Gastrointestinal disorders Very rare Nausea Instruction for use dry mouth /throat pancreatitis 1-NAME OF THE MEDICINAL PRODUCT vomiting Tarka 180 mg/2 mg, modified-release Hepatobiliary disorder tablet Very rare cholestasis 2- QUALITATIVE AND QUANTITATIVE COMPOSITION hepatitis Each tablet contains 180 mg of verapamil hydrochloride and 2 mg of increase in γGT trandolapril. increase in LDH 3-PHARMACEUTICAL FORM increase in lipase 4- CLINICAL PARTICULARS jaundice 4.1 Therapeutic indications Essential hypertension in patients whose blood pressure has been normalised with the individual Com- Skin and subcutaneous tissue ponents in the same proportion of doses. disorders Uncommon facial oedema 4.2 Posology and method of administration pruritus The usual dosage is one tablet once daily, taken in the morning half an hour before breakfast. rash The tablets should be swallowed whole. sweating increased Dosage in children: Tarka is contraindicated in children and adolescents (<18 years) rare alopecia Dosage in the elderly: As systemic availability is higher in elderly patients compared to younger hypertensives, some elderly patients might experience a more pronounced blood pressure lowering herpes simplex effect (see section 4.4) skin disorders, un- Dosage in renal failure: Tarka is contraindicated in severe renal impairment (see sections 4.3 and specified 4.4). Very rare angioneurotic oedema Dosage in hepatic insufficiency: the use of Tarka is not recommended in patients with severe liver (see also section 4.4) hepatic impairment; Tarka is contraindicated in patients with liver cirrhosis with ascites (see sections erythema multiform 4.3 and 4.4). exanthema or dermatitis 4.3 Contra-indications psoriasis known hypersensitivity to trandolapril or any other ACE inhibitor and/or verapamil or to any of the excipients. urticaria -History of angioneurotic oedema associated with previous ACE inhibitor therapy. Musculoskeletal -Hereditary/idiopathic angioneurotic oedema. Connective tissue and bone disorders -Cardiogenic shock. Very rare arthralgia -Recent myocardial infarction with complications. myalgia -Second- or third-degree AV block without a functioning pacemaker myasthenia -SA block -Sick sinus syndrome in patients without a functioning pacemaker Renal and urinary disorders -Congestive heart failure Uncommon polyuria -Atrial flutter/fibrillation in association with an accessory pathway (e.g. WPW-syndrome) Very rare acute renal failure (see -Severe renal impairment (creatinine clearance<10 ml/min) also section 4.4) -Dialysis Reproductive system and breast -Liver cirrhosis with ascites disorders Very rare gynecomastia -Aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy. impotence -Primary aldosteronism -Pregnancy General disorders and administration -Lactation site conditions common headache -Use in children and adolescents (< 18 years) uncommon chest pain 4.4 Special warnings and special precautions for use Very rare fatigue or asthenia Symptomatic hypotension: Investigations 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 uncommon liver function test, depletion, due to the use of diuretics, a low sodium diet dialysis, dehydration, diarrhea or vomiting; abnormal decreased left ventricular function, renovascular hypertension) rare hyperbilirubinemia Such patients should have their volume or salt depletion corrected beforehand and therapy should Very rare increase in alkaline preferably be Initiated in a hospital setting. Patients experiencing hypotension during titration should phosphatase lie down and may require volume expansion by oral fluid supply or intravenous administration of normal increase in serum saline. Tarka therapy can usually be continued once blood volume and pressure have been effectively potassium corrected increase in transam- Kidney function impairment (see also section 4.3) Patients with moderate renal impairment should have their kidney function monitored. inases Tarka may produce hyperkalemia in patients with renal dysfunction. The following adverse reactions have not yet been reported in relation to Tarka, but are generally Acute deterioration of kidney function (acute renal failure) may occur especially in patients with pre-ex- accepted as being attributable to ACE inhibitors: isting kidney function impairment, or congestive heart failure. - Blood and lymphatic system disorders: decreases in hemoglobin and hematocrit, There is insufficient experience with Tarka in secondary hypertension and particularly in renal vascular and in individual cases agranulocytosis. Isolated cases of hemolytic anemia have hypertension. Hence, Tarka should not be administered to these patients, especially since patients with been reported in patients with congenital G-6-PDH deficiency. bilateral renal artery stenosis or unilateral renal artery stenosis in individuals with a single functioning - Psychiatric disorders: occasionally confusion. kidney (e.g.,renal transplant patients) are endangered to suffer an acute loss of kidney function. - Nervous system disorders: rarely, sleep disorders. Proteinuria: - Ear and labyrinth disorders: rarely, problems with balance, tinnitus. Proteinuria may occur particularly in patients with existing renal function impairment or on relatively - Cardiac disorders/vascular disorders: Individual cases of arrhythmia, myocardial high doses of ACE inhibitors. infarction and transient ischemic attacks have been reported for ACE inhibitors in Severe hepatic impairment: association with hypotension. Since there is insufficient therapeutic experience in patients with severe hepatic Impairment as such, - Respiratory, thoracic and mediastinal disorders: Rarely, sinusitis, rhinitis, glossitis and bronchospasm. the use of Tarka cannot be recommended. Tarka is contraindicated in patients with liver cirrhosis with - Gastrointestinal disorders: occasionally indigestion. Individual cases of ileus. ascites (see also section 4.3). - Hepatobiliary disorders: individual cases of cholestatic icterus. Angioneurotic oedema: - Skin and subcutaneous tissue disorders: occasionally allergic and hypersensitivity reactions such as Rarely ACE inhibitors (such as trandolapril) may cause angioneurotic oedema that includes swelling of Stevens-Johnson syndrome, toxic epidemic necrolysis. This can be accompanied by fever, myalgia, the face, extremities, tongue, glottis, and/or larynx. Patients experiencing angioneurotic oedema must arthralgia, eosinophilia and / or increased ANA – titers. immediately discontinue trandolapril therapy and be monitored until oedema resolution. -Investigations: increases in blood urea and plasma creatinine may occur especially in the presence of Angioneurotic oedema confined to the face will usually resolve spontaneously. renal insufficiency, severe heart failure and renovascular hypertension. These increases are however Oedema involving not only the face but also the glottis may be life-threatening because of the risk of reversible on discontinuation. airway obstruction. Symptomatic or severe hypotension has occasionally occurred after initiation of therapy with ACE Compared to non-black patients a higher incidence of angioedema has been reported in black patients inhibitors. This occurs especially in certain risk groups, such as patients with a stimulated renin- angi- treated with ACE inhibitors. otensin-aldosterone system. Angioneurotic oedema involving the tongue, glottis or larynx requires immediate subcutaneous ad- The following adverse reactions have not yet been reported in relation to Tarka, but are generally ministration of 0.3-0.5 ml of epinephrine solution (1:1000) along with other therapeutic measures as accepted as being attributable to phenylalkylamine calcium-channel blockers: appropriate. -Nervous system disorders: in some cases, there may be extrapyramidal symptoms (Parkinson’s dis- Caution must be exercised in patients with a history of idiopathic angioneurotic oedema, and Tarka ease, choreoathetosis, dystonic syndrome). Experience so far has shown that these symptoms resolve is contraindicated If angioneurotic oedema was an adverse reaction to an ACE inhibitor (see also once the medicinal product is discontinued .There have been isolated reports of exacerbation of my- section 4.3) asthenia gravis, Lambert Eaton syndrome and advanced cases of Duchenne’s muscular dystrophy. Neutropenia/agranulocytosis: - Gastrointestinal disorders: gingival hyperplasia following long-term treatment is The risk of neutropenia appears to be dose-and type-related and is dependent on the patients clinical extremely rare and reversible after discontinuation of therapy. status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal - Skin and subcutaneous tissue disorders: Stevens- Johnson syndrome and impairment especially when it is associated with collagen vascular disease e.g. systemic lupus eryth- erythromelalgia have been described. In isolated cases allergic skin reactions like ematosus, scleroderma and therapy with immunosuppressive medicinal products. It is reversible after erythema. discontinuation of the ACE inhibitors. - Reproductive system and breast disorders: Hyperprolactinemia and galactorrhea have been Cough: described. During treatment with an ACE inhibitor a dry and non-productive cough may occur which disappears Excessive hypotension in patients with angina pectoris or cerebrovascular disease after discontinuation. treated with Verapamil may result in myocardial infarction or cerebrovascular accident. Hyperkalemia: 4.9 overdose Hyperkalemia may occur during treatment with an ACE inhibitor, especially in the presence of renal The highest dose used in clinical trials was 16 mg of trandolapril. This dose produced insufficiency and/or heart failure. Potassium supplements or potassium sparing diuretics are generally no signs or symptoms of intolerance. not recommended, since they may lead to significant increases in plasma potassium. If concomitant The most important symptom to be expected after a significant overdose is hypotension. use of the above mentioned medicinal products is deemed appropriate, they should be used with Administration of normal saline solution is recommended in this case. frequent monitoring of serum potassium. The most important signs and symptoms of a verapamil overdose are due to its pharmacologic ac- Elderly: tivity in the cardiovascular system and include hypotension arising from peripheral vasodilation and Tarka has been studied in a limited number of elderly hypertensive patients only. a negative inotropic effect, depression of impulse generation in the sinus node and cardiac impulse Pharmacokinetic data show that the systemic availability of Tarka is higher in elderly conduction disturbances that may result in sinus bradycardia, sinus arrest, AV block, and asystole. compared to younger hypertensives. Some elderly patients might experience a more Following oral verapamil overdose, the patient must be monitored and treat in an intensive care setting. pronounced blood pressure lowering effect than others. Evaluation of the renal Overdose management must be aimed at preventing the further absorption of verapamil from the gas- function at the beginning of treatment is recommended. trointestinal tract, providing symptomatic treatment of the toxic effects (see above), and compensating Surgical patients: for the calcium antagonistic effects of this active substance. In patients undergoing major surgery requiring general anaesthesia, ACE inhibitors Further absorption of verapamil from the gastrointestinal tract can be prevented by gastric lavage, may produce hypotension, which can be corrected by plasma volume expanders. administration of adsorbent material (activated charcoal) and a cathartic (sodium sulphate). Apart from Conduction disturbances: general supportive measures in response to severe hypotension (to the point of shock), i.e., mainte- Treatments should be used with caution in patients with first degree atrioventricular nance of an adequate circulating blood volume by administering plasma or a plasma expander, it may block. (see also section 4). be necessary to stimulate the heart muscle with such positive inotropic medicinal Bradycardia: products drugs as dopamine, dobutamine or isoproterenol. Tarka should be used with caution in patients with bradycardia. Atropine (or methylatropine) may be useful in the management of sinus bradycardia. Disease in which neuromuscular transmission is affected: AV block should be treated with sympathomimetic medicinal products (isoproterenol Tarka should be used with caution in patients with diseases in which neuromuscular or metaproterenol) or a pacemaker. transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Asystole should be handled by the usual measures including cardiopulmonary Duchenne muscular dystrophy). resuscitation, cardiac pacing, etc. The calcium-antagonistic effect can be offset by Hemodialysis patients (see also section 4.3) parenteral administration of calcium, for instance as calcium gluconate. Patients on concurrent ACE inhibitor therapy and hemodialysis with polyacrylonitrile 5.PHARMACOLOGICAL PROPERTIES methallyl sulfonate high-flux membranes (e.g. ‘AN 69’) have experienced 5.1 Pharmacodynamic properties anaphylactoid reactions. Such membranes should therefore not be used in these Pharmacotherapeutic group: Verapamil, combinations patients ATC code:CO8DA51 Desensitisation: Tarka is a fixed combination of the heart-rate lowering calcium antagonist verapamil Anaphylactoid reactions (in some cases life threatening) may develop in patients and the ACE inhibitor trandolapril. receiving ACE inhibitor therapy and concomitant desensitisation against animal Verapamil venoms. The pharmacologic action of verapamil is due to inhibition of the influx of calcium ions through the slow LDL-aphaeresis: channels of the cell membrane of vascular smooth muscle cells and of the conductile and contractile Life threatening anaphylactoid reactions have been noted when patients on LDL cells in the heart. aphaeresis take ACE inhibitors at the same time. The mechanism of action of verapamil produces the following effects: Evaluation of the patients should include assessment of renal function prior to 1.Arterial vasodilation initiation of therapy and during treatment. Verapamil reduces arterial pressure both at rest and at a given level of exercise by dilating peripheral Blood pressure readings for evaluation of therapeutic response to Tarka should arterioles. This reduction in total peripheral resistance (afterload) reduces myocardial oxygen require-- always be taken before the next dose. ments and energy consumption. Lactose 2.Reduction of myocardial contractility Tarka tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp The negative inotropic activity of verapamil can be compensated by the reduction in total peripheral lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. resistance. The cardiac index will not be decreased unless in patients with preexisting left ventricular Sodium dysfunction. This medicinal product contains. 1.12 mmol (or 25.76 mg) sodium per dose. To be Verapamil does not interfere with sympathetic regulation of the heart because it does not block the beta taken into consideration by patients on a controlled sodium diet. adrenergic receptors. Spastic bronchitis and similar conditions, therefore, are not contraindications to 4.5 Interaction with other medicinal products and other forms of interaction verapamil. Not recommended association Trandolapril Potassium sparing diuretics or potassium supplements: ACE inhibitors attenuate Trandolapril suppresses the plasma renin-angiotensin-aldosterone system (RAS). diuretic induced potassium loss. Potassium sparing diuretics e.g. spironolactone, Renin is an endogenous enzyme synthesized by the kidneys and released into the circulation where triamterene, or amiloride, potassium supplements, or potassium containing salt it converts angiotensinogen to angiotensin I a relatively inactive decapeptide. Angiotensin I is then substitutes may lead to significant increases in serum potassium, particularly in the converted by angiotensin converting enzyme, a peptidyldipeptidase, to angiotensin ll. presence of renal function impairment. If concomitant use is indicated because of Angiotensin ll is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood demonstrated hypokalemia they should be used with caution and with frequent pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. monitoring of serum potassium Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor -Dantrolene: The simultaneous use of verapamil with dantrolene is not recommended. activity and to reduce aldosterone secretion. Although the latter decrease is small, small increase in Precaution for use: serum potassium concentrations may occur, along with sodium and fluid loss. The cessation of the -Antihypertensive medicinal products: increase of the hypotensive effect of Tarka. negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin - Diuretics: patients on diuretics and especially those who are volume-and / or salts depleted may activity. experience an excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor. Another function of the converting enzyme is to degrade the potent vasodilating kinin peptide bradyki- The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing nin to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and volume or salt intake prior to intake and by initiation of therapy with low doses. Further increases in local kallikrein-kinin system which contributes to peripheral vasodilation by activating the prostaglan- dosage should be performed with caution. din system. It is possible that this mechanism is involved in the hypotensive effects of ACE inhibitors - Lithium: there have been reports of both an increase and a reduction in the effects of lithium used and is responsible for certain adverse reactions. In patients with hypertension administration of ACE concurrently with verapamil. The concomitant administration of ACE inhibitors with lithium may reduce inhibitors result in a reduction of supine and standing blood pressure to about the same extent with no the excretion of lithium. Serum lithium levels should be monitored frequently. compensatory increase of the heart rate. Peripheral arterial resistance is reduced with -Anesthetics: Tarka may enhance the hypotensive effects of certain anesthetic medicinal products. either no change or an increase in cardiac output. -Narcotics/antipsychotics: postural hypotension may occur. There is an increase in renal blood flow and glomerular filtration rate usually unchanged. -Allopurinol, cytostatic or immunosuppressive medicinal products, systemic corticosteroids or pro- Achievement of optimal blood pressure reduction may require several weeks of therapy in some cainamide: concomitant administration with ACE inhibitors may lead to an increased risk for patients. The antihypertensive effects are maintained during long term therapy. Abrupt withdrawal of leucopenia. therapy has not been associated with a rapid increase in blood pressure. the antihypertensive effect of -Cardiodepressive medicinal products: the concurrent use of verapamil and cardiodepressives, i.e., trandolapril sets in one hour post-dose and lasts for at least 24 hours, but trandolapril does not interfere medicinal products that inhibit cardiac impulse generation and conduction (e.g., beta-adrenergic block- with the circadian blood pressure pattern. ers, antiarrhythmic. inhalation anesthetics), may produce undesirable additive effects. Tarka - Quinidine: the concomitant use of quinidine and oral verapamil in patients with hypertrophic (obstruc- Neither animal studies nor healthy volunteer studies could demonstrate pharmacokinetic or RAS tive) cardiomyopathy has resulted in hypotension and pulmonary oedema in a small number of cases. interactions between verapamil and trandolapril. The observed synergistic activity of these two active - Digoxin: concurrent use of digoxin and verapamil has been reported to result in 50 -75 % substances must therefore be due to their complementary pharmacodynamic actions. higher digoxin plasma concentrations, requiring reduction of the digoxin dosage. In clinical trials Tarka was more effective in reducing high blood pressure than either active substance - Muscle relaxants: the effect of muscle relaxants may be enhanced. alone. In long-term trials, Tarka proved to be safe and well tolerable - Tranquillisers/antidepressants: as with all antihypertensives, there is an elevated 5.2 Pharmacokinetic properties risk of orthostatic hypotension when combining Tarka with major tranquillisers or Tarka tablets are film-coated and composed of a layer designed for sustained release of verapamil antidepressant medicinal products containing imipramine. hydrochloride and a separate layer intended for immediate release of trandolapril. Take into account Verapamil -Non-steroidal anti-inflammatory drugs (NSAIDs): the administration of a non- Absorption: steroidal anti-inflammatory drug may reduce the antihypertensive effect of an ACE inhibitor. About 90% of orally administered verapamil is absorbed. The mean bioavailability is as low as 22% Furthermore it has been described that NSAIDs and ACE inhibitors exert an additive effect on the because of extensive hepatic first-pass extraction, and shows great variation (10-35%). The mean increase in serum potassium, whereas renal function may decrease. bioavailability following repeated administration may increase to 30%. These effects are in principle reversible, and occur especially in patients with Food, especially fat food, may delay the absorption of verapamil from the tablet ,which results in higher compromised renal function. Tmax values and lower Cmax values, without influence on the bioavailability of verapamil. To prevent a - Antacids: induce decreased bioavailability of ACE inhibitors. potential delayed absorption it is recommended to take Tarka half an hour before breakfast. - Sympathomimetic: may reduce the antihypertensive effects of ACE inhibitors; Distribution and biotransformation: Patient should be carefully monitored to confirm that the desired effect is being obtained. The mean time to peak plasma concentration is 4 hours. The peak plasma concentration of norvera- - Alcohol: enhances the hypotensive effect. pamil is attained about 6 hours post-dose. - Verapamil may increase the plasma concentrations of carbamazepine, cyclosporine Steady state after multiple once daily dosing is reached after 3-4 days Plasma protein binding of and theophylline thus increasing risk of toxicity from these compounds. verapamil is about 90%. - Rifampin, phenytoin, and phenobarbital reduce the plasma concentrations of Elimination: verapamil, whereas cimetidine may increase the plasma concentrations of verapamil. The mean elimination half-life after repeated administration is 8 hours. 3-4% of a dose is excreted - Antidiabetics: a dose adjustment of antidiabetics or of Tarka may be necessary in renally as unchanged drug. Metabolite excretion is in the urine (70%) and in the faeces (16%). Nor- individual cases especially at the start of therapy due to increased reduction of blood glucose. verapamil is one of 12 metabolites identified in urine, has10 - 20% of the pharmacologic activity of - Grapefruit juice has been shown to increase the plasma levels of verapamil, which is a component of verapamil, and accounts for 6% of excreted drug. Tarka. Grapefruit juice should therefore not be ingested with Tarka. The steady-state plasma concentrations of norverapamil and verapamil are similar. -Food has been shown to decrease the rate but not the extent of absorption of verapamil. It is therefore verapamil kinetics is not altered by renal function impairment. recommended to take the medicinal product half an hour before breakfast (see section 4.2). The bioavailability and elimination half-life of verapamil are increased in patients with liver cirrhosis. 4.6Pregnancy and lactation Verapamil kinetics is, however, unchanged in patients with compensated hepatic dysfunction. Kidney Pregnancy function has no effect on verapamil elimination. The use of Tarka in pregnancy is contraindicated (see section 4.3). Trandolapril The safe use of Tarka in pregnant women is inadequately documented. However, there have been Absorption: anecdotal reports of neonatal lung hypoplasia, intra-uterine growth retardation, persistent ductus arte- Orally administered trandolapril is absorbed rapidly. Absorption is 40-60% and independent of the riosus, and cranial hypoplasia following exposure of foetuses to ACE inhibitors. presence of food. In addition, the pharmacologic activity of ACE inhibitors is compatible with the possibility of foetal The time to peak plasma concentration is about 30 minutes. hypotension, which may be associated with foetal/neonatal oliguria/anuria and oligohydramnios (see Distribution and biotransformation: also section 5.3). Trandolapril disappears very rapidly from plasma, and its half-life is less than one hour. Teratogenic effects are primarily expected when ACE inhibitors are used in the second and third tri- Trandolapril is hydrolysed in plasma to form trandolaprilat, a specific angiotensin mesters of pregnancy, and it is not known whether exposure of the embryo/foetus to an ACE inhibitor converting enzyme (ACE) Inhibitor. The amount of trandolaprilat formed is only in the first trimester is teratogenic or embryotoxic/foetotoxic. Women who wish to get pregnant Independent of food Intake. or are pregnant must consult their doctor without delay, so an alternative pharmacologic treatment The time to peak plasma concentration of trandolaprilat is 4-6 hours. can be prescribed. Plasma protein binding of trandolaprilat is greater than 80% trandolaprilat binds with great affinity Women of child-bearing potential to ACE, and this is a saturable process. Most of circulating trandolaprilat binds to albumin in non Doctors should instruct women of child-bearing potential accordingly before prescribing an ACE saturable process. Steady stats after multiple once daily dosing is reached after 4 days in healthy inhibitor. volunteers as well as in younger and elderly hypertensive patients. Lacation The effective. half-life calculated from accumulation is 16-24 hours. Tarka is contraindicated when breastfeeding (see section 4.3). Elimination: 4.7 Effects on ability to drive and use machines 10-15% of an administered trandolapril dose is excreted as unchanged trandolaprilat in urine. While no effect on the ability to drive and use machinery has been established, impairment of alertness Following oral administration of radioactively labelled trandolapril, one third of cannot be ruled out altogether, since Tarka may produce dizziness and fatigue. radioactivity is recovered in urine and two thirds in faeces. 4.8 Undesirable effects The renal clearance of trandolaprilat shows a linear correlation with creatinine clearance. The tran- The adverse drug reactions for Tarka are consistent with those known for its components or the dolaprilat plasma concentration is significantly higher in patients whose creatinine clearance is[.] respective class of medicinal products. The most commonly reported adverse drug reactions are 30 ml/min. cough, headache, constipation, vertigo, dizziness and hot flushes (see table below). Following repeated administration to patients with chronic renal dysfunction, steady state is, however, Adverse events either reported spontaneously or observed in clinical trials are depicted in the also reached after four days , independently of extent of kidney function impairment. following table. Within each system organ class, the ADRs are ranked under headings of frequency, The trandolapril plasma concentration may be 10 times higher in patients with liver cirrhosis than in using the following convention : common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare healthy volunteers. The plasma concentration and renal excretion of trandolaprilat are also increased (>1/10,000, <1/1.000), very rare (<1/10,000) including isolated reports. in cirrhotic patients, albeit to a lesser extent. System Organ class frequency Undesirable Effect Trandolapril(at) kinetics are unchanged in patients with compensated hepatic dysfunction. Tarka Blood and Iymphatic system disorders As there are no known kinetic interactions between verapamil and trandolapril or trandolaprilat, the Leukopenia single active substance kinetic parameters of these two active substances apply to the combination very rare Pancytopenia product as well. thrombocytopenia 5.3 Preclinical safety data General toxicity effects were observed in animals only at exposures that were sufficiently in excess of Immune system disorders the maximum human exposure to make any concern for human safety negligible. uncommon Allergic reaction. Genotoxicity assays revealed no special hazard for humans. Unspecified Animal studies have shown that ACE inhibitors tend to have an adverse effect on late foetal develop- very rare Increase in gamma- ment, resulting in foetal death and congenital’ abnormalities of the skull in particular. gloulin hypersensitivity, These cranial abnormalities are thought to be due to the pharmacologic activity of uspecified these active substances and be related to ACE inhibitor-induced oligohydramnios. Metabolism and nutritional disorders There is no evidence of tumorigenic potential with either trandolapril or verapamil. uncommon hyperlipidaemia 6. PHARMACEUTICAL PARTICULARS 6.1 Shelf life rare anorexia 3 years Psychiatric disorders 6.2 Special precautions for storage uncommon somnolence For oral administration only very rare aggression Store in the original pack. anxiety Store at room temperature 30 ◦C. depression Keep out of the reach of children. nervousness 6.3 Nature and contents of container Box of 14, 28, tablets in blister each of 14 bi-layered tablets. Nervous system disorders PVC/PVDC-aluminum blister common dizziness 6.4 Instructions for use and handling vertigo No special requirements. uncommon tremor 7. MARKETING AUTHORISATION HOLDER rare collapse Manufactured by ABBOTT GMBH & CO, KG very rare impaired balance LUDWIGSHAFEN, GERMANY insomnia PACKED BY KAHIRA PHARM.& CHEMI.IND.CO EGYPT paresthesia or hy- peresthesia Abbott syncope or acute circula- tory Failures with loss of consciousness taste aberration weakness Eye disorders Very rare Abnormal/blurred vision Cardiac disorders / vascular disorders common Hot flushes uncommon AV block, first degree Palpitation very rare angina pectoris atrial fibrillation AV block, complete AV block, unspecified bradycardia cardiac arrest cerebral hemorrhage oedema, peripheral oedema, unspecified flushing heart failure hypotensive events including orthostasis or fluctuation of blood pressure (see also section 4.4) tachycardia

System organ class Frequency Undesirable Effects

Respiratory, thoracic and mediastenal common Cough disorders very rare Asthma bronchitis dyspnea sinus congestion

Gastrointestinal disorders Common constipation uncommon abdominal pain diarrhea gastrointestinal disorders unspecified System organ class Frequency Undesirable Effects