Document: spc-doc_PL 39484-0014 change

• spc-doc_PL 15773-0055
• spc-doc_PL 17907-0039
• spc-doc_PL 20075-0310
• spc-doc_PL 20416-0309
• spc-doc_PL 39484-0014

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Captopril 50mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Captopril 50mg

3 PHARMACEUTICAL FORM

Tablet

White, round, semi-convex with a break score on one side and the imprint “C50” on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension:

Captopril is indicated for the first line treatment of mild to moderate hypertension.

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

Congestive Heart Failure:

Captopril is indicated for the treatment of congestive heart failure. The drug should be used together with diuretics and, where appropriate digitalis.

Myocardial Infarction:

Captopril is indicated following myocardial infarction in clinically stable patients with asymptomatic and symptomatic left ventricular dysfunction to improve survival, delay the onset of symptomatic heart failure, reduce hospitalisations for heart failure, and reduce recurrent myocardial infarction and coronary revascularisation procedures.

Determination of cardiac function by radionuclide ventriculography or echocardiography should be undertaken prior to initiation of preventative treatment with Captopril in post myocardial infarction patients.

Diabetic Nephropathy:

Captopril is indicated for the treatment of diabetic nephropathy (microalbuminuria greater than 30 mg/day) in insulin-dependent diabetics. In these patients, captopril prevents the progression of renal disease and reduces associated clinical events e.g. dialysis, renal transplantation and death.

4.2 Posology and method of administration

Adults:

Hypertension:

Treatment with Captopril should be at the lowest effective dose which should be titrated according to the needs of the patient.

Mild to Moderate Hypertension:

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

A thiazide diuretic may be added to Captopril if satisfactory response has not been achieved. The dose of diuretic may be increased at 1-2 week intervals to the level of optimum response or until the maximum dose is reached.

Severe Hypertension:

In severe hypertension where standard therapy is ineffective or inappropriate because of adverse effects, the starting dose is 12.5mg b.d. The dosage may be increased incrementally to a maximum of 50mg t.i.d. Captopril should be used together with other anti-hypertensive drugs but the dose of these should be individually titrated. A daily dose of 150mg of Captopril should not normally be exceeded.

Heart Failure:

Captopril therapy must be started under close medical supervision. Captopril should be introduced when diuretic therapy (such as frusemide 40-80mg or equivalent) is insufficient to control symptoms. A starting dose of 6.25mg or 12.5mg may minimise a transient hypotensive effect. The possibility of this occurring can be reduced by discontinuing or reducing diuretic therapy if possible, prior to initiating Captopril. The usual maintenance dose is 25mg 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 daily.

Myocardial Infarction:

Therapy may be initiated as early as three days following a myocardial infarction. After an initial dose of 6.25 mg, captopril therapy should be titrated to a final target dose of 150 mg daily in divided doses over the next several weeks.

Achievement of the target dose of 150 mg should be based on the patients tolerance to captopril during titration. If symptomatic hypotension occurs, a dosage reduction may be required.

Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g. thrombolytics, aspirin, beta blockers.

Diabetic Nephropathy:

The recommended daily dose of captopril is 75 to l00mg in divided doses.

If further blood pressure reduction is required, other antihypertensive agents such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril.

Elderly:

The dose should be titrated against the blood pressure response and kept as low as possible to achieve adequate control. Since elderly patients may have reduced renal function and other or any dysfunctions, it is suggested that a low dose of Captopril be used initially.

Children:

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

Experience in neonates, particularly premature infants, is limited. Because renal function in infants is not equivalent to that of older children and adults, lower doses of Captopril should be used with the patients under close medical supervision.

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

Patients With Renal Impairment:

Captopril in divided doses of 75 to 100 mg/day was well tolerated in patients with diabetic nephropathy and mild to moderate renal impairment (creatinine clearance at least 30 ml/min/l .73m²).

Patients with severely impaired renal function 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. These patients may therefore respond to smaller or less frequent doses.

Therefore, patients with severe renal impairment (creatinine clearance less than 30 ml/min/l.73m²), the initial daily dose should be 12.5 mg b.d. The dose can then 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 a thiazide diuretic should be the diuretic of choice.

Captopril is readily eliminated by haemodialysis.

4.3 Contraindications

A history of hypersensitivity to the active or any of listed excipients.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6) [Comment: No contraindication in Section 4.3 for lactation.]

4.4 Special warnings and precautions for use Precautions:

Evaluation of the patient should include assessment of renal function prior to initiation of therapy and at appropriate intervals thereafter. [See Recommended Dosage and Dosage Schedule Section].

Captopril should not be used in patients with aortic stenosis or outflow tract obstruction.

As limited experience has been obtained in the treatment of acute hypertensive crisis, the use of Captopril should be avoided in these patients.

Warnings:

The incidence of adverse reactions to captopril is principally associated with renal function since the drug is excreted primarily by the kidney. The dose should not exceed that necessary for adequate control and should be reduced in patients with impaired renal function.

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).

Haematological:

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving 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 (eg. 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 returned to normal upon discontinuing Captopril.

Renal:

Proteinuria in patients with prior normal renal function is rare.

Where proteinuria has occurred it has usually been in patients with severe hypertension or evidence of prior renal disease. Nephrotic syndrome occurred in some of these patients.

In patients with evidence of prior renal disease, monthly urinary protein estimations (dip stick) are recommended for the first 9 months of therapy. If repeated determinations show increasing amounts of urinary protein, a 24-hour quantitative determination should be obtained, and if this exceeds 1g/day, the benefits and risks of continuing Captopril should be evaluated.

In patients with diabetic nephropathy and proteinuria, who received captopril 75mg/day for a median of 3 years, there was a consistent reduction in proteinuria. It is unknown whether long-term therapy in patients with other types of renal disease would have similar effects.

Although membranous glomerulopathy was found in biopsies taken from some proteinuric patients, a causal relationship to Captopril has not been established.

Some patients with renal disease, particularly those with bilateral renal artery stenosis or unilateral renal artery stenosis in a single functioning kidney, have developed increased concentrations of blood urea and serum creatinine. Captopril dosage reduction and/or discontinuation of diuretic may be required. For some of these patients it may not be possible to normalise blood pressure and maintain adequate renal perfusion.

Recent clinical observations have shown a high incidence of anaphylactoidlike reactions during haemodialysis with high-flux dialysis membranes (e.g. AN69) in patients receiving ACE inhibitors. Therefore, this combination should be avoided.

Hypotension:

With the first one or two doses some patients may experience symptomatic hypotension. In most instances, symptoms are relieved simply by the patient lying down.

In patients with severe and renin dependent hypertension (e.g. renovascular hypertension) or severe congestive heart failure who are receiving large doses of diuretic, exaggerated hypotensive responses have occurred usually within one hour of the initial dose of Captopril. In these patients, by discontinuing diuretic therapy or significantly reducing the diuretic dose for four to seven days prior to initiating Captopril the possibility of this occurrence is reduced. By commencing Captopril therapy with small doses (6.25mg or 12.5mg) the duration of any hypotensive effect is lessened. Some patients may benefit from an infusion of saline. The occurrence of first dose hypotension does not preclude subsequent dose titration with Captopril.

Hypotension has been occasionally reported in patients on Captopril due to causes of acute volume depletion such as vomiting and diarrhoea.

Serum Potassium:

Since Captopril decreases aldosterone production, serum potassium is usually maintained in patients on diuretics. Potassium sparing diuretics or potassium supplements should not therefore be used routinely. In patients with marked renal impairment a significant elevation of serum potassium may occur.

Surgery/Anaesthesia:

In patients undergoing major surgery, or during anaesthesia with drugs which produce hypotension, captopril will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.

Clinical Chemistry:

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

4.5 Interaction with other medicinal products and other forms of interaction

Diuretics:    Diuretics potentiate the    anti-hypertensive

Indomethacin:	effectiveness of Captopril. Potassium-sparing diuretics (triamterene, amiloride and spironolactone), or potassium supplements may cause significant increase in serum potassium. A reduction of anti-hypertensive effectiveness may occur. This is probably also the case with other nonsteroidal anti-inflammatory drugs.
Vasodilators:	Captopril has been reported to act synergistically with peripheral vasodilators such as minoxidil. Awareness of this interaction may avert an initial hypotensive response.
Clonidine:	It has been suggested that the anti-hypertensive effect of Captopril can be delayed when patients treated with clonidine are changed to Captopril .
Allopurinol &	There have been reports of neutropenia and/or Stevens
Procainamide:	Johnson syndrome in patients on Captopril plus either allopurinol or procainamide. Although a causal relationship has not been established, these combinations should only be used with caution, especially in patients with impaired renal function.
Immunosuppressants:	Azathioprine and cyclophosphamide have been associated with blood dyscrasias in patients with renal failure who were also taking Captopril.
Probenecid:	The renal clearance of Captopril is reduced in the presence of probenecid.
Lithium:	Concomitant use of lithium and ACE-inhibitors may result in an increase of serum lithium concentration.
Hypoglycaemic Agents:	ACE Inhibitors have been shown to enhance insulin activity. There have been rare reports of hypoglycaemic episodes in diabetic patients treated concomitantly with ACE Inhibitors and antidiabetic medicines (insulin or oral hypoglycaemic drugs) This phenomenon may be more likely to occur during the

first few weeks of treatment, In such cases a reduction in the dose of the antidiabetic medicine may be required

4.6 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).

Lactation:

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 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 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

See warnings under hypotension section.

4.8 Undesirable effects

Idiosyncratic: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril. In this situation, the ACE inhibitor should be discontinued. Where swelling is confined to the face, lips and mouth the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, subcutaneous adrenaline (0.5m1, 1:1,000) should be administered promptly where indicated.

Haematological: Neutropenia, anaemia and thrombocytopenia (see Warnings). Rarely a positive ANA has been reported.

Renal: Proteinuria, elevated blood urea and creatinine, elevated serum potassium and acidosis (see Warnings).

Cardiovascular: Hypotension (see warnings), tachycardia.

Skin: Rashes, usually pruritic, may occur. They are usually mild, maculopapular, rarely urticarial and disappear within a few days of dosage reduction, short-term treatment with an antihistamine and/or discontinuing therapy. In a few cases the rash has been associated with fever. Pruritus, flushing, vesicular or bullous rash, and photosensitivity have been reported.

Gastrointestinal: Reversible and usually self-limiting taste impairment has been reported. Weight loss may be associated with the loss of taste. Stomatitis, resembling aphthous ulcers, has been reported. Elevation of liver enzymes has been noted in a few patients. Rare cases of hepatocellular injury and cholestatic jaundice have been reported. Gastric irritation and abdominal pain may occur. Pancreatitis has been reported rarely in patients treated with ACE Inhibitors; in some cases this has proved fatal.

Other: Paraesthesias of the hands, serum sickness, cough, bronchospasm and lymphadenopathy have been reported.

4.9 Overdose

In the event of overdosage, blood pressure should be monitored and if hypotension develops volume expansion is the treatment of choice. Captopril is removed by dialysis.

5.1 Pharmacodynamic properties

Captopril is a highly specific, competitive inhibitor of angiotensin-I converting enzyme. This enzyme is responsible for the conversion of angiotensin-I to angiotensin-II.

5.2 Pharmacokinetic properties

Total captopril:	tMAX	1 hour
	t1/2	8 hours
Free captopril:	tMAX	1 hour
	tl/2	1 hour

Lactation:

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

No further relevant data.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline Cellulose, Maize Starch , Lactose monohydrate, Stearic Acid.

6.2 Incompatibilities

Not applicable.

Shelf life

Three years.