SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Captopril 12.5 mg Tablets BP, Kaplon 12.5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 12.5 mg of Captopril.

Excipient(s) with known effect:

Each tablet contains 47.0 mg lactose

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

White, round, flat bevel-edged tablets marked 7C1 with breakline.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension

Captopril is indicated for the first line therapy of mild or moderate hypertension.

In severe hypertension captopril should be used where standard therapy is inappropriate or ineffective.

Congestive heart failure

Captopril is indicated for the treatment of congestive heart failure. It should be used in conjunction with diuretics and, where appropriate, digitalis.

4.2 Posology and method of administration

Posology

Hypertension

The lowest effective dosage of captopril should be titrated according to the requirements of each patient.

Mild to moderate hypertension:

The starting dose is 12.5 mg twice daily. The usual maintenance dose is 25 mg twice daily. This can be increased stepwise at 2-4 week intervals, until a satisfactory response is achieved, to a maximum of 50 mg twice daily.

A thiazide diuretic may be added, if a satisfactory response is not achieved with captopril alone.

Severe hypertension:

In severe hypertension where standard therapy is ineffective or inappropriate because of adverse effects, the starting dose is 12.5 mg twice daily. The dosage may be increased incrementally to a maximum of 50 mg three times a day. Captopril should be used together with other anti-hypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1) but the dose of these should be individually titrated. A daily dose of 150 mg of captopril should not normally be exceeded.

Special populations Patients with heart failure

Captopril therapy must be started under close medical supervision. Captopril should be introduced when diuretic therapy (such as frusemide 40-80 mg or equivalent) is insufficient to control symptoms. A starting dose of 6.25 mg or 12.5 mg may decrease the possibility of a transient hypotensive effect. The potential of this happening may be decreased further by a reduction or withdrawal of diuretic therapy before starting captopril treatment. The usual maintenance dose is 25 mg two or three times a day, which can be increased incrementally, with intervals of at least two weeks, until a satisfactory response is achieved. The usual maximum dose is 150 mg of captopril daily.

Older people :(older than 65 years of age)

The starting dose is 6.25 mg twice daily (mornings and evenings).

The usual maintenance dose is 25 - 50 mg of captopril per day in divided doses.

The usual maximum dose is 100 mg of captopril per day.

The dose should be titrated against the blood pressure response and kept as low as possible to achieve adequate control.

Paediatric population

Captopril is not recommended for the treatment of mild to moderate hypertension in children.

Lower doses of captopril should be used in neonates, particularly premature infants, as renal function in infants is not equivalent to that of older children and adults. Patients should be monitored under close medical supervision.

The starting dose should be 0.3 mg per Kg body weight up to a maximum of 6 mg per Kg body weight daily, in divided doses. According to the response the dose should be individualised and may be given two or three times daily.

Patients with hepatic impairment

The starting dose is 6.25 mg twice daily (mornings and evenings).

The usual maintenance dose is 25 - 50 mg of captopril per day in divided doses. The usual maximum dose is 100 mg of captopril per day.

Patients with renal impairment

Mild or moderate renal impairment (creatinine clearance at least 30 ml/min/1.73 m2), The starting dose is 6.25 mg twice daily (mornings and evenings).

The usual maintenance dose is 25 - 50 mg of captopril per day in divided doses.

The usual maximum dose is 75 mg of captopril per day in divided doses.

Patients with severely impaired renal function may respond to smaller or less frequent doses as they will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, the usual recommended daily dose should be 6.25 - 25 mg of captopril per day in divided doses in patients with severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m2). The dose should be titrated against the response but adequate time should be allowed between dosage adjustments. When concomitant diuretic therapy is required, a loop diuretic rather than thiazide diuretic should be the diuretic of choice. Captopril is readily eliminated by haemodialysis.

4.3 Contraindications

Captopril is contra-indicated in patients with: hypersensitivity to the active substance to any other ACE inhibitor, or to any of the excipients listed in section 6.1, a history of angioneurotic oedema associated with previous ACE inhibitor therapy, or hereditary/idiopathic angioneurotic oedema. Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

The concomitant use of Captopril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2 (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use 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.

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 of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Captopril. This may occur at any time during treatment. In such cases, Captopril 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 inhibitor 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 hemodynamically 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.

Proteinuria

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 life-threatening 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.

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

Captopril is not recommended in association with lithium due to the potentiation of lithium toxicity (see section 4.5).

Ethnic differences

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

Renal function should be assessed before therapy is started, as part of the patient evaluation, and assessed at appropriate intervals during therapy, especially in patients with salt and/or body fluid deficiencies, severe or renal hypertension, severe congestive heart failure and in older people (> 65 years).

Captopril should be avoided in the treatment of patients with acute hypertensive crises, as there is limited experience.

Patients with primary aldosteronism should not be treated with captopril as their renin-angiotensin system is affected by the primary disease.

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).

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 increases 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 sections 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.

Lactose

Captopril tablets contain lactose and therefore should not be used in cases of congenital galactosaemia and malabsorption of glucose and galactose or in lactase-deficient syndromes (rare metabolic diseases).

4.5 Interaction with other medicinal products and other forms of interaction

Potassium-sparing diuretics or potassium supplements:

Captopril attenuates diuretic induced potassium loss. Potassium sparing diuretics e.g .spironolactone, triamterene or amiloride, potassium supplements, potassium-containing salt substitutes or other potassium-increasing medical products (e.g. heparin) may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia such medicines should be used with caution and with frequent monitoring of serum potassium.

Diuretics:

Patients on diuretics and especially those who are volume- and/or salt depleted, may experience an excessive reduction of blood pressure after initiation of therapy with captopril. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to intake and by initiation of therapy with lower doses of captopril. Further increases in dosage should be performed with caution. However, no clinically significant drug interactions have been found in specific studies with hydrochlorothiazide or furosemide.

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 with lithium is therefore not recommended and careful monitoring of serum lithium levels should be performed if the combination proves necessary.

Anaesthetic drugs:

Captopril may enhance the hypotensive effects of certain anaesthetic drugs. Other antihypertensive agents:

captopril has been safely co-administered with other commonly used antihypertensive agents (e.g. beta-blockers and long-acting calcium channel blockers). Concomitant use of these agents may increase the hypotensive effects of captopril. Treatment with 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, 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).

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.

Narcotic drugs/Tricyclic antidepressants/Antipsychotics: ACE inhibitors may enhance the hypotensive effects of certain narcotic drugs, tricyclic antidepressants and antipsychotics. Postural hypotension may occur.

Clonidine: It has been suggested, when patients treated with clonidine are changed to captopril, the anti-hypertensive effect of captopril can be delayed

Allopurinol, procainamide, cytostatic or immunosuppressive agents:

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

Systemic corticosteroids have been associated with blood dyscrasias in patients with renal failure who were also taking captopril.

Non-Steroidal Anti-Inflammatory drugs (NSAIDs) : The administration of non-steroidal anti-inflammatory agents, eg indomethacin, may reduce the antihypertensive effect of captopril. Furthermore, it has been reported that NSAIDs 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 older or dehydrated people. Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor.

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.

Antacids: Induce decreased bioavailability of captopril.

Sympathomimetics: May reduce the antihypertensive effects of captopril, patients should he carefully monitored.

Probenecid: In the presence of probenecid, the renal clearance of captopril is reduced.

Alcohol: Enhances the hypotensive effect.

Clinical Chemistry

Captopril may cause a false-positive urine test for acetone.

4.6 Fertility, pregnancy and lactation

Pregnancy:

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 trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, 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).

Breast-feeding:

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 Captopril in breast-feeding 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 Captopril 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.

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.

Avoid driving vehicles or operating machinery until the effects of the drug are established, as it may cause weariness, dizziness and fainting.

4.8 Undesirable effects

List of adverse reactions

The frequencies of adverse events are defined using the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

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

Blood and lymphatic system 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.

Not known: leucocytosis

Metabolism and nutrition disorders:

Rare: anorexia

Very rare: hyperkalaemia, hypoglycaemia (see section 4.4)

Psychiatric disorders:

Common: sleep disorders Very rare: confusion, depression.

Nervous system disorders:

Common: taste impairment, dizziness.

Rare: drowsiness, headache and paraesthesia.

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

Eye disorders:

Very rare: blurred vision.

Ear and labyrinth disorders:

Not known: tinnitus, disorders of balance

Cardiac disorders:

Uncommon: tachycardia or tachyarrhythmia, angina pectoris, palpitations.

Very rare: cardiac arrest, cardiogenic shock.

Not known: myocardial infarction

Vascular disorders:

Uncommon: hypotension (see section 4.4), Raynaud syndrome, flush, pallor.

Not known: vasculitis

Respiratory, thoracic and mediastinal disorders:

Common: dry, irritating (non-productive) cough (see section 4.4) and dyspnoea. Rare: sinusitis, bronchitis

Very rare: bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia. Gastrointestinal disorders:

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

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

Very rare: glossitis, peptic ulcer, pancreatitis.

Not known: indigestion, ileus

Hepatobiliary 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, photo sensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis.

Not known: toxic epidermic necrolysis, psoriasis-like efflorescences, oncholysis

Musculoskeletal and connective tissue 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.

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 severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure.

After ingestion of an overdose, the patient should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently, as well as blood pressure. Therapeutic measures depend on the nature and severity of the symptoms. Measurements to prevent absorption such as gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes after intake and to hasten elimination should be applied if ingestion is recent. If hypotension occurs, the patient should be placed in the shock position and salt and volume supplementation should be given rapidly. Treatment with angiotensin II should be considered. Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be considered. Captopril may be removed from the circulation by haemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors, ATC code: CO9A AO1 (Agents acting on the renin-angiotensin system, converting enzyme blocker).

The beneficial effects of ACE inhibitors in hypertension and in heart failure appear to result primarily from the suppression of the plasma renin-angiotensin aldosterone system. Renin is an endogenous enzyme synthesized by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme, a peptidyldipeptidase, to angiotensin II. Angiotensin II is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity.

Another function of the converting enzyme is to degrade the potent vasodepressive kinin peptide bradykinin to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin system which contributes to peripheral vasodilation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effect of ACE inhibitors and is responsible for certain side effects.

In patients with hypertension administration of ACE inhibitors results in a reduction of supine and standing blood pressure to about the same extent with no compensatory increase of the heart rate. Peripheral arterial resistance is reduced with either no change or an increase in cardiac output.

There is an increase in renal blood flow and glomerular filtration rate is usually unchanged. Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy. Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

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

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 the aliskiren group than in the placebo group.

5.2    Pharmacokinetic properties

Approximately 70% - 75 % of an oral dose of captopril is absorbed by healthy fasting volunteers. Peak blood concentrations are achieved 0.5 - 1.5 hours after administration. Ingestion of captopril in the non-fasting state reduces absorption by 35 %. Captopril is an unstable compound in vivo. The formation of disulphide dimers and mixed conjugates occur rapidly and complicates measurement of drug levels. Captopril is covalently bound to plasma proteins. Peak blood levels are reached about an hour after an oral dose. Approximately 25 to 30% of the circulating drug is bound to plasma proteins. Excretion is delayed in the presence of renal impairment. Captopril is dialysable.

Breast-feeding:

In the report of twelve women taking oral captopril 100 mg 3 times daily, the average peak milk level was 4.7 qg/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

Pre-clinical information has not been included because the safety profile of captopril has been established after many years of clinical use. Please refer to section 4.

Captopril is safe with regard to genotoxicity. 2 year carcinogenicity studies with captopril in rats and mice failed to show any evidence of carcinogenic effects.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Monohydrate Microcrystalline Cellulose Pregelatinised Maize Starch Stearic Acid.

Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

HDPE containers with caps or child resistant closures in packs of 14, 20, 21, 28, 30, 50, 56, 60, 84, 100, 112, 120, 168, 250, 500, 1000 or 5000 tablets.

Blister strips (PVC/PVdC Al) in packs of 14, 20, 21, 28, 30, 56, 60, 84, 100, 112, 120 or 168 tablets.

Not all pack sizes may be marketed

6.6 Special precautions for disposal No special requirements

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road,

Hampden Park,

Eastbourne BN22 9AG England.

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/0312

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

6 August 1996 / 6 August 2001

DATE OF REVISION OF THE TEXT

18/12/2014