Drug Class Description
Calcium-channel blockers (class I calcium antagonists) / ACE inhibitors.

Generic Name
Verapamil, trandolapril

Drug Description
Each modified-release capsule contains 180 mg of verapamil hydrochloride and 2 mg of trandolapril.Excipient: 54.50 mg lactose monohydrate/modified-release capsule

Presentation
Modified-release capsulePale pink opaque

Indications
Essential hypertension in patients whose blood pressure has been normalised with the individual components in the same proportion of doses.

Adult Dosage
The usual dosage is one capsule once daily, taken in the morning before, with or after breakfast. The capsules should be swallowed whole.Renal insufficiency: Tarka is contraindicated in severe renal impairment.Hepatic insufficiency: the use of Tarka is not recommended in patients with severe hepatic impairment; Tarka is contraindicated in patients with liver cirrhosis with ascites

Child Dosage
Children and adolescents: Tarka is contraindicated in children and adolescents (<18 years).

Elderly Dosage
As systemic availability is higher in elderly patients compared to younger hypertensives, some elderly patients might experience a more pronounced blood pressure lowering effect.

Contra Indications
- Hypersensitivity to trandolapril or any other ACE inhibitor and/or verapamil or to any of the excipients- History of angioneurotic oedema associated with previous ACE inhibitor therapy- Hereditary/idiopathic angioneurotic oedema- Cardiogenic shock- Recent myocardial infarction with complications- Second- or third-degree AV block without a functioning pacemaker- SA block- Sick sinus syndrome in patients without a functioning pacemaker- Congestive heart failure- Atrial flutter/fibrillation in association with an accessory pathway (e.g. WPW-syndrome)- Severe renal impairment (creatinine clearance < 30 ml/min)- Dialysis- Liver cirrhosis with ascites- Aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy- Primary aldosteronism- 2nd and 3rd trimester of pregnancy- Use in children and adolescents (< 18 years)- Is contraindicated in patients concomitantly treated with i.v. ß-adrenoreceptor antagonists (exception: intensive care unit).

Special Precautions
Symptomatic hypotension:Under certain circumstances, Tarka may occasionally produce symptomatic hypotension. This risk is elevated in patients with a stimulated renin-angiotensin-aldosterone system (e.g., volume or salt depletion, due to the use of diuretics, a low-sodium diet, dialysis, dehydration, diarrhoea or vomiting; decreased left ventricular function, renovascular hypertension)Such patients should have their volume or salt depletion corrected beforehand and therapy should preferably be initiated 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. Tarka therapy can usually be continued once blood volume and pressure have been effectively corrected.Close monitoring during initiation of therapy and dose adjustment is also needed in patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.Kidney function impairment:Patients with moderate renal impairment should have their kidney function monitored.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, or congestive heart failure.There is insufficient experience with Tarka in secondary hypertension and particularly in renal vascular hypertension. Hence, Tarka should not be administered to these patients, especially since patients with bilateral renal artery stenosis or unilateral renal artery stenosis in individuals with a single functioning kidney (e.g., renal transplant patients) are endangered to suffer an acute loss of kidney function.Proteinuria:Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.Diabetic Patients:In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor.Severe hepatic impairment:Since there is insufficient therapeutic experience in patients with severe hepatic impairment, the use of Tarka cannot be recommended. Tarka is contraindicated in patients with severe liver cirrhosis with ascites. Very rarely, ACE inhibitor therapy has been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving Tarka who develop jaundice or marked elevations of hepatic enzymes should discontinue Tarka and receive medical follow-up.Angioneurotic oedema:Rarely, ACE inhibitors (such as trandolapril) may cause angioneurotic oedema that includes swelling of the face, extremities, tongue, glottis, and/or larynx. Patients experiencing angioneurotic oedema must immediately discontinue trandolapril therapy and be monitored until oedema resolution.Angioneurotic oedema confined to the face will usually resolve spontaneously. Oedema involving not only the face but also the glottis may be life-threatening because of the risk of airway obstruction.Compared to non-black patients a higher incidence of angioedema has been reported in black patients treated with ACE inhibitors.Angioneurotic oedema involving the tongue, glottis or larynx requires immediate subcutaneous administration of 0.3-0.5 ml of epinephrine solution (1:1000) along with other therapeutic measures as appropriate.Caution must be exercised in patients with a history of idiopathic angioneurotic oedema, and Tarka is contraindicated if angioneurotic oedema was an adverse reaction to an ACE inhibitor.Neutropenia/agranulocytosis:The risk of neutropenia appears to be dose-and type-related and is dependent on the patient's clinical status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal impairment especially when it is associated with collagen vascular disease e.g. systemic lupus erythematosus, scleroderma and therapy with immunosuppressive medicinal products. It is reversible after discontinuation of the ACE inhibitor.Cough:During treatment with an ACE inhibitor a dry and non-productive cough may occur which disappears after discontinuation.Hyperkalaemia:Hyperkalaemia may occur during treatment with an ACE inhibitor, especially in the presence of renal insufficiency and/or heart failure. Potassium supplements or potassium sparing diuretics are generally not recommended, since they may lead to significant increases in plasma potassium. If concomitant use of the above mentioned medicinal products is deemed appropriate, they should be used with frequent monitoring of serum potassium.Elderly:Tarka has been studied in a limited number of elderly hypertensive patients only. Pharmacokinetic data show that the systemic availability of Tarka is higher in elderly compared to younger hypertensives. Some elderly patients might experience a more pronounced blood pressure lowering effect than others. eva luation of the renal function at the beginning of treatment is recommended.Surgical patients:In patients undergoing major surgery requiring general anaesthesia, ACE inhibitors may produce hypotension, which can be corrected by plasma volume expanders.Conduction disturbances:Treatments should be used with caution in patients with first degree atrioventricular block.Bradycardia:Tarka should be used with caution in patients with bradycardia.Diseases in which neuromuscular transmission is affected:Tarka should be used with caution in patients with diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).Desensitisation:Anaphylactoid reactions (in some cases life threatening) may develop in patients receiving ACE inhibitor therapy and concomitant desensitisation against animal venoms.LDL-aphaeresis:Life threatening anaphylactoid reactions have been noted when patients on LDL-aphaeresis take ACE inhibitors at the same time.eva luation of the patients should include assessment of renal function prior to initiation of therapy and during treatment.Blood pressure readings for eva luation of therapeutic response to Tarka should always be taken before the next dose.Lactose:Tarka capsules contain lactose. Each modified-release capsule contains 54.50 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.Sodium:This medicinal product contains 1.12 mmol (or 25.71 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.Lithium:The combination of lithium and Tarka is not recommended.PregnancyACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.Lactation:The use of Tarka is not recommended in women whom are breastfeeding.

Interactions
Not recommended association- Potassium sparing diuretics or potassium supplements: ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g. spironolactone, triamterene, or amiloride, potassium supplements, or potassium containing salt substitutes may lead to significant increases in serum potassium, particularly in the presence of renal function impairment. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.- Dantrolene: The simultaneous use of verapamil with dantrolene is not recommended.Precaution for use- Antihypertensive medicinal products: increase of the hypotensive effect of Tarka.- 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 an ACE inhibitor. 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 low doses. Further increases in dosage should be performed with caution.- Lithium: there have been reports of both an increase and a reduction in the effects of lithium used concurrently with verapamil. The concomitant administration of ACE inhibitors with lithium may reduce the excretion of lithium. Serum lithium levels should be monitored frequently.- Anaesthetics: Tarka may enhance the hypotensive effects of certain anaesthetic medicinal products.- Narcotics/antipsychotics: postural hypotension may occur.- Allopurinol, cytostatic or immunosuppressive medicinal products, systemic corticosteroids or procainamide: concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.- Cardiodepressive medicinal products: the concurrent use of verapamil and cardiodepressives, i.e., medicinal products that inhibit cardiac impulse generation and conduction (e.g., beta-adrenergic blockers, antiarrhythmics, inhalation anaesthetics), may produce undesirable additive effects.- Quinidine: the concomitant use of quinidine and oral verapamil in patients with hypertrophic (obstructive) cardiomyopathy has resulted in hypotension and pulmonary oedema in a small number of cases.- Digoxin: concurrent use of digoxin and verapamil has been reported to result in 50-75% higher digoxin plasma concentrations, requiring reduction of the digoxin dosage.- Muscle relaxants: the effect of muscle relaxants (such as neuromuscular blockers) may be enhanced.- Tranquillisers/antidepressants: as with all antihypertensives, there is an elevated risk of orthostatic hypotension when combining Tarka with major tranquillisers or antidepressant medicinal products containing imipramine.Take into account- Non-steroidal anti-inflammatory drugs (NSAIDs): the administration of a non-steroidal anti-inflammatory drug may reduce the antihypertensive effect of an ACE inhibitor. Furthermore it has been described 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, and occur especially in patients with compromised renal function.- Antacids: induce decreased bioavailability of ACE inhibitors.- Sympathomimetics: may reduce the antihypertensive effects of ACE inhibitors; patient should be carefully monitored to confirm that the desired effect is being obtained.- Alcohol: enhances the hypotensive effect.In-vitro metabolic studies indicate that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil is a known inhibitor of CYP3A4 enzymes. Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil, while inducers of CYP3A4 have caused lowering of plasma levels of verapamil, therefore patients should be monitored for drug interactions. Examples of such interactions are:- Verapamil may increase the plasma concentrations of carbamazepine, cyclosporin, and theophylline thus increasing risk of toxicity from these compounds.- Rifampin, phenytoin, and phenobarbital reduce the plasma concentrations of verapamil, whereas cimetidine may increase the plasma concentrations of verapamil.- Verapamil may increase plasma concentrations of prazosin.- HMG-CoA Reductase Inhibitors: An increase in serum exposure has been reported for simvastatin (metabolised by CYP3A4) when concomitantly administered with verapamil. The concomitant administration of verapamil and high doses of simvastatin has been reported to increase the risk of myopathia/rabdomyolsis. The dose of simvastatin (and other statins metabolised by CYP3A4 such as atorvastatin and lovastatin) should be adapted accordingly- Antidiabetics: a dose adjustment of antidiabetics or of Tarka may be necessary in individual cases especially at the start of therapy due to increased reduction of blood glucose.- Acetylsalicylic Acid (Aspirin): The concomitant use of acetylsalicylic acid can increase the side effect profile of acetylsalicylic acid (may increase the risk of bleeding).- Grapefruit juice has been shown to increase the plasma levels of verapamil, which is a component of Tarka. Grapefruit juice should therefore not be ingested with Tarka.

Adverse Reactions
The adverse drug reactions for Tarka are consistent with those known for its components or the respective class of medicinal products. The most commonly reported adverse drug reactions are cough, headache, constipation, vertigo, dizziness and hot flushes (see table below). Adverse events either reported spontaneously or observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.System Organ ClassFrequencyUndesirable EffectsBlood and lymphatic system disordersvery rare- leucopenia- pancytopenia- thrombocytopeniaImmune system disordersuncommon- allergic reaction, unspecifiedvery rare- increase in gammaglobulin- hypersensitivity, unspecifiedMetabolism and nutritional disordersuncommon- hyperlipidaemiarare- anorexiaPsychiatric disordersuncommon- somnolencevery rare- aggression- anxiety- depression- nervousnessNervous system disorderscommon- dizziness- vertigouncommon- tremorrare- collapsevery rare- impaired balance- insomnia- paresthesia or hyperesthesia- syncope or acute circulatory failures with loss of consciousness- taste aberration- weaknessEye disordersvery rare- abnormal/blurred visionCardiac disorders/vascular disorderscommon- hot flushesuncommon- AV block, first degree- palpitationvery rare- angina pectoris- atrial fibrillation- AV block, complete- AV block, unspecified- bradycardia- cardiac arrest- cerebral haemorrhage- oedema, peripheral- oedema, unspecified- flushing- heart failure- hypotensive events including orthostasis or fluctuation of blood pressure- tachycardiaRespiratory, thoracic and mediastenal disorderscommon- coughvery rare- asthma- bronchitis- dyspnoea- sinus congestionGastrointestinal disorderscommon- constipationuncommon- abdominal pain- diarrhoea- gastrointestinal disorders unspecified- nauseavery rare- dry mouth/throat- pancreatitis- vomitingHepatobiliary disordersvery rare- cholestasis- hepatitis- increase in γGT- increase in LDH- increase in lipase- jaundiceSkin and subcutaneous tissue disordersuncommon- facial oedema- pruritus- rash- sweating increasedrare- alopecia- herpes simplex- skin disorders, unspecifiedvery rare- angioneurotic oedema- erythema multiforme- exanthema or dermatitis- psoriasis- urticariaMusculoskeletal,connective tissue and bone disordersvery rare- arthralgia- myalgia- myastheniaRenal and urinary disordersuncommon- polyuriavery rare- acute renal failureReproductive system and breast disordersvery rare- gynaecomastia- impotenceGeneral disorders and administration site conditionscommon- headacheuncommon- chest painvery rare- fatigue or astheniaInvestigationsuncommon- liver function test, abnormalrare- hyperbilirubinemiavery rare- increase in alkaline phosphatase- increase in serum potassium- increase in transaminasesThe following adverse reactions have not yet been reported in relation to Tarka, but are generally accepted as being attributable to ACE inhibitors:- Blood and lymphatic system disorders: decreases in haemoglobin and haematocrit, and in individual cases agranulocytosis. Isolated cases of haemolytic anaemia have been reported in patients with congenital G-6-PDH deficiency.- Psychiatric disorders: occasionally confusion.- Nervous system disorders: rarely, sleep disorders.- Ear and labyrinth disorders: rarely, problems with balance, tinnitus.- Cardiac disorders/vascular disorders: Individual cases of arrhythmia, myocardial infarction and transient ischemic attacks have been reported for ACE inhibitors in association with hypotension.- Respiratory, thoracic and mediastinal disorders: Rarely, sinusitis, rhinitis, glossitis, and bronchospasm.- Gastrointestinal disorders: occasionally indigestion. Individual cases of ileus.- Hepatobiliary disorders: individual cases of cholestatic icterus.- Skin and subcutaneous tissue disorders: occasionally allergic and hypersensitivity reactions such as Stevens-Johnson syndrome, toxic epidermic necrolysis. This can be accompanied by fever, myalgia, arthralgia, eosinophilia and / or increased ANA - titers.- Investigations: increases in blood urea and plasma creatinine may occur especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. These increases are however reversible on discontinuation.Symptomatic or severe hypotension has occasionally occurred after initiation of therapy with ACE inhibitors. This occurs especially in certain risk groups, such as patients with a stimulated renin-angiotensin-aldosterone system.The following adverse reactions have not yet been reported in relation to Tarka, but are generally accepted as being attributable to phenylalkylamine calcium-channel blockers:- Nervous system disorders: in some cases, there may be extrapyramidal symptoms (Parkinson's disease, choreoathetosis, dystonic syndrome). Experience so far has shown that these symptoms resolve once the medicinal product is discontinued. There have been isolated reports of exacerbation of myasthenia gravis, Lambert-Eaton syndrome and advanced cases of Duchenne's muscular dystrophy.- Gastrointestinal disorders: gingival hyperplasia following long-term treatment is extremely rare and reversible after discontinuation of therapy.- Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome and erythromelalgia have been described. In isolated cases allergic skin reactions like erythema.- Reproductive system and breast disorders: Hyperprolactinemia and galactorrhea have been described.Excessive hypotension in patients with angina pectoris or cerebrovascular disease treated with Verapamil may result in myocardial infarction or cerebrovascular accident.

Manufacturer
Abbott Laboratories Limited

Drug Availability
(POM)

Updated
23 June 2009