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Medically reviewed by Oliinyk Elizabeth Ivanovna, PharmD. Last updated on 16.05.2022
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Symptomatic Treatment of Chronic Stable Angina Pectoris: Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥70 bpm. Ivabradine is indicated: In adults unable to tolerate or with a contra-indication to the use of beta-blockers; or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose.
Treatment of Chronic Heart Failure: Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated..
An indication is a term used for the list of condition or symptom or illness for which the medicine is prescribed or used by the patient. For example, acetaminophen or paracetamol is used for fever by the patient, or the doctor prescribes it for a headache or body pains. Now fever, headache and body pains are the indications of paracetamol. A patient should be aware of the indications of medications used for common conditions because they can be taken over the counter in the pharmacy meaning without prescription by the Physician.Hypertension
Metoprolol 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 metoprolol.
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.
Metoprolol may be administered with other antihypertensive agents.
Angina Pectoris
Metoprolol is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.
Heart Failure
Metoprolol 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, Metoprolol decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.
Ivabradine works by affecting your heart's electrical activity in order to slow the heart rate.
Ivabradine is used in certain people with chronic heart failure, to help lower the risk of needing to be hospitalized when symptoms get worse. Ivabradine is not for use if you already have heart failure symptoms that recently got worse before starting this medicine.
Ivabradine may also be used for purposes not listed in this medication guide.
Metoprolol 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.
Metoprolol 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, metoprolol is used to treat patients with heart failure.
metoprolol 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.
metoprolol is available only with your doctor's prescription.
The recommended starting dose of Ivabradine is 5 mg twice daily with meals. Assess patient after two weeks and adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm) as shown in Table 1. Thereafter, adjust dose as needed based on resting heart rate and tolerability. The maximum dose is 7.5 mg twice daily.
In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose based on heart rate.
Table 1: Dose Adjustment
Heart Rate | Dose Adjustment |
> 60 bpm | Increase dose by 2.5 mg (given twice daily) up to a maximum dose of 7.5 mg twice daily |
50-60 bpm | Maintain dose |
< 50 bpm or signs and symptoms of bradycardia | Decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg twice daily, discontinue therapy* |
* |
How supplied
Dosage Forms And Strengths
Ivabradine 5 mg: salmon-colored, oval-shaped, film-coated tablet, scored on both edges, debossed with “5” on one face and bisected on the other face. The tablet is scored and can be divided into equal halves to provide a 2.5 mg dose.
Ivabradine 7.5 mg: salmon-colored, triangular-shaped, film-coated tablet debossed with “7.5” on one face and plain on the other face.
Storage And Handling
Ivabradine 5 mg tablets are formulated as salmon-colored, oval-shaped, film-coated tablets scored on both edges, marked with “5” on one face and bisected on the other face. They are supplied as follows:
Bottles of 60 tablets (NDC 55513-800-60)
Bottles of 180 tablets (NDC 55513-800-80)
Ivabradine 7.5 mg tablets are formulated as salmon-colored, triangular-shaped, film-coated tablets debossed with “7.5” on one face and plain on the other face. They are supplied as follows:
Bottles of 60 tablets (NDC 55513-810-60)
Bottles of 180 tablets (NDC 55513-810-80)
Storage
Store at 25°C (77°F); excursions permitted to 15° -30°C (59° -86°F).
Manufactured for: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799. Issued: 04/2015
Myocardial Infarction
Early Treatment: During the early phase of definite or suspected acute myocardial infarction, initiate treatment with Metoprolol 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 Metoprolol each; give the injections at approximately 2-minute intervals. During the intravenous administration of Metoprolol, monitor blood pressure, heart rate, and electrocardiogram.
In patients who tolerate the full intravenous dose (15 mg), initiate Metoprolol 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 Metoprolol 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 Metoprolol.
Special Populations
Pediatric patients: No pediatric studies have been performed. The safety and efficacy of Metoprolol in pediatric patients have not been established.
Renal impairment: No dose adjustment of Metoprolol is required in patients with renal impairment.
Hepatic impairment: Metoprolol blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, Metoprolol 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 Metoprolol (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
Metoprolol® Injection
Metoprolol injection, USP
Ampuls 5 mL - each containing 5 mg of Metoprolol
Carton of 10 ampuls
See also:
What is the most important information I should know about Ivabradine?
Hypersensitivity to ivabradine or to any excipients of Ivabradine.
Resting heart rate of <60 bpm prior to treatment; cardiogenic shock; acute myocardial infarction; severe hypotension (<90/50 mmHg); severe hepatic insufficiency; sick sinus syndrome; sino-atrial block; unstable or acute heart failure; pacemaker-dependent; unstable angina; AV-block of 3rd degree.
Combination with strong cytochrome P-450 3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone.
Use in pregnancy: Women of childbearing potential should use appropriate contraceptive measures during treatment.
There are no or limited amount of data from the use of ivabradine in pregnant women. Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects. The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.
Use in lactation: Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during breastfeeding. Women who need treatment with ivabradine should stop breastfeeding, and choose another way of feeding their child.
See also:
What is the most important information I should know about Metoprolol?
You should not use this medication if you are allergic to metoprolol, or if you have a serious heart problem such as heart block, sick sinus syndrome, or slow heart rate.
Before taking metoprolol, 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.
Metoprolol 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 metoprolol.
Do not stop taking metoprolol 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 metoprolol.
Metoprolol 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 ivabradine as directed by your doctor. Check the label on the medicine for exact dosing instructions.
- Ivabradine comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get ivabradine refilled.
- Take ivabradine by mouth with meals.
- Take as you have been told, even if you feel well.
- To gain the most benefit, do not miss doses.
- If you miss a dose of ivabradine, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.
Ask your health care provider any questions you may have about how to use ivabradine.
Use Metoprolol as directed by your doctor. Check the label on the medicine for exact dosing instructions.
- Metoprolol is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Metoprolol at home, a health care provider will teach you how to use it. Be sure you understand how to use Metoprolol. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
- Do not use Metoprolol 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 Metoprolol, 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 Metoprolol.
There are specific as well as general uses of a drug or medicine. A medicine can be used to prevent a disease, treat a disease over a period or cure a disease. It can also be used to treat the particular symptom of the disease. The drug use depends on the form the patient takes it. It may be more useful in injection form or sometimes in tablet form. The drug can be used for a single troubling symptom or a life-threatening condition. While some medications can be stopped after few days, some drugs need to be continued for prolonged period to get the benefit from it.Use: Labeled Indications
Heart failure: To reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic (NYHA class II to III according to the ACC/AHA/HFSA heart failure guidelines [Yancy 2016]) chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute (bpm) and either are on maximally tolerated doses of beta blockers or have a contraindication to beta-blocker use.
Off Label Uses
Inappropriate sinus tachycardia
Data from a small, prospective, randomized, placebo-controlled, crossover trial demonstrated that ivabradine significantly reduced daytime heart rate and improved exercise tolerance and symptoms in patients with inappropriate sinus tachycardia (IST). Additional data may be necessary to further define the role of ivabradine in this condition.
Based on the American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines for the management of patients with supraventricular arrhythmias, ivabradine may be a reasonable treatment option for ongoing management of symptomatic IST.
Stable angina
A multicenter, placebo-controlled trial evaluating the addition of ivabradine to current stable angina therapy demonstrated no significant differences in the incidence of primary end points (composite of death from cardiovascular events or nonfatal myocardial infarction) or incidence of primary end point components. In a single-center, placebo-controlled trial, ivabradine in combination with atenolol significantly improved total exercise endurance compared with atenolol alone in patients with stable angina. The long-term clinical and cost effectiveness of adding ivabradine to beta-blocker or calcium channel blocker therapy is unknown.
According to European and UK guidelines, ivabradine is recommended as second-line therapy (or as first-line therapy in select patients) for treatment of adults with chronic stable angina. Ivabradine is approved in Europe for symptomatic treatment of patients with chronic stable angina, normal sinus rhythm, and a heart rate of at least 70 bpm, specifically as monotherapy in cases unresponsive to or intolerant of beta-blockers, or as add-on therapy in cases uncontrolled by beta-blockers alone. US guidelines provide pharmacology and evidence for ivabradine; however, because ivabradine was not approved in the United States when the guidelines were published, no specific recommendation was made regarding its use.
There are specific as well as general uses of a drug or medicine. A medicine can be used to prevent a disease, treat a disease over a period or cure a disease. It can also be used to treat the particular symptom of the disease. The drug use depends on the form the patient takes it. It may be more useful in injection form or sometimes in tablet form. The drug can be used for a single troubling symptom or a life-threatening condition. While some medications can be stopped after few days, some drugs need to be continued for prolonged period to get the benefit from it.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 metoprolol 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 metoprolol, 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, metoprolol) 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, metoprolol) 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 metoprolol 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, metoprolol 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 metoprolol, 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 metoprolol is recommended for acute treatment in hemodynamically stable patients and oral metoprolol 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 metoprolol 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 metoprolol, 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 Ivabradine?
Pharmacodynamic Interactions: Concomitant Use Not Recommended: QT-Prolonging Medicinal Products: Cardiovascular QT-prolonging medicinal products (eg, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone); noncardiovascular QT-prolonging medicinal products (eg, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin IV).
The concomitant use of cardiovascular and noncardiovascular QT-prolonging medicinal products with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed.
Concomitant Use with Precaution: Potassium-depleting diuretics (thiazide and loop diuretics): Hypokalemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced.
Pharmacokinetic Interactions: Cytochrome P-450 3A4 (CYP3A4): Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with the risk of excessive bradycardia.
Contraindication of Concomitant Use: The concomitant use of potent CYP3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated. The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7- to 8-fold.
Concomitant Use Not Recommended: Moderate CYP3A4 Inhibitors: Specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with the heart rate-reducing agents diltiazem or verapamil resulted in an increase in ivabradine exposure (2- to 3-fold increase in AUC) and an additional heart rate reduction of 5 bpm. The concomitant use of ivabradine with these medicinal products is not recommended.
Concomitant Use With Precautions: Moderate CYP3A4 Inhibitors: The concomitant use of ivabradine with other moderate CYP3A4 inhibitors (eg, fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is >60 bpm, with monitoring of heart rate.
Grapefruit Juice: Ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore, the intake of grapefruit juice should be restricted during the treatment with ivabradine.
CYP3A4 Inducers: CYP3A4 inducers [eg, rifampicin, barbiturates, phenytoin, Hypericum perforatum (St. John's wort)] may decrease ivabradine exposure and activity. The concomitant use of CYP3A4-inducing medicinal products may require an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice daily with St. John's wort was shown to reduce ivabradine AUC by half. The intake of St. John's wort should be restricted during the treatment with ivabradine.
Other Concomitant Use: Specific drug-drug interaction studies have shown no clinically significant effect of the following medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: Proton-pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition, there was no clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.
In pivotal phase III clinical trials, the following medicinal products were routinely combined with ivabradine with no evidence of safety concerns: Angiotensin-converting enzyme inhibitors, angiotensin II antagonists, β-blockers, diuretics, anti-aldosterone, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton-pump inhibitors, oral antidiabetics, aspirin and other antiplatelet medicinal products.
Paediatric Population: Interaction studies have only been performed in adults.
See also:
What other drugs will affect Metoprolol?
Metoprolol is a CYP2D6 substrate. Drugs that inhibit CYP2D6 can have an effect on the plasma concentration of metoprolol. 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 Metoprolol might have to be reduced for patients treated with Metoprolol.
The Following Combinations with Metoprolol Should be Avoided: Barbituric Acid Derivatives: Barbiturates (investigated for pentobarbital) induce the metabolism of metoprolol by enzyme induction.
Propafenone: Upon administration of propafenone to 4 patients on metoprolol therapy, the plasma concentrations of metoprolol increased by 2-5 fold and 2 patients experienced side effects typical of metoprolol. 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 metoprolol 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 Metoprolol 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 metoprolol to alpha-hydroximetoprolol via CYP2D6 in fast hydroxylating persons. The effects of metoprolol 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 metoprolol 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 metoprolol 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 metoprolol can increase when cimetidine or hydralazine are administered simultaneously.
See also:
What are the possible side effects of Ivabradine?
Clinically significant adverse reactions that appear in other sections of the labeling include:
- Fetal Toxicity
- Atrial Fibrillation
- Bradycardia and Conduction Disturbances
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.
In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), safety was evaluated in 3260 patients treated with Ivabradine and 3278 patients given placebo. The median duration of Ivabradine exposure was 21.5 months.
The most common adverse drug reactions in the SHIFT trial are shown in Table 2.
Table 2: Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT
Ivabradine N=3260 | Placebo N=3278 | |
Bradycardia | 10% | 2.2% |
Hypertension, blood pressure increased | 8.9% | 7.8% |
Atrial fibrillation | 8.3% | 6.6% |
Phosphenes, visual brightness | 2.8% | 0.5% |
Luminous Phenomena (Phosphenes)
Phosphenes are phenomena described as a transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency). Phosphenes are usually triggered by sudden variations in light intensity. Ivabradine can cause phosphenes, thought to be mediated through Ivabradine’s effects on retinal photoreceptors. Onset is generally within the first 2 months of treatment, after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity and led to treatment discontinuation in < 1% of patients; most resolved during or after treatment.
Postmarketing Experience
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during post-approval use of Ivabradine: syncope, hypotension, angioedema, erythema, rash, pruritus, urticaria, vertigo, diplopia, and visual impairment.
See also:
What are the possible side effects of Metoprolol?
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 metoprolol succinate in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol 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 metoprolol 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 Metoprolol 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, metoprolol succinate 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol 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 metoprolol or immediate-release metoprolol. 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 metoprolol 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.
Ivabradine 5 mg: One film-coated tablet contains 5 mg ivabradine (equivalent to 5.390 mg ivabradine as hydrochloride).
Ivabradine 7.5 mg: One film-coated tablet contains 7.5 mg ivabradine (equivalent to 8.085 mg ivabradine hydrochloride).
Excipients/Inactive Ingredients: Ivabradine 5 mg: Excipient with Known Effect: 63.91 mg lactose monohydrate. Ivabradine 7.5 mg: Core:
Film-Coating: Hypromellose (E 464), titanium dioxide (E171), macrogol 6000, glycerol (E 422), magnesium stearate (E 470 B), yellow iron oxide (E172), red iron oxide (E172).
Metoprolol 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. Metoprolol 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, metoprolol 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, metoprolol 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. Metoprolol possesses a single chiral centre and is administered as a racemic mixture.