Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Blood creatinine increased, blood alkaline phosphatase increased, blood urea increased, blood lactate dehydrogenase increased, electrocardiogram abnormal, hyperkaelemia, hyperuricaemia, laboratory test abnormal, liver function test abnormal, platelet count decreased, transaminases increased. chest pain, fatigue, feeling abnormal, malaise, oedema, oedema peripheral. angina pectoris, bradycardia, cardiac failure, myocardial infarction, myocardial ischaemia, palpitations, tachycardia, ventricular tachycardia. dyspnoea, epistaxis, pharyngeal inflammation, pharyngolaryngeal pain, productive cough, respiratory disorder, upper respiratory tract congestion, upper respiratory tract inflammation. cerebrovascular accident, dysgeusia, migraine, migraine without aura, myoclonus, paresthesia, somnolence, syncope, tremor*.
| Placebo-Controlled Studies | | System Organ Class (SOC) | Trandolapril
(n=693)
% | Placebo
(n=194)
% | | Nervous System Disorders | | Headache | 2.31 | 0.5 | | Gastrointestinal Disorders | | Nausea | 1.15 | 0 | | Active-Controlled and Open-Label Studies | | System Organ Class (SOC) | Trandolapril
(n=1888)
% | | Nervous System Disorders | | Headache | 2.17 | | Dizziness | 1.59 | | Respiratory, Thoracic and Mediastinal Disorders | | Cough | 2.60 | | General Disorders and Administration Site Conditions | | Asthenia | 2.01 |
azotaemia, pollakiuria, polyuria, renal failure. congenital arterial malformation, ichthyosis. acne, angioneurotic oedema, dry skin, eczema, hyperhidrosis, pemphigus*, pruritus, psoriasis, rash, skin disorder. arthralgia, back pain, bone pain, muscle spasms, osteoarthritis, pain in extremity. bronchitis, pharyngitis, upper respiratory tract infection, urinary tract infection. hepatitis, hyperbiliruninaemia.
Adverse Reactions Reported with Trandolapril in Post Myocardial Infarction Patients in the TRACE Study That Occurred at a Frequency ≥1%
| System Organ Class (SOC) | Trandolapril
(n=876)
% | Placebo
(n=873)
% | | Nervous System Disorders | | Dizziness | 1.9 | 1.4 | | Respiratory, Thoracic and Mediastinal Disorders | | Cough | 3.9 | 0.9 | | Vascular Disorders | | Hypotension | 2.1 | 0.6 |
angiopathy, hot flush, hypertension, hypotension, orthostatic hypotension, peripheral vascular disorder, varicose vein. Rare cases of angioedema affecting the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with ACE inhibitor, including trandolapril. A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive anti-nuclear antibody (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur. Rare report of increased appetite has been observed. anorexia, enzyme abnormality, gout, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperuricaemia, hyponatraemia. anaemia, leukopenia, platelet disorder, thrombocytopenia, white blood cell disorder. anaphylactoid reaction*, hypersensitivity. agitation, anxiety, apathy, depression, hallucination, insomnia, libido decreased, sleep disorder. abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, esophagitis*, flatulence, gastritis, gastrointestinal disorder, gastrointestinal pain, haematemesis, nausea, vomiting. Haematocrit decreased, haemoglobin decreased.
Indications and Clinical Usefollowing acute myocardial infarction in clinically stable patients with left ventricular dysfunction, with or without symptoms of heart failure, to improve survival and reduce hospitalizations for heart failure. Sufficient experience in the treatment of patients with severe heart failure (NYHA Class IV) immediately after myocardial infarction is not yet available. The safety and effectiveness of trandolapril in children below the age of 18 have not been established. Therefore use in this age group is not recommended. treatment of patients with mild to moderate essential hypertension. It may be used alone or in association with thiazide diuretics. Trandolapril should normally be used in patients in whom treatment with a diuretic or a beta blocker was found ineffective or has been associated with unacceptable adverse effects. Trandolapril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta blockers are contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects. The safety and efficacy of trandolapril in patients with renovascular hypertension has not been established, therefore its use in these conditions is not recommended. In using trandolapril, consideration should be given to the risk of angioedema (see Warnings and Precautions). Although clinical experience has not identified differences in response between the elderly (≥65 years) and younger patients (<65 years), greater sensitivity of some older individuals cannot be ruled out (see Action and Clinical Pharmacology, Pharmacodynamics).
OverdosageFor management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Limited data are available regarding overdosage of MAVIK (trandolapril) in humans. The most likely clinical manifestation of overdosage of an ACE inhibitor such as trandolapril would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion with normal saline. It is not known if trandolapril or trandolaprilat can be removed from the body by hemodialysis. Dosage Forms, Composition and PackagingEach red opaque body and orange opaque cap, no. 4 gelatin capsule, contains: trandolapril 1 mg. Nonmedicinal ingredients: lactose, maize starch, povidone and sodium stearyl fumarate; capsule cap and body: erythrosine, iron oxides and hydroxides, sodium lauryl sulfate and titanium dioxide. HDPE plastic bottles of 100. Each red opaque body and yellow opaque cap, no. 4 gelatin capsule, contains: trandolapril 0.5 mg. Nonmedicinal ingredients: lactose, maize starch, povidone and sodium stearyl fumarate; capsule cap and body: erythrosine, iron oxides and hydroxides, sodium lauryl sulfate and titanium dioxide. HDPE plastic bottles of 100. Each red opaque body and brown opaque cap, no. 4 gelatin capsule, contains: trandolapril 4 mg. Nonmedicinal ingredients: lactose, maize starch, povidone and sodium stearyl fumarate; capsule cap and body: erythrosine, iron oxides and hydroxides, sodium lauryl sulfate and titanium dioxide. HDPE plastic bottles of 100. Each red opaque body and red opaque cap, no. 4 gelatin capsule, contains: trandolapril 2 mg. Nonmedicinal ingredients: lactose, maize starch, povidone and sodium stearyl fumarate; capsule cap and body: erythrosine, iron oxides and hydroxides, sodium lauryl sulfate and titanium dioxide. HDPE plastic bottles of 100.
Warnings and PrecautionsThe hypotensive effects of certain inhalation anesthetics may be enhanced by ACE inhibitors. In patients undergoing surgery or anesthesia with agents producing hypotension, trandolapril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it may be corrected by volume repletion. Teratology studies in the rat were carried out at doses of 0, 100, 300, or 1000 mg/kg/day. An increased incidence of minor defects (dilation of renal pelvis and ureters) over control values was found at the 1000 mg/kg/day dose series. In fertility studies, where doses of 0, 1, 10 or 100 mg/kg/day were used, the incidence of pelvic cavitation and dilated ureters was increased with the 10 and 100 mg/kg/day dose. Teratology studies were carried out in the rabbit, both with and without electrolyte supplementation. In two studies without supplementation covering the 0.1 to 0.8 mg/kg dose range, maternal deaths were seen at all doses with a dose-related incidence. These were associated with fetal toxicity and increased fetal loss. No teratological effect was seen. Supplementation with electrolytes allowed doses of 2 to 8 mg/kg to be given: maternal toxicity was again seen, particularly at 8 mg/kg, with weight loss and abortion. No teratological effect was seen. Two teratology studies were carried out in the cynomolgus monkey (doses of 0, 10, 50 or 250 mg/kg/day and also 5, 25 or 125 mg/kg/day): dosing was on days 20 to 50 of gestation with examination of the fetuses following caesarean section on day 100. Abortions were 3/10, 6/10, 5/11 and 7/10 at respectively 0, 10, 50 or 250 mg/kg/day and 1/10, 4/10, 4/10 and 7/10 at 0, 5, 25 or 125 mg/kg/day. Apart from one animal with a kinked tail in the group receiving 250 mg/kg/day, no other evidence of teratological effects attributable to treatment were observed. Symptomatic hypotension has occurred after administration of MAVIK (trandolapril), usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume and salt depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Reactions). Because of the potential fall in blood pressure in these patients, therapy with trandolapril should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of trandolapril is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been associated with oliguria, and/or progressive azotemia, and rarely, with acute renal failure and/or death. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which can be given, usually without difficulty, once the blood pressure has increased after volume expansion. However, lower doses of trandolapril and/or reduced concomitant diuretic therapy should be considered. If hypotension develops in patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of trandolapril (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction, and Dosage and Administration, Recommended Dose and Dosage Adjustment, Treatment Following Acute Myocardial Infarction). Angioedema has been reported in patients taking ACE inhibitors, including MAVIK (trandolapril). Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, trandolapril should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see Adverse Reactions). Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications). The incidence of angioedema during ACE inhibition therapy has been reported to be higher in black than in non-black patients. Intestinal angioedema has also been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Although clinical experience has not identified differences in response between the elderly (≥65 years) and younger patients (<65 years), greater sensitivity of some older individuals cannot be ruled out (see Action and Clinical Pharmacology, Pharmacodynamics). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected or if the patient is planning to become pregnant, MAVIK should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following ACE inhibitor exposure in the first trimester of pregnancy. Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. It is not known if trandolapril or trandolaprilat can be removed from the body by hemodialysis. As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk. Use of MAVIK (trandolapril) should include appropriate assessment of renal function. As with other ACE inhibitors, dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of trandolapril, has been reported. Such possibility should be considered as part of the differential diagnosis of cough. Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents. Trandolapril should be used with caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effect should apply. Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug. Elevations of liver enzymes and/or serum bilirubin have been reported with trandolapril (see Adverse Reactions). Should the patient receiving trandolapril experience any unexplained symptoms, particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigations be carried out. Discontinuation of trandolapril should be considered when appropriate. (See Action and Clinical Pharmacology, Pharmacokinetics.) The safety and effectiveness of trandolapril in children below the age of 18 have not been established. Therefore use in this age group is not recommended. Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Current experience with trandolapril shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease. Increases in serum potassium (upper limit of normal range 5.0 mmol/L) were observed in approximately 2.2% of patients in clinical trials treated with trandolapril, in most cases these resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy in any hypertensive patient. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (see Drug Interactions). The presence of concentrations of ACE inhibitor has been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding. If breast-feeding needs to be continued, alternative measures to control the patient's blood pressure need to be put in place. There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators.
Storage and StabilityStore trandolapril between 15 and 25°C in original container. Trandolapril should not be stored beyond the date indicated on the container. Action and Clinical PharmacologyIn patients with moderate to severe impairment of liver function, plasma trandolapril levels were approximately ten times higher than in healthy subjects. The plasma concentrations of trandolaprilat and the quantities excreted in the urine were also increased, although to a lesser degree. The dose should therefore be reduced in these patients. In one study, cirrhotic patients who received a single dose of trandolapril 2 mg exhibited a 9-fold increase in trandolapril Cmax and AUC values. The Cmax and AUC values of trandolaprilat were about doubled. Eighty percent (80%) of the circulating trandolapril and up to 94% of the circulating trandolaprilat are bound to plasma proteins. The protein binding is not saturable for trandolapril but is saturable for trandolaprilat. Following a single oral administration of trandolapril to healthy volunteers, trandolapril was detectable in the plasma 30 minutes later with peak concentrations reached within 1 hour. Trandolaprilat, the active metabolite, reached peak plasma concentrations after approximately 6 hours following trandolapril capsule administration. Plasma concentrations of both trandolapril and trandolaprilat were dose dependent. While food can delay the rate of absorption of trandolapril, there is no clinically significant effect on other pharmacokinetic and pharmacodynamic parameters of trandolaprilat. Approximately 40 to 60% of an administered oral dose of trandolapril is absorbed. MAVIK (trandolapril) is a non-sulphydryl angiotensin converting enzyme (ACE) inhibitor which is used in the treatment of mild to moderate essential hypertension and following acute myocardial infarction in clinically stable patients with left ventricular dysfunction. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pharmacologically active substance, angiotensin II, which is a vasopressor agent. In addition, angiotensin II stimulates aldosterone secretion by the adrenal cortex. Inhibition of angiotensin-converting enzyme results in a decreased plasma angiotensin II level. The resulting lack of negative feedback on renal renin secretion leads to an increased plasma renin activity. Angiotensin-converting enzyme is identical to kininase II. Thus, trandolapril administration may interfere with the degradation of the potent peptide vasodilator bradykinin, which may contribute to the therapeutic activity of trandolapril. Trandolapril is a prodrug, which is hydrolysed to its active diacid form, trandolaprilat, a potent ACE inhibitor. The antihypertensive effect of trandolapril is due to a reduction in peripheral vascular resistance with little or no change in cardiac output and heart rate. The decrease in blood pressure is not accompanied by water or sodium retention. No modification was found in the urinary excretion of chloride and potassium. Administration of trandolapril to patients with essential hypertension results in reduction of both supine and standing blood pressure. Pharmacokinetic differences have not been evaluated in different races. In patients with creatinine clearance ≤30 mL/min/1.73m2, the Cmax and AUC of trandolaprilat were approximately doubled after repeated oral administration, as compared to those of normal subjects. Trandolapril undergoes extensive first-pass metabolism in the liver, and this is the reason for its low bioavailability: 7.5% (ranging from 4 to 14%). In the liver it is transformed into its biologically active diacid form, trandolaprilat. Trandolaprilat itself is poorly absorbed after oral administration. Minor metabolic pathways lead to the formation of diketopiperazine derivatives of trandolapril and trandolaprilat. These molecules have no ACE inhibitory activity. Glucuronide conjugated derivatives of trandolapril and trandolaprilat are also produced.
| Parameters | 0.5 mg | 1 mg | 2 mg | 4 mg | Trandolaprilat
CLr0-96 h (L/h) | 0.15±0.05 | 1.03±0.18 | 2.02±0.25 | 3.93±0.39 |
Administration of trandolapril to patients with mild to moderate essential hypertension results in a reduction of both supine and standing blood pressure usually with little or no orthostatic change or change in heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients who are salt- and/or volume-depleted (see Warnings and Precautions). In mild to moderate hypertensive patients, significant reductions in blood pressure were seen at 2 hours, and peak antihypertensive effects were seen after approximately 8 hours. At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients who responded to trandolapril. Abrupt withdrawal of trandolapril has not resulted in rapid increase in blood pressure. Following single oral therapeutic doses in healthy male volunteers, a rapid onset of ACE inhibition was observed. The peak inhibition was reached between 2 and 4 hours after the initial dose. The effectiveness of trandolapril appears to be similar in the elderly (over 65 years of age) and younger adult patients given the same daily doses. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in non-blacks. The antihypertensive effect of trandolapril and thiazide diuretics used concurrently is greater than that seen with either drug used alone. Trandolapril pharmacokinetics have not been evaluated in patients less than 18 years of age.
ContraindicationsMAVIK (trandolapril) is contraindicated in patients who:
-
are pregnant or planning to become pregnant.
-
are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.
-
have a history of angioedema.
| 