Trandolapril 0.5 Mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Trandolapril 0.5 mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 0.5 mg trandolapril.
Excipient(s) with known effect:
31.5 mg lactose/capsule
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule, hard.
Body : Rich yellow, Imprinting: TD0.5 Cap: Medium orange, Imprinting: TD0.5
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Mild or moderate hypertension.
Left ventricular dysfunction after myocardial infarction.
It has been demonstrated that Trandolapril improves survival following myocardial infarction in patients with left ventricular dysfunction (ejection fraction < 35 percent), with or without symptoms of heart failure, and/or, with or without residual ischaemia. Long-term treatment with Trandolapril significantly reduces overall cardiovascular mortality. It significantly decreases the risk of sudden death and the occurrence of severe or resistant heart failure.
Trandolapril can be used alone or in combination with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1)
4.2 Posology and method of administration
Posology
Adults
Mild or moderate hypertension
For adults not taking diuretics, without congestive heart failure and without renal or hepatic insufficiency; the recommended initial dosage is 0.5 mg as a single daily dose. A 0.5 mg dose will only achieve a therapeutic response in a minority of patients. 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 range is 1 to 2 mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 4 mg Trandolapril, combination therapy should be considered. Trandolapril can be used alone or in combination with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).
Left ventricular dysfunction after myocardial infarction
Following a myocardial infarction, therapy may be initiated as early as on the third day. Treatment should be initiated at a daily dose of 0.5 mg. The dose should be progressively increased to a maximum of 4 mg as a single daily dose. Depending upon the tolerability such as symptomatic hypotension, this forced titration can be temporarily suspended.
In the event of hypotension, all concomitant hypotensive therapies such as vasodilators including nitrates, diuretics, must be carefully checked and if possible their dose reduced.
The dose of Trandolapril should be lowered only if the previous measures are not effective or not feasible.
Older people
The dose in older people is the same as in adults. There is no need to reduce the dose in older people with normal renal and hepatic function. Caution in older people 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.
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.
Cardiac Failure
In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients therapy should be started at a dose of 0.5 mg Trandolapril once daily under close medical supervision in hospital.
Patients with renal impairment
For patients with mild or moderate renal impairment (creatinine clearance of 10-70 ml/min) the usual adult and older people doses are recommended.
For patients with severe renal impairment (creatinine clearance of <10 ml/min) the usual adult and older people starting doses are also recommended but the maximum daily dose should not exceed 2 mg. In these patients therapy should be under close medical supervision.
Dialysis
It is not known for certain if trandolapril or trandolaprilat are removed by dialysis. However, it would be expected that dialysis could remove the active moiety, trandolaprilat, from the circulation, resulting in a possible loss of control of blood pressure. Therefore careful monitoring of the patient’s blood pressure during dialysis is required, and the dosage of trandolapril adjusted if needed.
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 Trandolapril should therefore be initiated at a dose of 0.5 mg once daily under close medical supervision.
Paediatric population
Trandolapril has not been studied in children and therefore use in this age group is not recommended.
4.3 Contraindications
Known hypersensitivity to trandolapril or any other ACE inhibitor or to any of the excipients listed in section 6.1
History of hypersensitivity including angioedema associated with administration of an ACE inhibitor.
Hereditary/idiopathic angioedema.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Use in children.
The concomitant use of trandolapril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).
4.4 Special warnings and precautions for use
Trandolapril should not be used in patients with aortic stenosis or outflow obstruction.
Assessment of Renal Function
Evaluation of the patient should include assessment of renal function prior to initiation of therapy and during treatment. Proteinuria may occur if renal impairment is present prior to therapy or relatively high doses are used.
Renal impairment
Patients with a creatinine clearance less than 30 mL/min may require reduced doses of trandolapril; their renal function should be closely monitored.
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 and severe hypotension. If recognised early, such impairment of renal function is reversible upon discontinuation of therapy. In these patients treatment should be started in hospital under close medical supervision with low doses and careful dose titration.
Renal failure in association with ACE inhibitors has mainly been reported in patients with severe heart failure or underlying renal disease, including renal artery stenosis.
Some hypertensive patients with no apparent pre-existing renal disease may develop increases in blood urea nitrogen and serum creatinine when trandolapril is given concomitantly with a diuretic. Proteinuria may occur. Dosage reduction of trandolapril 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.
Patients who are dialysed using high flux polyacrylonitrile membranes and treated with ACE inhibitors are likely to experience anaphylactoid reactions such as facial swelling, flushing, hypotension and dyspnoea within a few minutes of commencing haemodialysis. It is recommended to use an alternative membrane or an alternative anti hypertensive drug.
Patients with renovascular hypertension
ACE inhibitors may be of use until curative treatment of the renovascular hypertension can be effected, or if such a procedure is not to be carried out. The risk of severe arterial hypotension and renal insufficiency is increased when patients with prior unilateral or bilateral renal artery stenosis are treated with an ACE inhibitor. Diuretics may further increase the risk. Loss of renal function may occur with only small changes in the serum creatinine, even in patients with unilateral renal artery stenosis. For these patients treatment should be initiated in the hospital under close medical supervision with low doses and careful dose adjustment. Diuretic treatment should be discontinued, and renal function and serum potassium monitored during the early weeks of treatment.
General
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 trandolapril may be excessive.
Impaired Liver Function
Trandolapril is a prodrug metabolised to its active moiety in the liver. Thus particular caution and close monitoring should be applied to patients with impaired liver function as it may lead to elevated plasma levels, therefore dose adaptation may be required.
Symptomatic Hypotension
In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of Trandolapril as well as after increasing the dose of Trandolapril. ACE inhibitors may cause a profound fall in blood pressure. It has been reported mainly in patients with severe heart failure with or without renal insufficiency. It is also more likely to occur in patients who have been volume-and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. This is more likely to occur in patients on high dose loop diuretics, or those with hyponatraemia or functional renal impairment. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with Trandolapril. These patients should also be kept under very close medical supervision when starting treatment preferably in hospital with low doses and careful titration.
Similar considerations may apply to patients with ischemic heart disease or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
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
Trandolapril may usually be continued following restoration of effective blood volume and blood pressure. The appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with drug after effective management.
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. If it is not possible to withhold the ACE inhibitor, volume management should be handled with care.
Agranulocytosis and Bone Marrow Depression
In patients on angiotensin converting enzyme inhibitors, agranulocytosis and bone marrow depression have been seen. These reactions are more frequent in patients with renal impairment, especially those with 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.
Aortic stenosis/hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.
Proteinuria
It may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.
Hyperkalaemia
Elevated serum potassium has been observed in hypertensive patients.(see also section 4.5).
Risk factors for the development of hyperkalaemia include renal insufficiency, potassium sparing diuretics, the concomitant use of agents to treat hypokalaemia, diabetes mellitus and/or left ventricular dysfunction after myocardial infarction. 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 agents is deemed appropriate, they should be used with frequent monitoring of serum potassium.
Angioedema
Trandolapril may cause angioedema that includes swelling of the face, extremities, tongue, glottis and/or larynx. ACE inhibitors have been shown to cause a higher rate of angioedema in black patients than in non-black patients.
Intestinal angioedema has also been reported in patients treated with ACE inhibitors. This should be considered in patients on trandolapril presenting with abdominal pain (with or without nausea or vomiting).
Patients experiencing angioneurotic oedema must immediately discontinue Trandolapril therapy and given an agent belonging to another class of drugs and be monitored until oedema resolution.
Angioedema of 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.
Angioedema involving the tongue, glottis or larynx requires immediate subcutaneous administration of 0.3-0.5 ml of adrenaline solution (1:1000) or slow intravenous adrenalin (1mg/ml), with control of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Caution must be exercised in patients with a history of idiopathic angioneurotic oedema and Trandolapril is contraindicated if angioneurotic oedema was an adverse reaction to an ACE inhibitor (see Contraindications, section 4.3).
Cough
During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation.
Older people
Some older people may be more responsive to an ACE inhibitor than younger patients. Administration of low initial doses and evaluation of renal function at the beginning of the treatment is recommended.
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).
Anaphylactoid and Possibly Related Reactions
Desensitization
Anaphylactoid reactions (in some cases life threatening) may develop in patients receiving ACE inhibitor therapy and concomitant desensitization against animal venoms.
Low Density Lipoprotein (LDL)-apheresis
Life threatening anaphylactoid reactions have been noted when patients on LDL-apheresis take ACE inhibitors at the same time.
Paediatric population
The safety and efiicacy of trandolapril in children have not been studied.
This product contains 31.5 mg lactose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increase the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
4.5 Interaction with other medicinal products and other forms of interaction
Diuretic Therapy
Combination with diuretics or other antihypertensive agents may potentiate the antihypertensive response to Trandolapril. Adrenergic-blocking drugs 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,diabetes mellitus, and/or left ventricular dysfunction after myocardial infarction. In the randomized, placebo-controlled, parallel-group TRAndolapril Cardiac Evaluation (TRACE) Study in patients surviving an acute myocardial infarction with residual left ventricular systolic dysfunction hyperkalemia was observed as an adverse event in 5% (0.2% related) and 3% subjects (none related) in the trandolapril and placebo groups, respectively. Eighty (80%) subjects in this study received diuretics (see section 4.4).
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.
Antidiabetic Agents
As with all ACE-inhibitors, concomitant use of antidiabetic medicines (insulin or oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycaemia. Therefore, blood glucose should be closely monitored in diabetics treated with a hypoglycaemic agent and trandolapril, particularly when starting or increasing the dose of ACE-inhibitor, or in patients with impaired renal function.
Non-steroid anti-inflammatory medicinal products:
When ACE-inhibitors are administered simultaneously with non-steroidal antiinflammatory drugs (ie acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE-inhibitors and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Combinations Necessitating a Warning
In some patients already receiving diuretic treatment or are volume and/or salt depleted particularly if this treatment has been recently instituted, the fall in blood pressure on initiation of treatment with Trandolapril may be excessive. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with Trandolapril. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of Trandolapril.
Lithium
Trandolapril may reduce the elimination of lithium and serum levels of lithium should be monitored.
Other
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.
The hypotensive effects of certain inhalation anesthetics may be enhanced by ACE inhibitors.
Allopurinol, cytostatic or immunosuppresive agents, systemic corticosteroids or procainamide may increase the risk of leucopenia, if used concomitantly with ACE inhibitors.
As with all antihypertensives, NSAIDs may reduce the antihypertensive effects of trandolapril. Blood pressure monitoring should be increased when any NSAID is added or discontinued in a patient treated with trandolapril.
Antacids may cause reduced bioavailability of ACE inhibitors.
The antihypertensive effects of ACE inhibitors may be reduced by sympathomimetics, patients should be carefully monitored.
As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension.
No clinical interaction has been observed in patients with left ventricular dysfunction after myocardial infarction when Trandolapril has been concomitantly administered with thrombolytics, aspirin, beta blockers, calcium channel blockers, nitrates, anticoagulants, diuretics or digoxin.
Alcohol increases the risk of hypotension.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and
5.1)
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
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 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.
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 inhibitor 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 also sections 4.3 and 4.4).
Breast-feeding
Because no information is available regarding the use of Trandolapril during breast feeding, Trandolapril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects on ability to drive and use machines
Given the pharmacological properties of Trandolapril, no particular effect is expected. However, in some individuals, ACE inhibitors may affect the ability to drive or operate machinery particularly at the start of treatment, when changing over from other medication or during concomitant use of alcohol.
Therefore, after the first dose, or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.
4.8 Undesirable effects
The following table displays adverse reactions reported in hypertension(n=2,520) and post myocardial infarction (n=876) clinical trials and from postmarketing experience with trandolapril.
The reactions considered at least possibly related to trandolapril are displayed by system organ class and frequency using the following convention: common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) and not known (adverse reactions from postmarketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.
|
System Organ Class |
Frequency | |||
|
Common |
Uncommon |
Rare |
Not known | |
|
Infections and infestations |
Upper respiratory tract infection |
Urinary tract infection, bronchitis, pharyngitis | ||
|
Blood and lymphatic system disorders |
Leukopenia, anaemia, platelet disorder, white blood cell disorder |
Agranulocytosis, pancytopenia, platelet count decreased, haemoglobin decreased, haematocrit decreased | ||
|
Immune system disorders |
Hypersensitivity | |||
|
Endocrine disorders |
Hyperkalaemia | |||
|
Metabolism and nutrition disorders |
Hyperglycaemia, hyponatraemia, hypercholesterolaemia, hyperlipidaemia, hyperuricaemia, gout, anorexia, increased appetite, enzyme abnormality | |||
|
Psychiatric disorders |
Insomnia, libido decreased |
Hallucination, depression, sleep disorder, anxiety, agitation, apathy | ||
|
Nervous system disorders |
Headache, dizziness |
Somnolence |
Cerebrovascular accident, syncope, myoclonus, paresthesia, migraine, |
Transient ischemic attack, cerebral haemorrhage, |
|
migraine without aura, dysgeusia |
balance disorder | |||
|
Eye disorders |
Blepharitis, conjunctival oedema, visual impairment, eye disorder | |||
|
Ear and labyrinth disorders |
Vertigo |
Tinnitus | ||
|
Cardiac disorders |
Palpitations, cardiac failure |
Myocardial infarction, myocardial ischaemia, angina pectoris, ventricular tachycardia, tachycardia, bradycardia |
Atrioventricular block, cardiac arrest, arrhythmia, electrocardiogram abnormal | |
|
Vascular disorders |
Hypotension* |
Hot flush |
Hypertension, angiopathy, orthostatic hypotension, peripheral vascular disorder, varicose vein | |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
Upper respiratory tract inflammation, upper respiratory tract congestion |
Dyspnoea, epistaxis, pharyngeal inflammation, oropharyngeal pain, productive cough, respiratory disorder |
Bronchospasm |
|
Gastrointestinal disorders |
Nausea, diarrhoea, gastrointestinal pain, constipation, gastrointestinal disorder |
Haematemesis, gastritis, abdominal pain, vomiting, dyspepsia, dry mouth, flatulence |
Ileus, pancreatitis | |
|
Hepatobiliary disorders |
Hepatitis, hyperbilirubinaemia |
Jaundice, liver function test abnormal, transaminases increased | ||
|
Skin and subcutaneous tissue disorders |
Pruritus, rash |
Angioedema, psoriasis, hyperhidrosis, eczema, acne, dry skin, skin disorder |
Alopecia, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis | |
|
Musculoskeletal and connective tissue disorders |
Back pain, muscle spasms, pain in extremity |
Arthralgia, bone pain, osteoarthritis |
Myalgia | |
|
Renal and urinary disorders |
Renal failure, azotemia, polyuria, pollakiuria |
Blood creatinine increased, blood urea increased |
|
Reproductive system and breast disorders |
Erectile dysfunction | |||
|
Congenital, familial and genetic disorders |
Congenital arterial malformation, ichthyosis | |||
|
General disorders and administration site conditions |
Asthenia |
Malaise, chest pain, oedema peripheral, feeling abnormal |
Oedema, fatigue |
Pyrexia |
|
Investigations |
Blood alkaline phosphatase increased, blood lactate dehydrogenase increased, laboratory test abnormal | |||
|
Injury, poisoning and procedural complications |
Injury |
* Hypotension has a common frequency in patients with left ventricular dysfunction following myocardial infarction from the TRACE clinical study (n=876). However, it has an uncommon frequency in those patients from hypertension clinical trials (n=2,520).
The following adverse events have been reported with ACE inhibitors as a class with an unknown frequency.
|
System Organ Class |
Adverse Event |
|
Blood and lymphatic system disorders |
Haemolytic anaemia Eosinophilia and/or increased ANA (anti-nuclear antibody) |
|
Nervous system disorders |
Confusional state |
|
Eye disorders |
Vision blurred |
|
Respiratory, thoracic and mediastinal |
Sinusitis |
|
disorders |
Rhinitis Glossitis |
|
Gastrointestinal disorders |
Intestinal angioedema |
|
Skin and subcutaneous tissue |
Erythema multiforme |
|
disorders |
Dermatitis psoriasiform |
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professional are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms
Symptoms of overdose are severe hypotension, shock, stupor, bradycardia, electrolyte disturbance and renal failure.
After ingestion of an overdose, the patient should be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently.
Therapeutic procedures depend on the severity of the symptoms. If ingestion is recent, take measures aimed at eliminating trandolapril (e.g. emesis, gastric lavage, administration of absorbents, and sodium sulphate). In the event of symptomatic hypotension the patient should be placed in the shock position and treatment with physiological salt solution or other forms of plasma expansion should be initiated as soon as possible. Treatment with angiotensin II should be considered. Bradycardia or severe vaso-vagale reactions should be treated with atropine. Pacemaker therapy should be considered, It is unknown if trandolaprilat can be eliminated from the body by haemodialysis.
Treatment
There is no specific antidote for trandolapril overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: cardiovascular system - agents acting on the renin-angiotensin system - ACE inhibitors, plain, ATC code: C09A A 10.
Trandolapril capsules contain the prodrug trandolapril, a non-peptide angiotensin converting enzyme (ACE) inhibitor with a carboxyl group but without a sulphydryl group. Trandolapril is rapidly absorbed and then nonspecifically hydrolysed to its potent, long-acting active metabolite, trandolaprilat.
Trandolaprilat binds tightly and in a saturable manner to ACE.
The beneficial effects of ACE inhibitors in hypertension and in heart failure appear to result primarily from the suppression of the plasma angiotensin aldosterone system.
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. Renin is an endogenous enzyme synthesised by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin I. Angiotensin I is then converted by angiotensin converting enzyme to angiotensin II which is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of ACE results in a decreased plasma angiotensin II leading to decreased vasopressor activity and to reduced aldosterone secretion. The cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity. ACE also degrades the potent vasodepressive kinin peptide bradykinin to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin-system which contributes to peripheral vasodilation by activating the prostaglandin system. Trandolapril thus modulates the renin-angiotensin-aldosterone system which plays a major part in regulating blood volume and blood pressure and consequently has a beneficial antihypertensive effect.
The administration of usual therapeutic doses of Trandolapril to hypertensive patients produces a marked reduction of both supine and erect blood pressure. The antihypertensive effect is evident after 1 hour, with a peak effect between 8 and 12 hours, persisting for at least 24 hours.
The properties of trandolapril might explain the results obtained in the regression of cardiac hypertrophy with improvement of diastolic function, and improvement of arterial compliance in humans. In addition a decrease in vascular hypertrophy has been shown in animals.
Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive effects are maintained during long term therapy.
The haemodynamic effects of ACE therapy in patients with heart failure result from both arteriolar and venodilatation. Systemic vascular resistance is decreased and venous capacity increased. Thus, pre - and after - load are reduced. Consequences are a decrease in left ventricular filling pressure/capillary wedge pressure and an increase in cardiac output; heart rate remains unchanged or may even decrease. Clinically, signs and symptoms of the heart failure will improve and exercise capacity will increase. These effects are maintained during long term treatment.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
5.2 Pharmacokinetic properties
Trandolapril is very rapidly absorbed after oral administration. The amount absorbed is equivalent to 40 to 60% of the administered dose and is not affected by food consumption.
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 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 plasma trandolaprilat is more than 80% protein-bound. It binds saturably, with a high affinity, to angiotensin 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 older people hypertensives. The effective half-life of trandolaprilat is between 16 and 24 hours. The terminal half life of elimination is between 47 and 98 hours, depending on dose. This terminal phase probably represents binding/dissociation kinetics of the trandolaprilat/ACE complex.
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 a 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.
5.3 Preclinical safety data
Acute oral toxicity studies of trandolapril and its active metabolite, trandolaprilat, in rats and mice showed both compounds to be non-toxic with respective LD50 values of > 4000 mg/kg and > 5000 mg/kg.
Repeat dose oral toxicity was evaluated in the rat and dog with studies of up to 18 and 12 months duration respectively. The principal observations in these studies were of anaemia (doses of 20 mg/kg/day and above in the rat 30 day study and 25 mg/kg/day and above in the dog 6 month study), gastric irritation and ulceration (doses of 20 mg/kg/day and above in the rat 30 day study and 125 mg/kg/day in the dog 6 month study) and renal lesions (20 mg/kg/day and above in the rat 30 day study and 10 mg/kg/day in the dog 30 day study): renal lesions were also seen in the 6 month studies in the rat and dog (from doses of 0.25 and 25 mg/kg/day respectively) - these were reversible on cessation of treatment.
Reproduction toxicity studies showed effects on renal development in offspring with increased incidence of renal pelvic dilation; this was seen at doses of 10 mg/kg/day and above in the rat but these changes did not affect the normal development of the offspring.
Trandolapril was not mutagenic or carcinogenic.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule contents: Povidone PVP K-30 Lactose anhydrous Pregelatinised starch Sodium stearyl fumarate
Capsule shell:
Erythrosin (E127) Titanium dioxide (E171) Yellow iron oxide (E172) Gelatin
Quinoline yellow (E104)
Printing ink:
Shellac
Iron oxide black (E172)
Propylene glycol
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Aluminium-aluminium blisters.
Blister packs of 14, 20, 28, 30, 50, 60, 98 & 100 capsules. Calendar packs of 14, 28 capsules.
Hospital packs of 40, 50 & 200 (5x40) capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road, Hampden Park Eastbourne, BN22 9AG England
MARKETING AUTHORISATION NUMBER(S)
8
PL 00289/0800
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/01/2008
10 DATE OF REVISION OF THE TEXT
07/10/2015