Captopril/Hydrochlorothiazide EG

Treatment of essential hypertension.

This fixed dose combination is indicated in patients whose blood pressure is not adequately controlled by captopril alone or hydrochlorothiazide alone.

Posology

Captopril/Hydrochlorothiazide EGe can be administered in a single or two divided doses/day with or without food in patients whose blood pressure is not adequately controlled by captopril alone or hydrochlorothiazide alone.

A maximum daily dose of 50 mg captopril/25 mg hydrochlorothiazide should not be exceeded. If satisfactory reduction of blood pressure has not been achieved, additional antihypertensive medication may be added.

Adults: the administration of the fixed combination of captopril and hydrochlorothiazide is usually recommended after dosage titration with the individual components. The usual maintenance dose is 50 mg/25 mg, once a day, in the morning. When clinically appropriate a direct change from monotherapy to the fixed combination may be considered.

Renal impairment: Creatinine clearance between 30 and 80 ml/min: the initial dose is usually 25 mg/12.5 mg once a day, in the morning.

The combination captopril/hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min).

Special populations: in salt/volume depleted patients, elderly patients, and diabetic patients, the usual starting dose is 25 mg/12.5 mg once a day.

Paediatric population: There is no relevant indication for use of Captopril/Hydrochlorothiazide EGe in children.

Method of administration

For oral use.

- -derived drug.

- History of angioedema associated with previous ACE inhibitor therapy.

- Hereditary/idiopathic angioneurotic oedema.

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

- Severe hepatic impairment.

- Second and third trimesters of pregnancy.

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

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.

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 edema 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.

Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus).

Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).

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 .

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.

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. 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.

Hyperkalaemia: Hyperkalaemia may occur during treatment with an ACE inhibitor. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, hypoaldosteronism or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other active substances associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole). 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 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.

As with other angiotensin converting enzyme inhibitors, Captopril/Hydrochlorothiazide EGe 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.

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.

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.

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, hyponatraemia, 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.

Dilutional hyponatraemia 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 analytic 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.

Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure glaucoma without definite causal association have been reported so far with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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.

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/Hydrochlorothiazide EGe is not recommended in association with lithium due to the potentiation of lithium toxicity.

Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Frequency is 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) and not known (cannot be estimated from the available data).

CAPTOPRIL

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

Blood and lymphatic system disorders:

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

Metabolism and nutrition disorders:

Uncommon: anorexia.

Very rare: hyperkalaemia, hypoglycaemia.

Psychiatric disorders:

Common: sleep disorders.

Very rare: confusion, depression.

Nervous system disorders:

Uncommon: headache, paraesthesia.

Common: taste impairment, dizziness.

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 , Raynaud syndrome, flush, pallor.

Respiratory, thoracic and mediastinal disorders:

Common: dry, irritating (non-productive) cough 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.

Very rare: glossitis, pancreatitis.

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, rash, alopecia.

Uncommon: angioedema.

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

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.

HYDROCHLOROTHIAZIDE

Infections and infestations:

sialadenitis.

Blood and lymphatic system disorders:

leukopenia, 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.

Hepatobiliary disorders:

jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders:

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

Musculoskeletal and connective tissue 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.

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 case 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.

Pharmacotherapeutic group: captopril and diuretics, ATC code: C09BA01

Captopril/Hydrochlorothiazide EGe is a combination of an ACE inhibitor, captopril, and an antihypertensive diuretic, hydrochlorothiazide. The combination of these agents has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

- Captopril is an angiotensin converting enzyme (ACE) inhibitor, i.e. it inhibits ACE, the enzyme involved in the conversion of angiotensin I to angiotensin II - a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex.

Such inhibition leads to:

- reduced aldosterone secretion,

- increased plasma renin activity, since aldosterone no longer exerts negative feedback,

- a drop in total peripheral resistance (with a preferential effect on muscles and kidneys) which is not accompanied by water and sodium retention or reflex tachycardia during long-term treatment.

Captopril also exerts its antihypertensive effect in subjects with low or normal renin concentrations.

Captopril is effective at all stages of hypertension, i.e. mild, moderate or severe. A reduction in supine and standing systolic and diastolic blood pressures is observed.

After a single dose, the antihypertensive effect is evident fifteen minutes post-dose and reaches a maximum between 1 h and 1.5 h after administration of the drug. Its duration of action is dose-dependent and varies from 6 to 12 hours.

Blood pressure becomes normalised (seated DBP < 90 mmHg) in patients after two weeks to one month of treatment and the drug retains its effectiveness over the course of time. Patients are also classified as responders if seated DBP decreased by 10% or more from baseline-BP.

Rebound hypertension does not occur when treatment is discontinued.

The treatment of hypertension with captopril leads to an increase in arterial compliance, a rise in renal blood flow without any significant drop in the glomerular filtration rate, and a decrease in left ventricular hypertrophy.

- Hydrochlorothiazide is a thiazide diuretic which acts by inhibiting the reabsorption of sodium in the cortical diluting segment of renal tubules. It increases the excretion of sodium and chloride in urine and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urinary output and exerting an antihypertensive effect.

The time to onset of diuretic activity is approximately 2 hours. Diuretic activity reaches a peak after 4 hours and is maintained for 6 to 12 hours. Above a certain dose, thiazide diuretics reach a plateau in terms of therapeutic effect whereas adverse reactions continue to multiply. When treatment is ineffective, increasing the dose beyond recommended doses serves no useful purpose and often gives rise to adverse reactions.

- The concomitant administration of captopril and hydrochlorothiazide in clinical trials led to greater reductions in blood pressure than when either of the products was administered alone.

The administration of captopril inhibits the renin angiotensin aldosterone system and tends to reduce hydrochlorothiazide-induced potassium loss.

Combination of an ACE inhibitor with a thiazide diuretic produces a synergistic effect and also lessens the risk of hypokalaemia provoked by the diuretic alone.

- Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

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.

Captopril is quickly absorbed after oral administration and maximum serum concentrations are obtained around one hour after administration. Minimum mean absorption is approximately 75%. Peak plasma concentrations are reached within 60-90 minutes. The presence of food in the gastrointestinal tract reduces absorption by about 30-40%. Approximately 25-30% of the circulating drug is bound to plasma proteins. The apparent elimination half-life of unchanged captopril in blood is about 2 hours.

Greater than 95% of the absorbed dose is eliminated in the urine within 24 hours; 40-50% is unchanged drug and the remainder are inactive disulphide metabolites (captopril disulphide and captopril cysteine disulphide). Impaired renal function could result in drug accumulation.

Studies in animals indicate that captopril does not cross the blood-brain barrier to any significant extent.

Oral absorption of hydrochlorothiazide is relatively rapid. The mean plasma half-life in fasted individuals has been reported to be 5 to 15 hours. Hydrochlorothiazide is eliminated rapidly by the kidney, and excreted unchanged (> 95%) in the urine.

Lactation:

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

Not applicable.

Dispose of the medication in accordance with local regulations for medical waste.