Trandolapril is a medication that belongs to a class of drugs known as angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are commonly prescribed to treat various cardiovascular conditions, primarily hypertension (high blood pressure) and heart failure.

Angiotensin-converting enzyme inhibitor trandolapril (Mavik) is used to treat heart failure and hypertension in individuals.

Trandolapril Uses:

• Hypertension
  • Use to manage high blood pressure .
  • Guidelines:
    • In the absence of comorbidities (such as cerebrovascular disease, chronic kidney disease, diabetes, heart failure [HF], ischemic heart disease, etc.), the 2017 Guideline for the Prevention, Detection, Evaluation, and Management of
    • Hypertension in Adults suggests that thiazide-like diuretics or dihydropyridine calcium channel blockers may be preferable options due to improved cardiovascular endpoints (eg, prevention of HF and stroke).
    • ARBs and ACE inhibitors are also suitable for monotherapy.
    • Combination therapy is initially favoured in patients at high risk (stage 2 hypertension or atherosclerotic cardiovascular disease [ASCVD] risk 10%) and may be necessary to reach blood pressure objectives.
• Post-myocardial infarction (MI) heart failure dysfunction:
  • Treatment of post-myocardial infarction left ventricular dysfunction in stable patients who have signs of left ventricular systolic dysfunction or post-myocardial infarction heart failure in patients who experience symptoms of the condition within a few days of suffering an acute myocardial infarction (identified by wall motion abnormalities)
• Off Label Use in Adults:
  • Non–ST-elevation acute coronary syndrome
  • ST-elevation acute coronary syndrome
  • Stable coronary artery disease
  • Heart failure

Trandolapril (Mavik) Dose in Adults

Treatment of Hypertension:

• Start with a small dose of 1 milligram (1 mg) once a day.
• If needed, your doctor may increase the dose gradually, but not more than 4 mg once a day.
• They'll check how you respond to the medicine and adjust the dose based on that.
• It's rare for people to take more than 8 mg in a day because there isn't much experience with higher doses.

Trandolapril (Mavik) Dose in the treatment of Post-MI heart failure or LV dysfunction:

• Start with a small dose of 1 milligram (1 mg) once a day.
• If you can tolerate it well, your doctor may gradually increase the dose towards a target dose of 4 mg once a day.
• However, if the 4 mg dose causes problems or is not well-tolerated, you can still continue with the highest dose that you can handle without side effects.

In some cases, doctors may recommend starting with an even smaller dose of 0.5 mg and then gradually increasing it up to 4 mg a day, depending on how well you can tolerate it.

So, the goal is to find the right dose that works for you and helps your heart condition while minimizing any side effects.

Treatment of Heart failure with reduced ejection fraction:

• Start with a small dose of 1 milligram (1 mg) taken orally once a day.
• The goal is to work up to a target dose of 4 milligrams (4 mg) once a day.

This means that you begin with a low dose and gradually increase it to reach the desired dose of 4 mg daily, as recommended by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) guidelines.

Use in Children:

Not indicated.

Pregnancy Risk Factor D

[US Boxed Warning]

• Drugs that act on the renin-angiotensin system can be harmful to a developing fetus and may lead to injury or death.
• If pregnancy is detected, these drugs should be discontinued as soon as possible.
• The use of these drugs during pregnancy is associated with a condition called oligohydramnios, which can harm the fetus by causing decreased fetal renal function, leading to fetal lung hypoplasia and skeletal malformations.
• Adverse effects in fetuses and neonates can include anuria (lack of urine production), hypotension, renal failure, skull hypoplasia, and even death.
• Teratogenic effects (birth defects) may occur if an ACE inhibitor is taken during the first trimester of pregnancy.
• It's important to note that adverse fetal events can occur even with exposure later in pregnancy, so ACE inhibitor use is generally not recommended during pregnancy.
• Infants exposed to ACE inhibitors in the womb should be monitored for specific health issues like hyperkalemia (elevated blood potassium levels), hypotension, and reduced urine output.
• Oligohydramnios may not become apparent until after irreversible harm has been done to the fetus.
• In some cases, exchange transfusions or dialysis may be necessary to address hypotension or improve kidney function in affected neonates.
• ACE inhibitors are not recommended for treating uncomplicated hypertension during pregnancy, and they may be contraindicated for hypertension and chronic heart failure during pregnancy according to certain guidelines.
• In general, ACE inhibitors should be avoided in women of reproductive age. If hypertension or chronic heart failure treatment is necessary during pregnancy, alternative medications should be considered.

These warnings emphasize the potential risks of using ACE inhibitors in pregnant women and the importance of careful consideration and monitoring if such medications are prescribed during pregnancy.

Trandolapril use during breastfeeding:

• Trandolapril's presence in breast milk is not well-established, and the manufacturer does not recommend breastfeeding while taking this medication.
• This caution is because medications can sometimes pass into breast milk and potentially affect the nursing infant.

Trandolapril (Mavik) Dose in Kidney Disease:

For patients with Creatinine Clearance (CrCl) ≥30 mL/minute:

• There are no dosage adjustments provided in the manufacturer's labeling, meaning the standard dose can be used.

For patients with CrCl <30 mL/minute according to the manufacturer's labeling:

• Start with a lower initial dose of 0.5 mg once daily.
• Gradually increase the dose as tolerated until you achieve the optimal response.

Alternate dosing guidelines (Aronoff 2007) based on initial doses of 1 to 2 mg/day in individuals with normal renal function:

• If your Glomerular Filtration Rate (GFR) is >50 mL/minute, no dosage adjustment is necessary.
• If your GFR is between 10 to 50 mL/minute, you should receive 50% to 100% of the standard dose.
• If your GFR is <10 mL/minute, you should receive 50% of the standard dose.

These guidelines take into account the level of kidney function to ensure that trandolapril is dosed appropriately for each individual's renal status.

Trandolapril (Mavik) Dose in Liver disease:

Mild to severe hepatic impairment:

• The manufacturer's labeling does not provide specific dosage adjustments for hepatic impairment.
• However, it suggests considering lower doses in patients with hepatic impairment.

For individuals with cirrhosis (a severe form of liver disease):

• The recommended initial dose is 0.5 mg taken orally once daily.
• Gradually increase the dose as tolerated until you achieve the optimal therapeutic response.

Data from trials on hypertension and heart failure are included in the frequency ranges. Patients with heart failure have often been found to experience higher rates of adverse effects. In this demographic, however, there are also more harmful effects linked to placebos.

Common Side Effects of Trandolapril (Mavik):

• Cardiovascular:
  • Hypotension
• Central nervous system:
  • Dizziness
• Endocrine & metabolic:
  • Increased uric acid
• Respiratory:
  • Cough

Less Common Side Effects of Trandolapril (Mavik):

• Cardiovascular:
  • Syncope
  • Bradycardia
  • Cardiogenic Shock
  • Intermittent Claudication
  • Cerebrovascular Accident
• Endocrine & Metabolic:
  • Hyperkalemia
  • Hypocalcemia
• Gastrointestinal:
  • Gastritis
  • Diarrhea
• Neuromuscular & Skeletal:
  • Myalgia
  • Weakness
• Renal:
  • Increased Serum Creatinine
  • Increased Blood Urea Nitrogen

Contraindications to Trandolapril (Mavik):

Do not use trandolapril if:

• You are allergic to trandolapril or any part of the medication.
• You are taking aliskiren and have diabetes.
• You have a condition called hereditary or idiopathic angioedema.
• You've had angioedema (swelling of the deeper layers of the skin) due to a previous ACE inhibitor.
• You are taking or have recently taken a neprilysin inhibitor (like sacubitril) or have switched to or from it within the last 36 hours.

Important notes:

• There is limited information about allergic reactions to ACE inhibitors like trandolapril, so it's possible that if you're allergic to one, you might react to others.
• In Canada, there are some additional contraindications, which are not listed in the US labeling. These include:
  • Hypersensitivity to other ACE inhibitors.
  • Pregnancy, plans to become pregnant, or women who can get pregnant and are not using proper birth control methods.
  • Breastfeeding.
  • Low blood pressure or unstable circulation problems.
  • Significant narrowing of arteries, especially in the kidneys or if you only have one functioning kidney.
  • Use with certain medications like sacubitril/valsartan, other ACE inhibitors, angiotensin receptor blockers (ARBs), or aliskiren in specific situations.
  • Some hereditary conditions like galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Warnings and precautions

Angioedema

• While taking ACE inhibitors like trandolapril, there's a rare but serious risk of angioedema, which can cause swelling of the head, neck (possibly affecting breathing), or the intestines (causing abdominal pain).
• African Americans and those with hereditary or unexplained angioedema may be at higher risk.
• This risk can also increase if you're using medications like everolimus or sacubitril.
• If severe swelling affects the tongue, throat, or voice box, it can block the airway, especially if you've had airway surgery before.
• It's crucial to monitor for these symptoms and seek prompt medical attention if they occur.
• If you've had angioedema from ACE inhibitors in the past, you should not use trandolapril.

Cholestatic jaundice

• In rare cases, ACE inhibitors like trandolapril can lead to a condition called cholestatic jaundice, which affects the liver and causes yellowing of the skin and eyes.
• In severe cases, this can progress to a very serious condition called fulminant hepatic necrosis, which can be fatal.
• If you experience a significant increase in liver enzymes in your blood or develop jaundice (yellowing of the skin or eyes), you should stop taking trandolapril immediately and seek medical attention.
• This is a rare but potentially severe side effect that needs prompt attention.

Cough:

• Some people taking ACE inhibitors like trandolapril may develop a persistent dry cough, typically within the first few months of starting the medication.
• This cough is usually nonproductive, meaning it doesn't bring up mucus.
• If you experience this cough, it's essential to consider other potential causes (like heart failure-related lung congestion) and rule them out before discontinuing the ACE inhibitor.
• However, if the cough is indeed due to the medication, it should generally go away within 1 to 4 weeks after you stop taking it.

Hematologic effects

• There's a potential concern with ACE inhibitors like trandolapril regarding their effects on blood cells.
• In particular, another ACE inhibitor called captopril has been linked to rare but serious conditions like neutropenia (a low white blood cell count) with myeloid hypoplasia and agranulocytosis (severe reduction in a type of white blood cell), as well as anemia (low red blood cell count) and thrombocytopenia (low platelet count).
• People with kidney problems are at a higher risk of developing neutropenia, and those with both kidney issues and collagen vascular diseases like systemic lupus erythematosus are at an even higher risk.
• To monitor for these potential complications, it's important to periodically check a complete blood count (CBC) with a differential count in patients with these risk factors.

Hyperkalemia:

• While taking ACE inhibitors like trandolapril, it's possible to develop high levels of potassium in your blood, a condition known as hyperkalemia.
• Several factors increase the risk of hyperkalemia, including kidney problems, diabetes, and the concurrent use of potassium-sparing diuretics, potassium supplements, or foods high in potassium.

Hypersensitivity reactions

• Hypersensitivity reactions, including anaphylactic or anaphylactoid reactions, can sometimes occur with ACE inhibitors like trandolapril.
• These reactions can be severe and may even occur during certain medical procedures like hemodialysis with specific dialysis membranes or low-density lipoprotein apheresis with dextran sulfate cellulose.
• In rare cases, anaphylactoid reactions have been reported in patients receiving treatment for sensitization to bee or wasp venom while taking ACE inhibitors.
• If you experience symptoms of a severe allergic reaction, such as difficulty breathing, swelling of the face or throat, or a rapid heart rate, seek immediate medical attention.

Hypotension/syncope

• Symptomatic low blood pressure (hypotension) with or without fainting (syncope) can sometimes happen when you start taking ACE inhibitors like trandolapril, especially with the first few doses.
• This is more likely in patients who have lower blood volume, so it's crucial to correct any dehydration before starting the medication.
• Close monitoring is essential, especially when you first start taking it or when your dose is increased.

Renal function deterioration:

• ACE inhibitors like trandolapril can sometimes lead to a decline in kidney function, causing an increase in blood urea nitrogen (BUN) and serum creatinine levels.
• This effect is more likely to occur in patients with conditions that reduce blood flow to the kidneys, such as renal artery stenosis or heart failure, especially when the kidneys depend on angiotensin II for their filtration rate.
• As a result, kidney function may worsen, leading to symptoms like reduced urine output, acute kidney failure, and increasing levels of waste products in the blood (azotemia).
• In some cases, there may be a small, non-concerning increase in serum creatinine when you first start the medication.
• However, discontinuation of the ACE inhibitor should only be considered in patients with significant and progressive deterioration in kidney function.

Aortic stenosis

• In patients with a condition called aortic stenosis, the use of ACE inhibitors like trandolapril should be approached with caution.
• This is because ACE inhibitors can reduce coronary perfusion, potentially leading to inadequate blood supply to the heart muscle, which can result in ischemia (lack of oxygen to the heart).

Ascites:

• Trandolapril should be avoided in patients with ascites caused by cirrhosis or refractory ascites (ascites that doesn't respond to treatment).
• If, in rare cases, its use cannot be avoided in patients with cirrhotic ascites, close monitoring of blood pressure and kidney function is crucial to prevent the rapid development of renal failure.

Cardiovascular disease

• When starting treatment with trandolapril in patients with ischemic heart disease or cerebrovascular disease, it's essential to closely monitor these individuals because of the potential risks associated with lowering blood pressure.
• A significant drop in blood pressure can have serious consequences like heart attacks (MI) or strokes.
• If a patient experiences low blood pressure, fluid replacement may be necessary to restore their blood pressure to a safe level, and then the therapy can be resumed.
• However, if hypotension (low blood pressure) recurs or becomes problematic, it may be necessary to discontinue the medication.
• Close observation and careful management are essential in these cases to balance the benefits of the medication with the risk of low blood pressure-related complications.

Collagen vascular disease:

• In patients with collagen vascular disease, especially if they also have kidney problems, the use of trandolapril should be approached with caution.
• This caution is due to the potential increased risk of experiencing hematologic toxicity (adverse effects on blood cells).

Hepatic impairment

• For individuals with hepatic (liver) impairment, trandolapril should be used cautiously.
• If you have cirrhosis or any form of hepatic impairment, your healthcare provider may recommend adjusting the dosage of trandolapril.
• In some cases, lower doses may be necessary to ensure the medication's safety and effectiveness.

Hypertrophic cardiomyopathy with outflow tract obstruction (HCM)

• In patients with hypertrophic cardiomyopathy (HCM) and outflow tract obstruction, the use of trandolapril should be approached with caution.
• Trandolapril, as an ACE inhibitor, can reduce the heart's afterload, which is the resistance the heart has to overcome when pumping blood out of the left ventricle.
• In some cases, this reduction in afterload can worsen symptoms associated with HCM, particularly in patients with outflow tract obstruction.

Renal artery stenosis

• In patients with unstented unilateral (one-sided) or bilateral (both sides) renal artery stenosis (narrowing of the arteries that supply the kidneys with blood), the use of trandolapril should be approached with caution.
• When bilateral renal artery stenosis is present and not treated with stents, trandolapril use is typically avoided because it carries an increased risk of worsening kidney function.
• However, in some cases, the potential benefits of using the medication may outweigh the risks.

Renal impairment

• Trandolapril should be used with caution in individuals with renal impairment, especially those with a Creatinine Clearance (CrCl) less than 30 mL/minute.
• In such cases, a dosage adjustment is typically recommended to ensure the medication's safety and effectiveness.
• It's important to avoid rapidly increasing the dosage, as this can potentially worsen renal impairment.

Trandolapril: Drug Interaction

Monitoring parameters:

For Patients with Blood Pressure Issues:

• Regularly monitor blood pressure.
• Check BUN (Blood Urea Nitrogen), serum creatinine, and electrolyte levels.
• For those with collagen vascular disease and/or kidney problems, also periodically monitor CBC (Complete Blood Count) with a differential count.

For Patients with Heart Failure:

• Within 1 to 2 weeks after starting treatment, and at times afterward, assess renal function and serum potassium levels.
• Especially important for those with preexisting hypotension, low sodium levels, diabetes, kidney issues, or those taking potassium supplements.

For Patients with Hypertension:

• Follow the 2017 Guidelines for Hypertension Management:
  • If you have confirmed hypertension and known cardiovascular disease (CVD) or a high 10-year risk of CVD, aim for a blood pressure target of less than 130/80 mm Hg.
  • If you have confirmed hypertension without markers of increased CVD risk, a target blood pressure of less than 130/80 mm Hg may be reasonable.

For Patients with Diabetes and Hypertension:

• Follow guidelines from the American Diabetes Association (ADA):
  • If you're 18 to 65 years old, without CVD and have a low 10-year CVD risk, aim for a blood pressure target of less than 140/90 mm Hg.
  • If you're 18 to 65 years old and have known CVD or a high 10-year CVD risk, a target blood pressure of less than 130/80 mm Hg may be appropriate if it's safe for you.
  • If you're over 65 years old and generally healthy or have intermediate health, aim for a blood pressure target of less than 140/90 mm Hg.
  • If you're over 65 years old and have complex or poor health, aim for a blood pressure target of less than 150/90 mm Hg.

These monitoring guidelines help ensure that patients with different medical conditions receive appropriate care and medication adjustments based on their specific needs and risk factors.

How to administer Trandolapril (Mavik)?

• Can be administered with no regard to meals. To avoid first-dose hypotension, the patient must be asked to remain seated for 30 minutes after the first dose.

Mechanism of action of Trandolapril (Mavik):

• Trandolapril needs to go through a process called enzymatic hydrolysis, primarily in the liver, to become its active form, called trandolaprilat, which has the desired effects in the body.
• It's believed that the medication's ability to lower blood pressure might also involve a mechanism in the central nervous system (CNS), where angiotensin II increases the release of certain nerve signals.
• Additionally, ACE inhibitors like trandolapril may reduce the activity of specific enzymes that play a role in regulating blood pressure, contributing to their blood pressure-lowering effects.

Absorption:

• Taking trandolapril with food slows down its absorption in the body.

Distribution:

• Trandolapril has a distribution volume of about 18 liters in the body.

Protein Binding:

• Trandolapril is about 80% bound to proteins in the blood.
• Trandolaprilat, its active form, is bound to proteins at a rate of 65% to 94%, depending on its concentration in the blood.

Metabolism:

• The liver processes trandolapril, turning it into its active form, trandolaprilat, as well as at least seven other metabolites.

Bioavailability:

• Only about 10% of the trandolapril you take is available in your bloodstream.
• Trandolaprilat, the active form, has a bioavailability of around 70%.

Elimination:

• Trandolapril has an elimination half-life of approximately 6 hours.
• Trandolaprilat, the effective form, has a half-life of about 22.5 hours.
• Trandolapril peaks in your bloodstream around 1 hour after you take it, while trandolaprilat peaks between 4 to 10 hours later.

Excretion:

• Your body gets rid of trandolapril and trandolaprilat mainly through your urine (about 33%) and, to a lesser extent, in your feces (about 66%).
• The rate at which your kidneys clear the drug depends on the dose you've taken and is reduced in people with kidney problems.

International Brand Names of Trandolapril:

• Mavik
• AURO-Trandolapril
• Odrik
• PMS-Trandolapril
• SANDOZ Trandolapril
• TEVA-Trandolapril
• Actapril
• Dolapril
• Gopten
• Larineo
• Mavik
• Nortensin
• Odace
• Odrik
• Tranalpha
• Trandoged
• Udrik

Trandolapril Brand Names in Pakistan: