Side Effects of Mavik (trandolapril)

Mavik (trandolapril) is an angiotensin converting enzyme (ACE) inhibitor used to treat high blood pressure. 

Blood pressure is dependent on the degree of narrowing of the arteries and veins; the narrower the arteries and veins, the higher the blood pressure. Angiotensin II is a chemical substance made in the body that causes the muscles in the walls of arteries and veins to contract, narrowing the arteries and veins and thereby elevating blood pressure. Angiotensin II is formed by ACE. 

Mavik is an inhibitor of ACE and blocks the formation of angiotensin II thereby lowering blood pressure. The drop in blood pressure also means the heart doesn't have to work as hard because the pressure it must pump blood against is less. The efficiency of a failing heart improves, and the output of blood from the heart increases. Thus, ACE inhibitors such as Mavik in addition to high blood pressure, are also useful in treating heart failure. 

Common side effects of Mavik include:

• headache,
• cough,
• dizziness,
• diarrhea,
• fatigue,
• nausea,
• vomiting,
• sexual dysfunction, and
• abnormal liver tests.

Serious side effects of Mavik include:

• impaired kidney function (especially in patients with severe heart failure or pre-existing kidney disease),
• low white blood cell counts and increased risk of infection (rare), and
• hypersensitivity reactions and angioedema (swelling of face, lips, tongue, throat).

Drug interactions of Mavik include diuretics, which when taken with Mavik can cause an excessive drop in blood pressure, causing symptoms of weakness, dizziness, and lightheadedness. 

Combining Mavik with potassium supplements, potassium containing salt substitutes, or potassium-conserving diuretics can lead to dangerously high blood levels of potassium. 

Mavik taken at the same time as aluminum- or magnesium-based antacids decreases its absorption into the body. 

Mavik can cause an increase in the amount of lithium in the body and increase the effects of lithium toxicity. 

Nitritoid reactions (with symptoms of facial flushing, nausea, vomiting, and low blood pressure) may occur when injectable gold is combined with Mavik. 

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the effects of Mavik. 

ACE inhibitors, including Mavik, can be harmful to a fetus and should not be taken by pregnant women. Mavik is secreted in breast milk and is not recommended for breastfeeding mothers.

Trandolapril is generally well tolerated. The most common side effects are:

• headache,
• cough,
• dizziness,
• diarrhea,
• fatigue,
• nausea,
• vomiting,
• sexual dysfunction, and
• abnormal liver tests.

Impairment of kidney function has been reported with ACE inhibitors, especially in patients with severe heart failure or pre-existing kidney disease. In rare instances, low white blood cell counts have been reported with the use of trandolapril. Low white blood cells increase the risk of infections. Trandolapril may cause hypersensitivity reactions and angioedema (swelling of face, lips, tongue, throat).

The safety experience in U.S. placebo-controlled trials included 1069 hypertensive patients, of whom 832 received Mavik. Nearly 200 hypertensive patients received Mavik for over one year in open-label trials. In controlled trials, withdrawals for adverse events were 2.1% on placebo and 1.4% on Mavik. Adverse events considered at least possibly related to treatment occurring in 1% of Mavik-treated patients and more common on Mavik than placebo, pooled for all doses, are shown below, together with the frequency of discontinuation of treatment because of these events.

ADVERSE EVENTS IN PLACEBO-CONTROLLED HYPERTENSION TRIALS

Headache and fatigue were all seen in more than 1% of Mavik-treated patients but were more frequently seen on placebo. Adverse events were not usually persistent or difficult to manage.

Left Ventricular Dysfunction Post Myocardial Infarction

Adverse reactions related to Mavik occurring at a rate greater than that observed in placebo-treated patients with left ventricular dysfunction, are shown below. The incidences represent the experiences from the TRACE study. The follow-up time was between 24 and 50 months for this study.

Percentage of Patients with Adverse Events Greater Than Placebo

Clinical adverse experiences possibly or probably related or of uncertain relationship to therapy occurring in 0.3% to 1.0% (except as noted) of the patients treated with Mavik (with or without concomitant calcium ion antagonist or diuretic) in controlled or uncontrolled trials (N=1134) and less frequent, clinically significant events seen in clinical trials or post-marketing experience include (listed by body system):

General Body Function

Chest pain.

Cardiovascular

AV first degree block, bradycardia, edema, flushing, and palpitations.

Central Nervous System

Drowsiness, insomnia, paresthesia, vertigo.

Dermatologic

Pruritus, rash, pemphigus.

Eye, Ear, Nose, Throat

Epistaxis, throat inflammation, upper respiratory tract infection.

Emotional, Mental, Sexual States

Anxiety, impotence, decreased libido.

Gastrointestinal

Abdominal distention, abdominal pain/cramps, constipation, dyspepsia, diarrhea, vomiting, nausea.

Hemopoietic

Decreased leukocytes, decreased neutrophils.

Metabolism And Endocrine

Increased liver enzymes including SGPT (ALT).

Musculoskeletal System

Extremity pain, muscle cramps, gout.

Pulmonary

Dyspnea.

Postmarketing

The following adverse reactions were identified during post approval use of Mavik. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General Body Function

Malaise, fever.

Cardiovascular

Myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, ventricular tachycardia, tachycardia, transient ischemic attack, arrhythmia.

Central Nervous System

Cerebral hemorrhage.

Dermatologic

Alopecia, sweating, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Emotional, Mental, Sexual States

Hallucination, depression.

Gastrointestinal

Dry mouth, pancreatitis, jaundice and hepatitis.

Hemopoietic

Agranulocytosis, pancytopenia.

Metabolism And Endocrine

Increased SGOT (AST).

Pulmonary

Bronchitis.

Renal And Urinary

Renal failure.

Clinical Laboratory Test Findings

Hematology

Thrombocytopenia.

Serum Electrolytes

Hyponatremia.

Creatinine And Blood Urea Nitrogen

Increases in creatinine levels occurred in 1.1% of patients receiving Mavik alone and 7.3% of patients treated with Mavik, a calcium ion antagonist and a diuretic. Increases in blood urea nitrogen levels occurred in 0.6% of patients receiving Mavik alone and 1.4% of patients receiving Mavik, a calcium ion antagonist, and a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis.

Liver Function Tests

Occasional elevation of transaminases at the rate of 3X upper normals occurred in 0.8% of patients and persistent increase in bilirubin occurred in 0.2% of patients. Discontinuation for elevated liver enzymes occurred in 0.2% of patients.

Other

Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.

Dual Blockade Of The Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Mavik and other agents that affect the RAS.

Do not co-administer aliskiren with Mavik in patients with diabetes. Avoid use of aliskiren with Mavik in patients with renal impairment (GFR <60 ml/min).

Concomitant Diuretic Therapy

As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may experience an excessive reduction of blood pressure after initiation of therapy with Mavik. The possibility of exacerbation of hypotensive effects with Mavik may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Mavik. If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced.

Agents Increasing Serum Potassium

Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium.

Antidiabetic Agents

Concomitant use of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia.

Lithium

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.

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 including Mavik.

Mammalian Target of Rapamycin (mTOR) Inhibitors

Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Neprilysin Inhibitor

Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema.

Other

No clinically significant pharmacokinetic interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide.

The anticoagulant effect of warfarin was not significantly changed by trandolapril.

The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m²/day) or rats dosed up to 8 mg/kg/day (60 mg/m²/day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surfacearea, respectively assuming a 50 kg individual.

The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays.

Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m²/day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.

Nursing Mothers

Radiolabeled trandolapril or its metabolites are secreted in rat milk. Mavik should not be administered to nursing mothers.

Geriatric Use

In placebo-controlled studies of Mavik, 31.1% of patients were 60 years and older, 20.1% were 65 years and older, and 2.3% were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients. (Greater sensitivity of some older individual patients cannot be ruled out).

Pediatric Use

Neonates With A History Of In Utero Exposure To Mavik

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The safety and effectiveness of Mavik in pediatric patients have not been established.