Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial, Estate, Dublin 13, Ireland
Hypersensitivity to trandolopril or to any of the excipients or any other ACE-inhibitor.
History of angioneurotic oedema associated with administration of an ACE inhibitor.
Hereditary/idiopathic angioneurotic oedema.
Concomitant use with sacubitril/valsartan therapy. Odrik must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5).
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
The concomitant use of Odrik with aliskiren-containing product is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²) (see sections 4.5 and 5.1).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Trandolapril should not be used in patients with aortic stenosis or outflow obstruction.
Patients with a creatinine clearance less than 30ml/min may require reduced doses of trandolapril; their renal function should be closely monitored.
Severe water and sodium depletion (salt-free diet or prolonged diuretic treatment), known or suspected renal artery stenosis, congestive heart failure and cirrhosis with ascites. ACE inhibitors may cause severe hypotension, particularly at the time of the first dose and during the first two weeks of treatment. Renal function may be impaired by Odrik in patients with renal insufficiency, congestive heart failure, bilateral renal artery stenosis and unilateral renal artery stenosis in the single kidney; in such patients, renal function should be monitored and therapy discontinued if renal impairment occurs.
Renal function (increased BUN, creatinine and proteinuria) may be impaired in patients with normal renal function when Odrik is administered with a diuretic.
Additionally, in patients with renal insufficiency, the risk of hyperkalaemia should be considered and the patient’s electrolyte status checked regularly.
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases 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.
As trandolapril is a prodrug metabolised to its active moiety in the liver, particular caution and close monitoring should be applied to patients with impaired liver function.
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. It is more likely to occur in patients who have been volumeand salt depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with trandolapril.
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.
In patients on ACE inhibitors, agranulocytosis and bone marrow depression have been seen (see Section 4.8 Undesirable Effects). The risk of neutropenia appears to be dose- and type-related and is dependent on the patient’s clinical status. 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 (e.g. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy, particularly with corticosteroids and antimetabolites. It is reversible after discontinuation of the ACE inhibitor.
Angioedema has been reported with ACE inhibitors, including trandolapril. ACE inhibitors have been shown to cause a higher rate of angioedema in black patients than in non-black patients.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of trandolapril. Treatment with trandolapril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.
In patients experiencing angioedema, trandolapril should be discontinued immediately and the patient observed. Where swelling is confined to the face, extremities, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airways obstruction, which may be life-threatening, appropriate therapy such as immediate subcutaneous adrenaline (0.3-0.5 ml 1:1000) should be administered along with other therapeutic measures as appropriate.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also section 4.3 “Contraindications” and section 4.8 Undesirable Effects).
Other hypersensitivity reactions have been reported.
Intestinal angioedema has also been associated with ACE inhibitor therapy and must be considered in the differential diagnosis of abdominal pain in patients being treated with trandolapril.
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. Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors. 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.
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.
Very rare cases of neutropenia have been reported in association with the use of ACE inhibitors, although a causal relationship has not been established. As with any ACE inhibitor, consideration should be given to monitoring the white blood cell count, particularly in patients with renal and/or connective tissue disease.
Anaphylactoid reactions to high flux polyacrylonitrile membranes used in haemodialysis have been reported in patients treated with ACE inhibitors. As with other ACE inhibitors, this combination should therefore be avoided either by use of alternative antihypertensive drugs or alternative membranes for haemodialysis.
Concomitant administration of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycaemic agents) may cause an increase in blood glucose lowering effect with the risk of hypoglycaemia. The phenomena may be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
In patients undergoing surgery or during anesthesia with agents producing hypotension, trandolapril may block angiotensin II formation secondary to compensatory renin release.
Anaphylactoid reactions (in some cases life threatening) may develop in patients receiving ACE inhibitor therapy and concomitant desensitization against animal venoms.
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.
Life threatening anaphylactoid reactions have been noted when patients on LDL-apheresis take ACE inhibitors at the same time.
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption
During treatment with an ACE inhibitor, a dry and non-productive cough may occur which disappears after discontinuation.
The safety and efficacy of trandolapril in children have not been established.
ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5). The risk of hyperkalaemia may also be increased in patients with diabetes mellitus and/or left ventricular dysfunction after myocardial infarction, especially in combination with these other risk factors.
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor use 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 (see sections 4.3 and 4.6).
Because no information is available regarding the use of trandolapril during breastfeeding, trandolapril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
The medicine contains lactose, therefore patients with rare hereditary forms of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
The safety and efficacy of trandolapril in children has not been studied.
No pharmacodynamic interaction has been noted when Odrik has been combined with digoxin, furosemide or nifedipine. Odrik may be administered in combination with other antihypertensive agents and an additional reduction in blood pressure may occur. No modification of the anticoagulant properties of warfarin has been observed following simultaneous administration of Odrik and warfarin.
Drugs/Agents with antihypertensive potential (e.g. diuretics, anaesthetics, narcotic drugs, antipsychotic drugs): the hypotensive effects may be enhanced. Adrenergic-blocking drugs should only be combined with trandolapril under careful supervision.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after taking the last dose of trandolapril therapy. Trandolapril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).
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 Odrik may be excessive. The risk of symptomatic hypotension may be reduced by stopping the diuretic a few days before starting treatment with Odrik. If it is necessary to continue the diuretic treatment, the patient should be monitored, at least after the initial administration of Odrik. As with all antihypertensives, combination with a neuroleptic or tricyclic antidepressant increases the risk of orthostatic hypotension. Odrik may reduce the elimination of lithium and serum levels of lithium should be monitored.
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with trandolapril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when trandolapril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of trandolapril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.
The concomitant use of trandolapril with potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes particularly increases the risk of hyperkalaemia 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.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
As with all ACE inhibitors, concomitant use of antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia (see Section 4.4 Special Warnings and Precautions).
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).
Trandolapril may reduce the elimination of lithium. Serum lithium levels should be monitored.
Anaphylactoid reactions to high-flux polyacrylonitrile membranes used in hemodialysis 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.
As with all antihypertensives, NSAIDs (including acetylsalicylic acid used in higher doses as an anti-inflammatory drug e.g. for pain relief) 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.
NSAIDs including acetylsalicylic acid, unless acetylsalicylic acid is used in lower doses as a platelet aggregation inhibitor, should be avoided with ACE inhibitors in patients with heart failure.
The hypotensive effects of certain inhalation anaesthetics may be enhanced by ACE inhibitors.
Antacids cause reduced bioavailability of ACE inhibitors.
Alcohol increases the risk of hypotension.
The antihypertensive effects of ACE inhibitors may be reduced by sympathomimetics; patients should be carefully monitored. Allopurinol, cytostatic or immunosuppressive agents or systemic corticosteroids or procainamide may increase the risk of leukopenia, if used concomitantly with ACE inhibitors.
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 or digoxin.
No clinically significant interaction has been found between trandolaprilat (the active metabolite of Trandolapril) and cimetidine.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.
Interaction studies have only been performed in adults.
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated 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 the 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.
ACE inhibitor therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased, renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see section 5.3). Should exposure to trandolapril have occurred from the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Because no information is available regarding the use of trandolapril during breastfeeding, 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.
Given the pharmacological properties of Odrik, 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.
The listed ADRs have been reported during the clinical phase, the post-marketing surveillance or the phase IV clinical trials
The following convention is used for the frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). When frequency cannot be estimated from the available data, category frequency: Not known (cannot be estimated from the available data) applies.
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.
| MedDRA System Organ Class | Common | Uncommon | Rare | Very rare | Not known |
|---|---|---|---|---|---|
| Infections and infestations | Upper respiratory tract infection | Urinary tract infection, bronchitis, pharyngitis | Sinusitis** Rhinitis** Glossitis** | ||
| Blood and lymphatic system disorders | Leukopenia, anemia, platelet disorder, white blood cell disorder | Agranulocytosis, pancytopenia, platelet count decreased, Hemolytic anemia** Eosinophilia and/or increased ANA (anti-nuclear antibody)** | |||
| Immune system disorders | Hypersensitivity | ||||
| Metabolism and nutrition disorders | Hyperglycemia, hyponatremia, Hypercholesterolemia, hyperlipidemia, hyperuricemia, gout, anorexia, increased appetite, enzyme abnormality | Hyperkalemia | |||
| Psychiatric disorders | Insomnia, libido decreased | Hallucination, depression, sleep disorder, anxiety, agitation, apathy | Confusional state** | ||
| Nervous system disorders | Headache, dizziness | Somnolence | Cerebrovascular accident, syncope, myoclonus, paresthesia, migraine, migraine without aura, dysgeusia | Transient ischemic attack, cerebral hemorrhage, balance disorder, | |
| Eye disorders | Blepharitis, conjunctival edema, visual impairment, eye disorder | Blurred vision** | |||
| Ear and labyrinth disorders | Vertigo | Tinnitus | |||
| Cardiac disorders | Palpitations | Myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, bradycardia | Atrioventricular block, cardiac arrest, arrhythmia | ||
| 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 | Dyspnea, epistaxis, pharyngeal inflammation, oropharyngeal pain, productive cough, respiratory disorder | Bronchospasm | |
| Gastrointestinal disorders | Nausea, diarrhea, gastrointestinal pain, constipation, gastrointestinal disorder | Hematemesis, gastritis, abdominal pain, vomiting, dyspepsia, dry mouth, flatulence | Ileus, pancreatitis, Intestinal angioedema** | ||
| Hepatobiliary disorders | Hepatitis | Cholestasis | Jaundice, liver function test abnormal, transaminases increased | ||
| Skin and subcutaneous tissue disorders | Pruritus, rash | Angioedema, psoriasis, hyperhidrosis, eczema, acne, dry skin, skin disorder | Psoriasis | Alopecia, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, Erythema multiforme** Dermatitis psoriasiform** | |
| 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 | ||||
| Reproductive system and breast disorders | Erectile dysfunction | ||||
| Congenital, familial and genetic disorders | Congenital arterial malformation, ichtyosis | ||||
| General disorders and administration site conditions | Asthenia | Malaise, chest pain, edema peripheral, feeling abnormal | Edema, fatigue | Pyrexia | |
| Investigations | hyperbilirubinemia | Blood Potassium increased | Platelet count decreased, Blood creatinine increased, blood urea increased, hemoglobin decreased, hematocrit decreased, Blood alkaline phosphatase increased, blood lactate dehydrogenase increased, laboratory test abnormal electrocardiogram abnormal, Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatic enzymes increased | ||
| 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).
** Indicates ACEis' class ADR’s
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 professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Website: www.hpra.ie.
Not applicable.
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