INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
TARKA® capsules

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

TARKA^® capsules

COMPOSITION:
Each TARKA capsule contains 180 mg verapamil hydrochloride and 2 mg trandolapril.

PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Other hypotensives.

PHARMACOLOGICAL ACTION:
TARKA capsules contain the pro-drug trandolapril, a non peptide angiotensin converting enzyme (ACE) inhibitor with a carboxyl group but without a sulphydryl group and verapamil, a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist).
Verapamil exerts its pharmacological effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Verapamil reduces myocardial oxygen consumption in vitro directly by intervening in the energy consuming metabolic processes of the myocardial cell, and indirectly by diminishing the peripheral resistance (afterload). It prolongs impulse conduction in the AV node.
Trandolapril is rapidly absorbed in the fasting state and then non-specifically hydrolysed to its active metabolite, trandolaprilat.
Trandolapril 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. Trandolapril 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.
Tarka: Neither animal studies nor healthy volunteer studies could demonstrate pharmacokinetic or renin-angiotensin-aldosterone-system interactions between verapamil and trandolapril.

PHARMACOKINETIC PROPERTIES:
As there are no known kinetic interactions between verapamil and trandolapril or trandolaprilat, the single-agent kinetic parameters of these two agents apply to the combination product as well.
Verapamil:
About 90% of orally administered verapamil is absorbed. The presence of food has no effect on the bioavailability of verapamil.
The mean time to peak plasma concentration is 4 hours. The peak plasma concentration of norverapamil is attained after about 6 hours. Steady state after multiple once daily dosing is reached after 3-4 days.
The protein binding of verapamil is about 90%, it is bound mainly to a₁ - acid glycoprotein and albumin.
The mean elimination half-life after repeated administration is 8 hours. Approximately 70% of an administered dose is excreted mainly as metabolites in urine and about 16% in faeces. Norverapamil has 10 - 20% of the pharmacological activity of verapamil, and accounts for 6% of the dose excreted in the urine. In steady state its concentrations are approximately equal to that of verapamil.
The bioavailability and elimination half-life of verapamil are increased in patients with liver cirrhosis. The pharmacokinetics of verapamil are unchanged in patients with renal insufficiency.
Trandolapril:
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 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 trandolapril 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:
TARKA is indicated for the treatment of hypertension in patients not adequately controlled with trandolapril alone.

CONTRA-INDICATIONS:

-	Known hypersensitivity to either one of the active components
-	Pregnancy and lactation
-	History of angioneurotic oedema associated with administration of an ACE- inhibitor.
-	Hypotension associated with cardiogenic shock.
-	Complicated acute myocardial infarction (bradycardia, pronounced hypotension, left ventricular failure).
-	Retarded AV conduction (second and third degree AV block).
-	Sinoatrial block
-	Sick-sinus syndrome (bradycardia-tachycardia syndrome)
-	Congestive heart failure
-	Moderate to severe liver function impairment; severe renal function impairment.
-	Aortic stenosis, mitral valve stenosis.
-	Hypertrophic obstructive cardiomyopathy.

WARNINGS:
Trandolapril 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. Premature and low birth mass can occur.
Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.
Hypotension: Verapamil may occasionally produce symptomatic hypotension in normotensive patients. In hypertensive patients, decreases in blood pressure below normal values are unusual.
Elevated liver enzymes: Elevation of transaminases with and without concomitant elevations in alkaline phosphotase and bilirubin have been reported. Such elevations are normally transient and may disappear even in the face of continued verapamil treatment.
Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed an increased anterograde conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk.
Atrioventricular block: The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early phases of therapy. Marked first-degree block or progressive development to second- or third-degree AV block requires, in rare instances, discontinuation of the drug.
Patients with hypertrophic cardiomyopathy (IHSS): A variety of serious adverse effects can occur in patients with hypertrophic cardiomyopathy - pulmonary oedema and/or severe hypotension, sinus bradycardia, AV block and sinus arrest.

DOSAGE AND DIRECTIONS FOR USE:
ADULTS:
One capsule daily.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Trandolapril:
The most frequent reported adverse events are cough, headaches, asthenia and dizziness.
Symptomatic hypotension and palpitations, 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 TARKA must be discontinued and appropriate therapy instituted immediately. (See special precautions).
Verapamil:
Constipation, headache, fatigue, palpitations, first and second degree AV block, SA block, epigastric pain, flush, dizziness, urticaria and temporary skin rash may occur.
Reports of individuals experiencing exacerbation of arthritis, increased urination, burning sensations of the gums, mild tremor and severe facial pain are known.

The following special precautions should be mentioned:
Kidney function impairment:
Changes in renal function are not usually observed during TARKA therapy.
Patients with impaired renal function require regular monitoring of kidney function and it may be necessary to discontinue treatment with the fixed combination in these patients.
TARKA may, produce hyperkalaemia in patients with renal dysfunction.
Acute deterioration of kidney function (acute renal failure) may occur especially in patients with pre-existing kidney function impairment, congestive heart failure, or renovascular hypertension, particularly in patients with bilateral renal arterial stenosis or unilateral renal artery stenosis in individuals with a sole (functioning) kidney, such as renal transplant patients for instance. Concurrent diuretic therapy may be a contributing factor. This acute loss of kidney function is usually reversible after discontinuation of TARKA. Regular kidney function monitoring is therefore recommended for these groups of patients.
It should however, also be borne in mind that patients with two functioning kidneys may experience unilateral renal arterial stenosis and hence acute, reversible loss of function of the affected kidney without significant deterioration of renal function.
Renography is indicated in this case unless surgical intervention is scheduled within one month.
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:
The first dose of an ACE inhibitor (in this case trandolapril) may occasionally produce symptomatic hypotension and this risk is elevated in patients with a stimulated renin-angiotensin-aldosterone system, for instance in the following conditions:

-	volume or salt depletion, for instance due to the use of diuretics, a low-sodium diet, dialysis, diarrhoea or vomiting;
-	cardiac insufficiency;
-	liver cirrhosis with ascites.

Such patients should have their volume or salt depletion corrected beforehand and preferably be started on an ACE inhibitor in a hospital setting.
Patients experiencing hypotension during titration should lie down and may require volume expansion by oral fluid supply or intravenous administration of normal saline. The therapy can usually be continued once blood volume and pressure have been effectively corrected.
Surgery/anaesthesia: In patients undergoing surgery or during anaesthesia with agents producing hypotension, trandolapril may block angiotensin 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.
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. In such cases TARKA 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.
Use of verapamil in patients with impaired hepatic function: Since verapamil is highly metabolised by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 15 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients.
Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacological effects should be carried out.
Use in patients with attenuated neuromuscular transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchennés muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vercuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Interactions:
TARKA may enhance the effect of other antihypertensive drugs.
Some patients on diuretic therapy may experience excessive blood pressure reduction when starting TARKA. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with TARKA. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of TARKA.
Potassium sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements may increase the risk of hyperkalaemia particularly in renal failure.
Trandolapril 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. The concurrent use of verapamil and cardiodepressive medicines i.e. medicines that inhibit cardiac impulse generation and conduction (eg beta-adrenergic blocking agents, antiarrhythmic agents, inhalation anaesthetics) may produce undesirable additive effects.
As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension.
Serum levels of lithium should be monitored when used concurrently with TARKA.
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.
Concurrent use of digoxin and verapamil has been reported to result in 50 - 70% higher digoxin plasma concentrations, requiring either a reduction or temporary discontinuation of the digoxin dose.
Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarisation. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of AV conduction.
In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. There has been a report of increased quinidine levels during verapamil therapy.
Verapamil has been given concomitantly with short-and long-acting nitrates without any undesirable drug interactions.
The pharmacological profile of both agents and the clinical experience suggest beneficial interactions. Cimetidine may increase the effect of verapamil.
Verapamil may increase the levels of carbamazine, cyclosporin and theophyllin.
Rifampicin, phenytoin and phenobarbital may reduce the efficacy of verapamil.
Neuromuscular blocking agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarising). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Bradycardia, hypotension, atrioventricular dissociation, hypoglycaemia.
In the event of overdosage following recent ingestion, emptying of the stomach contents should be considered.
Treatment of overdosage is symptomatic and supportive.

IDENTIFICATION:
TARKA is a pale pink coloured capsule containing white granules and a white oblong film-coated tablet.

PRESENTATION:
Packs of 30 capsules in blister strips of 10 capsules.

STORAGE DIRECTIONS:
Store in a cool place, below 25°C.
Protect from light and humidity. Keep out of reach of children.

REGISTRATION NUMBER:
31/7.1.3/0631

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Knoll Pharmaceuticals South Africa (Pty) Ltd
P.O. Box 3030,
HALFWAY HOUSE
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
6 July 1998

                        Knoll logo
                989820/1
                Davbar Dbn.

Current: June 2003
Source: Community Pharmacy
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