INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo GOPTEN® 0,5 mg Capsules
GOPTEN® 1 mg Capsules
GOPTEN® 2 mg Capsules

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

GOPTEN® 0,5 mg Capsules
GOPTEN
® 1 mg Capsules
GOPTEN
® 2 mg Capsules

COMPOSITION
Gopten
® 0,5 mg contains 0,5 mg trandolapril
Gopten® 1 mg contains 1 mg trandolapril
Gopten
® 2 mg contains 2 mg trandolapril

PHARMACOLOGICAL CLASSIFICATION
A. 7.1.3 Other hypotensives

PHARMACOLOGICAL ACTION
Gopten capsules contain the pro-drug trandolapril, a non-peptide angiotensin converting enzyme (ACE) inhibitor with a carboxyl group but without a sulphydryl group. Trandolapril is rapidly absorbed in the fasting state and then non-specifically hydrolysed to its active metabolite, trandolaprilat.
Trandolaprilat binds tightly and in a saturable manner to ACE.
The administration of trandolapril causes decreases in the concentrations of angiotensin II, aldosterone and atrial natriuretic factor and increases in plasma renin activity and concentrations of angiotensin I. Gopten thus modulates the renin-angiotensin-aldosterone system which plays a major part in regulating blood volume and blood pressure. The blood pressure lowering effect is evident after 1 hour, with a peak effect between 8 and 12 hours. The antihypertensive effect persists for at least 24 hours.
Pharmacokinetics
The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption.
In normal volunteers the peak plasma concentration of trandolapril is observed 30 minutes after administration. Trandolapril disappears rapidly from the plasma with a half-life of less than one hour.
Trandolapril is hydrolysed to the active component trandolaprilat, a specific angiotensin converting enzyme inhibitor. The amount of trandolaprilat formed is not modified by food consumption. The peak plasma concentration of trandolaprilat is reached after 4 to 6 hours in the fasting state.
In the plasma trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to converting enzyme. The major proportion of circulating trandolaprilat is also non-saturably bound to albumin.
After repeated administration of Gopten in a single daily dose steady state is reached on average in four days, both in healthy volunteers and in young or elderly hypertensives. The effective accumulation half-life of trandolaprilat is between 16 and 24 hours.
Trandolaprilat eliminated in the urine in the unchanged form accounts for 10 to 15% of the dose of trandolapril administered. After oral administration of the labelled product in man, 33% of the radioactivity is found in the urine and 66% in the faeces.
The renal clearance of trandolaprilat is proportional to the creatinine clearance. The plasma concentrations of trandolaprilat are significantly higher in patients with creatinine clearance less than or equal to 30 mL/min. However, after repeated dosing in patients with chronic renal failure steady state is also reached on average in four days, whatever the degree of renal failure.

INDICATIONS
Mild to moderate hypertension.

CONTRA-INDICATIONS
Known hypersensitivity to trandolapril.
Pregnancy and lactation.
History of angioneurotic oedema associated with administration of an ACE inhibitor.

WARNINGS
Gopten should not be used in patients with aortic stenosis or outflow obstruction.

Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and switched to a different medicine.
Should a woman contemplate pregnancy, the doctor should consider alternative medication.
ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.

DOSAGE AND DIRECTIONS FOR USE
Adults: The recommended initial dosage is 0,5 mg as a single daily dose. Dosage should be doubled incrementally at intervals of 2 to 4 weeks, based on patient response, up to a maximum of 4 mg as a single daily dose. The usual maintenance dose is 2 mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 4 mg Gopten, combination therapy should be considered.
Elderly: The dose in elderly patients is the same as in adults. There is no need to reduce the dose in elderly patients with normal renal and hepatic function. Caution should be exercised in elderly patients with concomitant use of diuretics, congestive heart failure or renal or hepatic insufficiency. The dose should be titrated according to the need for the control of blood pressure. In these patients therapy should be initiated at a dose of 0,5 mg daily.
Prior diuretic treatment: In patients who are at risk from a stimulated renin-angiotensin system (eg. patients with water and sodium depletion) the diuretic should be discontinued 2-3 days before beginning therapy with 0,5 mg trandolapril to reduce the likelihood of symptomatic hypotension. The diuretic may be resumed later if required.
Dosage adjustment in renal impairment: For patients with a creatinine clearance of > 30 mL/min the usual adult dosages are recommended. For patients with a creatinine clearance of 30 mL/min or less the initial dose is 0,5 mg daily and the maximum daily dose should not exceed 2 mg. In these patients therapy should be under close medical supervision.
Dosage adjustment in hepatic impairment: In patients with severely impaired liver function a decrease in the metabolic clearance of the parent compound trandolapril and the active metabolite trandolaprilat results in a large increase in plasma trandolapril levels and to a lesser extent an increase in trandolaprilat levels. Treatment with Gopten should therefore be initiated at a dose of 0,5 mg once daily under close medical supervision.
Children: Gopten has not been studied in children and therefore use in this age group is not recommended.
Food: The absorption of Gopten is not affected by food.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The most frequent reported adverse events are cough, headaches, asthenia and dizziness.
Cardiovascular: symptomatic hypotension and palpitations.
Gastrointestinal: nausea.
Allergic hypersensitivity reactions such as pruritis and rash may occur.
Angioneurotic oedema: angioneurotic oedema may occur less frequently. If laryngeal stridor or angioedema of the face, tongue or glottis occurs treatment with Gopten must be discontinued and appropriate therapy instituted immediately. (See special precautions).
Special precautions
Assessment of renal function: Evaluation of the patient should include assessment of renal function prior to initiation of therapy and during treatment.
Impaired renal function: Patients with severe renal insufficiency may require reduced doses of Gopten; their renal function should be closely monitored. In the majority, renal function will not alter. In patients with renal insufficiency, congestive heart failure or unilateral or bilateral renal artery stenosis in the single kidney as well as after renal transplantation, there is a risk of impairment of renal function. If recognised early, such impairment of renal function is reversible upon discontinuation of therapy. Some patients with no apparent pre-existing renal disease, may develop minor and usually transient increases in blood urea nitrogen and serum creatinine when Gopten is given concomitantly with a diuretic. Dosage reduction of Gopten and/or discontinuation of the diuretic may be required. Additionally, in patients with renal insufficiency the risk of hyperkalaemia should be considered and the patient's electrolyte status checked regularly.
Impaired liver function: As trandolapril is a prodrug metabolised to its active moiety in the liver, particular caution and close monitoring should be applied to patients with impaired liver function.
Symptomatic hypotension: In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of Gopten as well as after increasing the dose of Gopten. It is more likely to occur in patients who have been volume- and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with Gopten. If symptomatic hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline. Intravenous atropine may be necessary if there is associated bradycardia. Treatment with Gopten may usually be continued following restoration of effective blood volume and blood pressure.
Surgery/anaesthesia: In patients undergoing surgery or during anaesthesia with agents producing hypotension, Gopten may block angiotension II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by appropriate treatment.
Agranulocytosis and bone marrow depression: In patients on angiotensin converting enzyme inhibitors agranulocytosis and bone marrow depression have been seen rarely. They are more frequent in patients with renal impairment, especially if they have a collagen vascular disease. However, regular monitoring of white blood cell counts and protein levels in urine should be considered in patients with collagen vascular disease (eg. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy particularly with corticosteroids and antimetabolites.
Hyperkalaemia: Elevated serum potassium has been observed less frequently in hypertensive patients. Risk factors for the development of hyperkalaemia include renal insufficiency, potassium sparing diuretics and the concomitant use of agents to treat hypokalaemia.
Hypersensitivity/Angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Gopten. In such cases Gopten 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 such as subcutaneous epinephrine solution 1:1000 (0,3 mL to 0,5 mL) should be administered promptly. Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor.
Interactions
Combinations with diuretics or other antihypertensive agents may potentiate the antihypertensive response to Gopten. Adrenergic-blocking agents should only be combined with trandolapril under careful supervision.
Potassium sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements may increase the risk of hyperkalaemia particularly in renal failure. Gopten may attenuate the potassium loss caused by thiazide-type diuretics. If concomitant use of these agents is indicated, they should be given with caution and serum potassium should be monitored regularly.
Combinations necessitating a warning: In some patients already receiving diuretic treatment, particularly if this treatment has been recently instituted, the fall in blood pressure on initiation of treatment with Gopten may be excessive. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with Gopten. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of Gopten. As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension. Gopten may reduce the elimination of lithium and serum levels of lithium should be monitored.
Anaphylactoid reactions to high-flux polyacrylonitrile membranes used in haemodialysis have been reported in patients treated with ACE inhibitors. As with other antihypertensives of this chemical class this combination should be avoided when prescribing ACE inhibitors to renal dialysis patients.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In the event of overdosage following recent ingestion, emptying of the stomach contents should be considered. Blood pressure should be monitored and if hypotension develops, volume expansion should be considered.

IDENTIFICATION
Gopten 0,5 mg is a No. 4 capsule consisting of a red body and a yellow cap, containing practically white granules.
Gopten 1 mg is a No. 4 capsule consisting of a red body and an orange cap, containing practically white granules.
Gopten 2 mg is a No. 4 capsule consisting of a red body and a red cap, containing practically white granules.

PRESENTATION:
Packs of 30 capsules.

STORAGE INSTRUCTIONS
Store in a cool place, below 30°C.
Protect from humidity.
Keep out of reach of children.

REGISTRATION NUMBERS
Gopten
® 0,5 mg: 28/7.1.3/0261
Gopten
® 1 mg: 28/7.1.3/0262
Gopten
® 2 mg: 28/7.1.3/0263

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Knoll Pharmaceuticals South Africa (Pty) Ltd
Reg No. 85/03220/07
Cor. George Road and 16th Street,
Midrand
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
3 January 1994

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