Meprol

Meprol is a cardioselective β1-adrenergic blocking agent used for acute myocardial infarction (MI), heart failure, angina pectoris and mild to moderate hypertension. It may also be used for supraventricular and tachyarrhythmias and prophylaxis for migraine headaches. Meprol is structurally similar to bisoprolol, acebutolol and atenolol in that it has two substituents in the para position of the benzene ring. The β1-selectivity of these agents is thought to be due in part to the large substituents in the para position. At low doses, Meprol selectively blocks cardiac β1-adrenergic receptors with little activity against β2-adrenergic receptors of the lungs and vascular smooth muscle. Receptor selectivity decreases with higher doses. Unlike propranolol and pindolol, Meprol does not exhibit membrane-stabilizing or intrinsic sympathomimetic activity. Membrane-stabilizing effects are only observed at doses much higher than those needed for β-adrenergic blocking activity. Meprol possesses a single chiral centre and is administered as a racemic mixture.

Hypertension

Meprol is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including Meprol.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Meprol may be administered with other antihypertensive agents.

Angina Pectoris

Meprol is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.

Heart Failure

Meprol is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, Meprol decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

Meprol is used alone or together with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. A lower blood pressure can reduce the risk of strokes and heart attacks.

Meprol is also used to treat severe chest pain (angina) and lowers the risk of repeated heart attacks. It is given to people who have already had a heart attack. In addition, Meprol is used to treat patients with heart failure.

Meprol is a beta-blocker. It works by affecting the response to nerve impulses in certain parts of the body, like the heart. As a result, the heart beats slower and decreases the blood pressure. When the blood pressure is lowered, the amount of blood and oxygen is increased to the heart.

Meprol is available only with your doctor's prescription.

Myocardial Infarction

Early Treatment: During the early phase of definite or suspected acute myocardial infarction, initiate treatment with Meprol as soon as possible after the patient's arrival in the hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized.

Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of Meprol each; give the injections at approximately 2-minute intervals. During the intravenous administration of Meprol, monitor blood pressure, heart rate, and electrocardiogram.

In patients who tolerate the full intravenous dose (15 mg), initiate Meprol tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the maintenance dosage is 100 mg orally twice daily.

Start patients who appear not to tolerate the full intravenous dose on Meprol tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance, discontinue Meprol.

Special Populations

Pediatric patients: No pediatric studies have been performed. The safety and efficacy of Meprol in pediatric patients have not been established.

Renal impairment: No dose adjustment of Meprol is required in patients with renal impairment.

Hepatic impairment: Meprol blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, Meprol should be initiated at low doses with cautious gradual dose titration according to clinical response.

Geriatric patients ( > 65 years): In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Method Of Administration

Parenteral administration of Meprol (ampoule) should be done in a setting with intensive monitoring.

Note:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How supplied

Meprol® Injection

Meprol tartrate injection, USP

Ampuls 5 mL - each containing 5 mg of Meprol tartrate

Carton of 10 ampuls

See also:
What is the most important information I should know about Meprol?

You should not use this medication if you are allergic to Meprol, or if you have a serious heart problem such as heart block, sick sinus syndrome, or slow heart rate.

Before taking Meprol, tell your doctor if you have congestive heart failure, low blood pressure, circulation problems, pheochromocytoma, asthma or other breathing problems, diabetes, depression, liver or kidney disease, a thyroid disorder, or severe allergies.

Meprol may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can increase certain side effects of Meprol.

Do not stop taking Meprol without first talking to your doctor. Stopping suddenly may make your condition worse.

If you need surgery, tell the surgeon ahead of time that you are using Meprol.

Meprol is only part of a complete program of treatment for hypertension that may also include diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely if you are being treated for hypertension.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Use Meprol tartrate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Meprol tartrate is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Meprol tartrate at home, a health care provider will teach you how to use it. Be sure you understand how to use Meprol tartrate. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Do not use Meprol tartrate if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Meprol tartrate, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Meprol tartrate.

Use: Labeled Indications

Angina: Long-term treatment of angina pectoris.

Heart failure with reduced ejection fraction (ER oral formulation): Treatment of stable, symptomatic (NYHA class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin to reduce the rate of mortality plus hospitalization in patients already receiving angiotensin-converting enzyme inhibitors, diuretics, and/or digoxin.

Hypertension: Management of hypertension. Note: Beta-blockers are not recommended as first-line therapy (ACC/AHA [Whelton 2017]).

Myocardial infarction: Treatment of hemodynamically stable acute myocardial infarction to reduce cardiovascular mortality (injection to be used in combination with Meprol oral maintenance therapy).

Off Label Uses

Atrial fibrillation/flutter

Based on the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for the management of patients with atrial fibrillation (AF), the use of beta-blockers, including Meprol, for ventricular rate control in patients with paroxysmal, persistent, or permanent AF is effective and recommended.

Atrial fibrillation prevention after cardiac surgery

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for coronary artery bypass graft surgery, beta-blockers are recommended to help prevent postoperative atrial fibrillation.

Hypertrophic cardiomyopathy

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the diagnosis and treatment of hypertrophic cardiomyopathy, a beta blocker (eg, Meprol) is an effective and recommended agent for the treatment of symptoms (eg, angina, dyspnea) in patients with obstructive or nonobstructive hypertrophic cardiomyopathy.

Marfan syndrome with aortic aneurysm

Based on the American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery (ACCF/AHA/AATS) guideline for the diagnosis and management of patients with thoracic aortic disease, a beta blocker (eg, Meprol) is an effective and recommended agent to reduce the rate of aortic dilatation in patients with Marfan syndrome and aortic aneurysm, unless a contraindication exists.

Migraine prophylaxis

Data from small, randomized, active-controlled trials support the use of Meprol for prevention of migraines.

Based on evidence-based guidelines for pharmacologic treatment for episodic migraine prevention in adults from the American Academy of Neurology and the American Headache Society, Meprol is effective for migraine prevention in adults.

Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal atrial tachycardia)

Based on the American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for the management of adult patients with supraventricular tachycardia, the use of an oral or intravenous beta-blocker, including Meprol, is effective and recommended for a variety of symptomatic supraventricular tachycardias (atrioventricular nodal reentrant tachycardia [AVNRT], atrioventricular reentrant tachycardia [AVRT], focal atrial tachycardia [AT], and multifocal atrial tachycardia [MAT]). In patients without pre-excitation, intravenous Meprol is recommended for acute treatment in hemodynamically stable patients and oral Meprol is recommended for ongoing management of symptomatic supraventricular tachycardias in patients who are not candidates for, or prefer not to undergo, catheter ablation.

Intravenous or oral Meprol may be useful for rate control in the acute treatment or ongoing management of hemodynamically stable patients with atrial flutter.

Thyrotoxicosis

Based on the American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis, beta-blockers, including Meprol, are effective and recommended in the treatment of symptomatic thyrotoxicosis. Beta-blockers should also be considered in asymptomatic patients who are at increased risk of complications due to worsening hyperthyroidism.

Ventricular arrhythmias

Based on the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for management of patients with ventricular arrhythmias and prevention of sudden cardiac death, beta-blockers are effective for control of ventricular arrhythmias and ventricular premature beats.

See also:
What other drugs will affect Meprol?

Meprol is a CYP2D6 substrate. Drugs that inhibit CYP2D6 can have an effect on the plasma concentration of Meprol. Examples of drugs that inhibit CYP2D6 are quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenon and diphenhydramine. When treatment with these drugs are initiated, the dose of Meprol might have to be reduced for patients treated with Meprol.

The Following Combinations with Meprol Should be Avoided: Barbituric Acid Derivatives: Barbiturates (investigated for pentobarbital) induce the metabolism of Meprol by enzyme induction.

Propafenone: Upon administration of propafenone to 4 patients on Meprol therapy, the plasma concentrations of Meprol increased by 2-5 fold and 2 patients experienced side effects typical of Meprol. The interaction was confirmed in 8 healthy volunteers. The interaction is probably explained by the fact that propafenone, similarly to quinidine, inhibits the metabolism of Meprol via cytochrome P450 2D6. The combination is probably difficult to handle since propafenone also has beta-receptor blocking properties.

Verapamil: In combination with beta-receptor blocking drugs (described for atenolol, propranolol and pindolol), verapamil may cause bradycardia and fall in blood pressure.

Verapamil and beta-blockers have additive inhibitory effects on AV-conduction and sinusnode function.

The Following Combinations with Meprol may require Modified Drug

Dosage:

Antiarrhythmics, Class I: Class I antiarrhythmics and beta-receptor blocking drugs have additive negative inotropic effects which may result in serious haemodynamic side effects in patients with impaired left ventricular function. The combination should also be avoided in "sick sinus syndrome" and pathological AV-conduction. The interaction is best documented for disopyramide.

Nonsteroidal Anti-Inflammatory/Antirheumatic Drugs (NSAIDs): NSAID-antiphlogistics have been shown to counteract the antihypertensive effect of beta-receptor blocking drugs. Primarily, indomethacin has been studied. This interaction probably does not occur with sulindac. A negative interaction study on diclofenac has been performed.

Diphenhydramine: Diphenhydramine decreases (2.5 times) clearance of Meprol to alpha-hydroximetoprolol via CYP2D6 in fast hydroxylating persons. The effects of Meprol are enhanced. Diphenhydramine may probably inhibit the metabolism of other CYP2D6 substrates.

Digitalis Glycosides: Digitalis glycosides in association with beta-blockers, may increase AV conduction time and may induce bradycardia.

Diltiazem: Diltiazem and beta-receptor blockers have additive inhibitory effects on the AV-conduction and sinusnode function. Pronounced bradycardia has been observed (case reports) during combination treatment with diltiazem.

Epinephrine: There are about 10 reports on patients treated with nonselective beta-receptor blockers (including pindolol and propranolol) that developed pronounced hypertension and bradycardia after administration of epinephrine (adrenaline). These clinical observations have been confirmed in studies in healthy volunteers. It has also been suggested that epinephrine in local anaesthetics may provoke these reactions upon intravasal administration. The risk is probably less with cardioselective beta-receptor blockers.

Phenylpropanolamine: Phenylpropanolamine (norephedrine) in single doses of 50 mg may increase the diastolic blood pressure to pathological values in healthy volunteers. Propranolol generally counteracts the rise in blood pressure induced by phenylpropanolamine. However, beta-receptor blockers may provoke paradoxical hypertensive reactions in patients who take high doses of phenylpropranolamine. Hypertensive crisis during treatment with only phenylpropanolamine have been described in a couple of cases.

Quinidine: Quinidine inhibits the metabolism of Meprol in so-called rapid hydroxylators (>90% in Sweden) with markedly elevated plasma levels and enhanced beta-blockade as a result. A corresponding interaction might occur with other beta-blockers metabolised by the same enzyme (cytochrome P450 2D6).

Clonidine: The hypertensive reaction when clonidine is suddenly withdrawn may be potentiated by beta-blockers. If concomitant treatment with clonidine is to be discontinued, the beta-blocker medication should be withdrawn several days before clonidine.

Rifampicin: Rifampicin may induce the metabolism of Meprol resulting in decreased plasma levels.

Patients receiving concomitant treatment with other beta-blockers (ie, eye drops) or MAO Inhibitors should be kept under close surveillance. In patients receiving beta-receptor blocker therapy, inhalation anaesthetics enhance the cardio-depressant effect. The dosages of oral antidiabetics may have to be readjusted in patients receiving beta-blockers. The plasma concentration of Meprol can increase when cimetidine or hydralazine are administered simultaneously.

See also:
What are the possible side effects of Meprol?

The following adverse reactions are described elsewhere in labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Hypertension and Angina: Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.

Heart Failure: In the MERIT-HF study comparing Meprol succinate in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of Meprol succinate patients discontinued for adverse events vs. 12.2% of placebo patients.

The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the Meprol succinate group and greater than placebo by more than 0.5%, regardless of the assessment of causality.

Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1% in the Meprol Succinate Group and Greater Than Placebo by More Than 0.5%

Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, Meprol succinate 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Meprol succinate use was associated with a higher incidence of bradycardia (6.6% vs. 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs. 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of extended-release Meprol or immediate-release Meprol. 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.

Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.

Respiratory: Wheezing (bronchospasm), dyspnea.

Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia.

Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.

Hypersensitive Reactions: Pruritus.

Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance.

Potential Adverse Reactions: In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Meprol succinate.

Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive Reactions: Laryngospasm, respiratory distress.