaphylactoid reactions during high-flux dialysis / lipoprotein apheresis membrane exposure: Anaphylactoid reactions have been reported in patients haemodialysed with high-flux dialysis membranes or undergoing low-density lipoprotein apheresis with dextran sulphate absorption. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication.

Surgery/Anaesthesia: Hypotension may occur in patients undergoing major surgery or during treatment with anaesthetic agents that are known to lower blood pressure. If hypotension occurs, it may be corrected by volume expansion.

Diabetic patients: The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.

As with other angiotensin converting enzyme inhibitors, Co-zidocapt is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of lowrenin states in the black hypertensive population.

HYDROCHLOROTHIAZIDE

Renal impairment: In patients with renal disease, thiazides may precipitate azotaemia. Cumulative effects of the drug may develop in patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by a rising non-protein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy (see section 4.3).

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

Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Electrolyte imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatremia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with captopril may reduce diuretic induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Dilutional hyponatremia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does not require treatment.

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

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Anti-doping test: hydrochlorothiazide contained in this medication could produce a positive analytical result in an anti-doping test.

Other: Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

CAPTOPRIL/HYDROCHLOROTHIAZIDE COMBINATION Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Risk of hypokalaemia: The combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of kalaemia should be performed.

Combination with lithium: Co-zidocapt is not recommended in association with lithium due to the potentiation of lithium toxicity (see section 4.5).

Lactose: Co-zidocapt contains lactose. Therefore, it should not be used in cases of patients with rare hereditary problems of galactose intolerance, congenital galactosaemia, glucose and galactose malabsorption or the Lapp lactase deficiency syndromes (rare metabolic diseases).

4.5 Interaction with other medicinal products and other forms of interaction

It has been suggested that the anti-hypertensive effect of captopril can be delayed when patients treated with clonidine are changed to Co-zidocapt 25/12.5mg Tablets.

CAPTOPRIL

Potassium sparing diuretics or potassium supplements: ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Diuretics (thiazide or loop diuretics): Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with captopril (see 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of captopril. However, no clinically significant drug interactions have been found in specific studies with hydrochlorothiazide or furosemide.

Other antihypertensive agents: captopril has been safely co-administered with other commonly used anti-hypertensive agents (e.g. beta-blockers and long-acting calcium channel blockers). Concomitant use of these agents may increase the hypotensive effects of captopril. Nitroglycerine and other nitrates, or other vasodilators, should be used with caution.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hypokalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see section 4.3, 4.4, and 5.1).

Alpha blocking agents: Concomitant use of alpha blocking agents may increase the antihypertensive effects of captopril and increase the risk of orthostatic hypotension.

Treatments of acute myocardial infarction: Captopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates in patients with myocardial infarction.

Tricyclic antidepressants/Antipsychotics: ACE inhibitors may enhance the hypotensive effects of certain tricyclic antidepressants and antipsychotics (see section 4.4). Postural hypotension may occur.

Allopurinol, procainamide, cytostatic or immuno-suppressant agents:

Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia, especially when the latter are used at higher than currently recommended doses.

Sympathomimetics: May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored.

Antidiabetics: Pharmacological studies have shown that ACE inhibitors, including captopril, can potentiate the blood glucose reducing effects of insulin and oral antidiabetics, such as sulphonylurea, in diabetics. Should this very rare interaction occur, it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE inhibitors.

Angiotensin II receptor blockers or aliskiren: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

HYDROCHLOROTHIAZIDE

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulant laxatives: Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

Calcium salts: Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.

Cardiac glycosides: Enhanced possibility of digitalis toxicity associated with thiazide induced hypokalaemia.

Cholestyramine resin and colestipol: May delay or decrease absorption of hydrochlorothiazide. Sulphonamide diuretics should be taken at least one hour before or four to six hours after these medications.

Nondepolarising muscle relaxants (e.g. tubocurarine chloride): Effects of these agents may be potentiated by hydrochlorothiazide.

Drugs associated with torsades de pointes: Because of the risk of hypokalaemia, caution should be used when hydrochlorothiazide is co-administered with drugs associated with torsades de pointes, e.g. some anti-arrhythmics, some antipsychotics and other drugs known to induce torsades de pointes.

Carbamazepine: Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used.

CAPTOPRIL/HYDROCHLOROTHIAZIDE COMBINATION

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. The combination of captopril and hydrochlorothiazide with lithium is therefore not recommended and careful monitoring of serum lithium levels should be performed if the combination proves necessary.

Non-steroidal anti-inflammatory medicinal products: It has been described that non-steroidal anti-inflammatory medicinal products (NSAIDs) such as indomethacin and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are, in principle, reversible. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated. Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. The administration of NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.

Clinical Chemistry

Captopril may cause a false-positive urine test for acetone. Hydrochlorothiazide may cause diagnostic interference of the bentiromide test. Thiazides may decrease serum PBI (Protein Bound Iodine) levels without signs of thyroid disturbance.

4.6 Fertility, pregnancy and lactation

Pregnancy

ACE-inhibitors:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimester is known to induce human foetotoxicity (decreased renal function, ologohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

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 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. Moreover, rare cases of hypoglycaemia in neonates have been reported in case of exposure near term.

Breast-feeding

Captopril:

Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of Co-zidocapt in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience.

In the case of an older infant, the use of Co-zidocapt in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Co-zidocapt during breast feeding is not recommended. If Co-zidocapt is used during breast feeding, doses should be kept as low as possible.

Hypersensitivity to sulphonamide-derived drugs, hypokalaemia and nuclear icterus might occur.

4.7 Effects on ability to drive and use machines

As with other antihypertensives, the ability to drive and use machines may be reduced, e.g. at the start of the treatment or when the dose is modified, and also when used in combination with alcohol, but these effects depend on the individual's susceptibility.

4.8 Undesirable effects

Frequency is defined using the following convention: common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000) and very rare (< 1/10,000).

CAPTOPRIL

Undesirable effects reported for captopril and/or ACE inhibitor therapy include: Blood and lymphatic disorders:

Very rare: neutropenia/agranulocytosis (see section 4.4), pancytopenia, particularly in patients with renal dysfunction (see section 4.4), anaemia (including aplastic and haemolytic), thrombocytopenia, lymphadenopathy, eosinophilia, auto-immune diseases and/or positive ANA-titres.

Metabolism and nutrition disorders:

Rare: anorexia

Very rare: hyperkalaemia, hypoglycaemia and acidosis can occur (see section 4.4)

Psychiatric disorders:

Common: sleep disorders Very rare: confusion, depression

Nervous system disorders:

Common: taste impairment, dizziness Uncommon: headache, paraesthesia Rare: drowsiness

Very rare: cerebrovascular incidents, including stroke, cerebrovascular insufficiency and syncope

Eye disorders:

Very rare: blurred vision.

Cardiac disorders:

Uncommon: tachycardia or tachyarrhythmia, angina pectoris, palpitations Very rare: cardiac arrest, cardiogenic shock.

Vascular disorders:

Uncommon: hypotension (see section 4.4), Raynaud syndrome, flush, pallor Immune system disorders: serum sickness

Respiratory, thoracic and mediastinal disorders:

Common: dry, irritating (non-productive) cough (see 4.4) and dyspnoea Very rare: bronchospasm, rhinitis, allergic alveolitis/ eosinophilic pneumonia

Gastrointestinal disorders:

Common: nausea, vomiting, gastric irritations, abdominal pain, diarrhoea, constipation, dry mouth, peptic ulcer

Rare: stomatitis/aphthous ulcerations, intestinal angioedema (see section 4.4).

Very rare: glossitis, pancreatitis

Hepato-biliary disorders:

Very rare: impaired hepatic function and cholestasis (including jaundice), hepatitis including necrosis, elevated liver enzymes and bilirubin.

Skin and subcutaneous tissue disorders:

Common: pruritus with or without a rash, rash, and alopecia Uncommon: angioedema (see section 4.4)

Very rare: urticaria, Stevens Johnson syndrome, erythema multiforme, photosensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis.

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia

Renal and urinary disorders:

Rare: renal function disorders, including renal failure, polyuria, oliguria, increased

urine frequency

Very rare: nephrotic syndrome

Reproductive system and breast disorders:

Very rare: impotence, gynaecomastia

General disorders and administration site conditions:

Uncommon: chest pain, fatigue, malaise Very rare: fever

Investigations:

very rare: proteinuria, eosinophilia, increase of serum potassium, decrease of serum sodium, elevation of BUN, serum creatinine and serum bilirubin, decreases in haemoglobin, haematocrit, leucocytes, thrombocytes, positive ANA-titre, elevated ESR, weight loss.

HYDROCHLOROTHIAZIDE

Infections and infestations:

sialadenitis

Blood and lymphatic system disorders: leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression

Metabolism and nutrition disorders:

anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides.

Psychiatric disorders:

restlessness, depression, sleep disturbances

Nervous system disorders:

loss of appetite, paraesthesia, light-headedness

Eye disorders:

xanthopsia, transient blurred vision, acute myopia and secondary acute angle-closure glaucoma

Ear and labyrinth disorders: vertigo

Cardiac disorders:

postural hypotension, cardiac arrhythmias Vascular disorders:

necrotising angiitis (vasculitis, cutaneous vasculitis)

Respiratory, thoracic and mediastinal disorders:

respiratory distress (including pneumonitis and pulmonary oedema)

Gastrointestinal disorders:

gastric irritation, diarrhoea, constipation, pancreatitis

Hepato-biliary disorders:

jaundice (intrahepatic cholestatic jaundice)

Skin and subcutaneous tissue disorders:

photosensitivity reactions, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, purpura, anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal and connective tissue and bone disorders:

muscle spasm

Renal and urinary disorders:

renal dysfunction, interstitial nephritis

General disorders and administration site conditions:

fever, weakness

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdosage are: increased diuresis, electrolyte imbalance, severe hypotension, depression of consciousness (including coma), convulsions, paresis, cardiac arrhythmias, Bradycardia and renal failure.

Measures to prevent absorption (e.g. gastric lavage, administration of absorbing agents and sodium sulphate within 30 minutes of intake) and hasten elimination should be applied if ingestion is recent. If hypotension occurs, the patient should be placed in the shock position and sodium chloride and volume supplementation should be given rapidly. Treatment with angiotensin-II can be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered. Constant monitoring of water, electrolyte and acid base balance, and

blood glucose is essential. In the event of hypokalaemia, potassium substitution is necessary.

Captopril may be removed from circulation by haemodialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Captopril

Pharmacotherapeutic group: captopril and diuretics, ATC code: C09BA01

Captopril is an angiotensin-converting enzyme inhibitor. The angiotensinconverting enzyme (ACE) is a peptidyl dipeptidase which converts angiotensin to angiotensin II, a substance which induces vasoconstriction. Inhibition of ACE leads to diminished formation of the vasoconstrictor angiotensin II in tissue and plasma. A decrease in aldosterone secretion thereby results with a consequent rise in the serum potassium concentration. The negative feedback of angiotensin II on renin secretion is blocked, leading to an increase in the plasma renin activity. As ACE also catalyses the metabolism of bradykinin, a vasodepressor peptide, the inhibition of ACE results in increased activity of the circulating and local kallikrein-kinin systems (and thereby results in activation of the prostaglandin system). It is possible that this mechanism is involved in the antihypertensive action of ACE inhibitors.

Captopril lowers the blood pressure in patients with hypertension both in the supine as well as in the standing position without causing a compensatory increase in cardiac frequency.

It has been demonstrated in haemodynamic studies that captopril causes a marked diminution in peripheral arterial resistance. As a rule, no clinically relevant changes in the renal blood flow or the glomerular filtration rate were observed.

The initial antihypertensive effect has been observed in most patients approximately 20 to 30 minutes after oral administration of captopril, and the maximum effect was achieved after 60 to 90 minutes.

With the recommended daily dose, the antihypertensive effect is maintained also during long term therapy. Abrupt withdrawal of captopril does not lead to a rapid, excessive rise in blood pressure (rebound effect).

ALTITUDE (Aliskiren trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in aliskiren group than in the placebo group

Hydrochlorothiazide

Hydrochlorothiazide is a benzothiadiazide. Thiadiazides act directly on the kidneys by increasing the elimination of sodium chloride and therefore the associated elimination of water. The early distal tubule is the major and clinically relevant site of action. This is the site where thiazides inhibit the electrically-neutral NaCl-co-transport in the luminal cell membrane. More potassium and magnesium are excreted in a higher extent, while calcium is eliminated to a lower extent. Hydrochlorthiazide induces a diminished bicarbonate excretion, and the excretion of chloride exceeds that of sodium. Metabolic acidosis can develop with hydrochlorothiazide therapy. Like other organic acids, hydrochlorothiazide is actively excreted in the proximal tubule. The diuretic effect is sustained in cases of metabolic acidosis.

The antihypertensive effect of hydrochlorothiazide may be associated with mechanisms such as altered sodium balance, reduction in extracellular water and plasma volume, change in renal vascular resistance as well as reduced reactivity to norepinephrine and angiotensin II.

The hydrochlorothiazide-induced excretion of electrolytes and water sets in after two hours: the maximum effect is achieved after 3-6 hours and lasts 6-12 hours.

The antihypertensive effect occurs first after 3-4 days and can last up to a week after finishing therapy.

Co-zidocapt 25/12.5mg Tablets and Co-zidocapt 50/25mg Tablets have been designed as an aid to drug compliance by providing a convenient once daily preparation for the treatment of mild to moderate hypertension. By combining lower doses than might be required if each component were used alone, side

effects, especially the hypokalaemia associated with diuretics can be minimised.

5.2 Pharmacokinetic properties

Captopril

Absorption

Approximately 70% of administered captopril is absorbed after oral administration. Maximum plasma concentrations are achieved after approximately one hour. The level of protein binding is approximately 25 to 30%. In healthy subjects the average volume of distribution in the steady state is around 0.71/kg. This can rise to 2.05 /kg when there is increased uptake of captopril in the various tissues.

Distribution

Captopril is metabolised into the inactive disulphide to a level of almost 50%. The elimination half-life of unchanged captopril is approximately two hours and that of the S-bound captopril around 12 hours. Approximately 95% of the captopril is excreted within 24 hours in the urine, 40-50% in the unchanged form and 50 -60% excreted as captopril disulphide and captopril cysteine disulphide.

Elimination

The rate of captopril excretion is lower in renal insufficiency. For this reason, the dose needs to be reduced or the dosage interval extended in patients with renal impairment.

Hydrochlorothiazide:

Absorption

In respect of hydrochlorothiazide, 60-80% of that administered orally is absorbed. A maximum plasma hydrochlorothiazide concentration of 70 ng/ml was achieved 1.5 to 4 hours after administering an oral dose of 12.5 mg of hydrochlorothiazide while administration of 25 mg results in a maximum plasma concentration of 142 ng/ml 2-5 hours after administration, and with 50 mg the maximum plasma concentration is 260 ng/ml achieved after 2-4 hours.

Distribution

65% is bound to plasma proteins; the relative volume of distribution is 0.5-1.11/kg. Hydrochlorothiazide is almost completely excreted in unchanged form via the kidneys (>95%). After a single oral dose, 50-70% of that administered is excreted within 24 hours, and the substance detectable in urine after 60 minutes. The elimination half-life is 6-8 hours.

The rate of hydrochlorothiazide excretion is lower in renal insufficiency, and the half-life prolonged. The renal clearance of hydrochlorothiazide closely correlates with the creatinine clearance.

Captopril/ Hydrochlorothiazide:Combination

A bioavailability study of the combination tablet of 50 mg captopril and 25 mg hydrochlorothiazide in 24 volunteers gave respectively Cmax of 384.52 +/-154.3 and 141.08+/- 32.62 ng/ml, Tmax of 1.02+/-0.61 and 2.36+/- 1.04 hours and AUC (0-14) of 492.0 +/-136.72 and 939.38+/- 196.05 ng/ml/h.

Lactation

In the report of twelve women taking oral captopril 100 mg 3 times daily, the average peak milk level was 4.7pg/L and occurred 3.8 hours after the dose. Based on these data, the maximum daily dosage that a nursing infant would receive is less than 0.002% of the maternal daily dosage.

5.3    Preclinical safety data

Animal studies performed during organogenesis with captopril and/or hydrochlorothiazide have not shown any teratogenic effect but captopril has produced foetal toxicity in several species, including foetal mortality during late pregnancy, growth retardation and postnatal mortality in the rat. Preclinical data reveal no other specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicology, genotoxicity and carcinogenicity.

6    PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Lactose monohydrate Magnesium stearate Maize starch

Microcrystalline cellulose Stearic acid

Incompatibilities

None known

6.3 Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents of container

Blister strips of 300 pm white opaque non-toxic polypropylene welded on to 15 pm internally film-coated aluminium semi-rigid support, packed into lithographed cardboard cartons with the relevant package leaflet.

Pack sizes of 20, 28, 50 and 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

Tillomed Laboratories Ltd 3, Howard Road Eaton Socon St. Neots Cambs.

PE198ET United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0030

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 31/07/2000 Date of renewal: 23/09/ 2005

10    DATE OF REVISION OF THE TEXT

15/09/2016