Cardiac tachyarrhythmia, including supraventricular and ventricular arrhythmias

Confirmed or suspected acute myocardial infarction, for secondary prevention after myocardial infarction

Hypertension: as monotherapy or for use in combination with other antihypertensives, for example, a diuretic, peripheral vasodilator or angiotensin converting-enzyme (ACE) inhibitor

Angina pectoris: For long-term prophylaxis Nitroglycerin should be used, if necessary, for alleviating acute attacks.

Hyperthyroidism (as adjunctive medication)

Functional heart disorders with palpitation

Prevention of migraine

Dosage regimen

General target population

The dosage should be adapted to the requirements of the individual patient. The following dosage recommendations may be taken as a guide:

Cardiac tachyarrhythmia

Tablets

The daily dose is 100 to 150 mg, given in 2 or 3 divided doses; if necessary, the daily dose can be increased to 300 mg

Myocardial infarction

 

a) Treatment in the acute stage

The below recommended dosage can be reduced depending on the hemodynamic status of the patient.

Lopresor should be administered as soon as possible after the patient's arrival in hospital . Under constant hemodynamic monitoring (ECG, blood pressure, heart rate) one 5 mg bolus injection should be given intravenously, and repeated at 2 minute-intervals up to a total dose of 15 mg. Should any of the conditions listed under section 4.3 “Contraindications” arise, intravenous administration should be stopped immediately and appropriate measures instituted (see also section 4.9 “Overdose”). Provided the full intravenous dose (15 mg) has been tolerated well, oral therapy should be started 15 minutes later with 50 mg every 6 hours for 48 hours. For patients who do not tolerate the full intravenous dose, oral therapy should be initiated cautiously, starting with half the aforementioned oral dose.

b) Maintenance treatment

The oral maintenance dose is 200 mg daily, given in 2 divided doses. The treatment should be continued for at least 3 months.

Angina pectoris

The daily oral dose is 100 to 200 mg, given in 2 divided doses; if necessary, the daily dose can be increased up to 400 mg

Hyperthyroidism

The daily oral dose is 100 to 200 mg, given either as a single dose in the morning or as 2 divided doses (morning and evening). If necessary, another antihypertensive can be prescribed in addition (see section 4.1 “therapeutic Indications”).

Functional heart disorders with palpitation

The daily oral dose is 100 mg, given as a single dose in the morning. If necessary, the dose can be increased to 200 mg, given in 2 divided doses (morning and evening)

Prevention of migraine

The daily oral dose is 100 mg, given as a single dose in the morning. If necessary, the daily dose can be increased to 200 mg, given in 2 divided doses (morning and evening)

Special populations

Pediatric patients

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

Renal impairment

No dosage regimen adjustment of Lopresor is required in patients with renal impairment

Hepatic impairment

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

Geriatric patients (>65 years)

No dosage regimen adjustment of Lopresor is required in geriatric patients but it should be given with caution due to increased likelihood of adverse events

Method of administration

For oral treatment, the tablets should be swallowed whole with a glass of water.

Lopresor should always be taken in standardized relation with meals. If the physician asks the patient to take Lopresor either before or with breakfast, then the patient should continue taking Lopresor with the same schedule over the course of therapy.

• Known hypersensitivity to metoprolol and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross-sensitivity between beta blockers can occur) • Atrioventricular block of second or third degree • Decompensated heart failure • Clinically-relevant sinus bradycardia (heart rate less than 45 to 50 beats/min) • Sick sinus syndrome • Severe peripheral arterial circulatory disorders • Cardiogenic shock • Untreated pheochromocytoma (see section 4.4 “Special Warnings and precautions for use”) • Hypotension • For oral use: severe bronchial asthma or history of severe bronchospasm • Patients with myocardial infarction who have a heart rate of less than 45 to 50 beats/min, P-R interval of greater than 0.24 sec, a systolic blood pressure of less than 100 mmHg, and/or severe heart failure

Bronchospastic diseases

In general, patients with bronchospastic diseases should not be given beta blockers, including Lopresor  However, due to its relative cardioselectivity, oral Lopresor may be administered with caution to patients with mild or moderate bronchospastic diseases who do not respond to, or cannot tolerate, other suitable treatments Since beta₁-selectivity is not absolute, a beta₂-agonist should be administered concomitantly, and the lowest possible dose of Lopresor should be used

Diabetic patients

Lopresor should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycemic agents (see section 4.5 “Interactions”). Diabetic patients should be warned that beta blockers, including Lopresor, may mask the tachycardia occurring with hypoglycemia. However, other manifestations of hypoglycemia such as dizziness and sweating may not be significantly suppressed, and sweating may be increased

Cardiovascular system

Beta blockers, including Lopresor, should not be used in patients with untreated congestive heart failure. This condition should first be stabilized

Due to their negative effect on atrioventricular conduction, beta blockers, including Lopresor, should be only given with caution to patients with first-degree atrioventricular block.

If the patient develops increasing bradycardia (heart rate less than 50 to 55 beats/min), the dosage should be gradually reduced or treatment gradually stopped.

Myocardial infarction

If significant hypotension occurs in patients with myocardial infarction, Lopresor should be discontinued, and the hemodynamic status of the patient and the extent of myocardial ischemia carefully assessed. Intensive hemodynamic monitoring may be required and appropriate treatment modalities should be instituted. If hypotension is associated with significant bradycardia or atrioventricular block, treatment should be directed at reversing these.

Peripheral circulatory disorders

Lopresor should be used with caution in patients with peripheral arterial circulatory disorders (for example, Raynaud's disease or phenomenon, intermittent claudication), because beta blocker treatment may aggravate such conditions.

Pheochromocytoma

In patients with known or suspected pheochromocytoma, Lopresor should always be given in combination with an alpha blocker and only after the alpha blocker has been initiated.

Anesthesia and surgery

Chronically administered beta blocker therapy should not be routinely stopped prior to major surgery. The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. If a patient treated with Lopresor needs general anesthesia, the anesthetist should be informed that the patient is receiving a beta blocker. An anesthetic agent with as little cardiodepressant effect as possible should be used (see section 4.5 “Interactions”). If it is thought necessary to stop beta blocker therapy, including Lopresor, before surgery, this should be done gradually and completed approximately 48 hours before the general anesthetic

Abrupt discontinuation

Lopresor treatment should not be stopped suddenly, especially in patients with ischemic heart disease. To prevent exacerbation of angina pectoris, the dosage should be gradually reduced over 1 to 3 weeks and, if necessary, replacement therapy should be initiated at the same time

Anaphylactic reactions

Anaphylactic reactions precipitated by other agents may be particularly severe in patients taking beta blockers, and may be resistant to normal doses of adrenaline. Whenever possible, beta blockers, including Lopresor, should be avoided in patients who are at increased risk of anaphylaxis

Prinzmetal's angina

Beta blockers may increase the number and duration of angina attacks in patients with Prinzmetal's angina (variant angina pectoris). Relatively selective beta₁-receptor blockers, such as Lopresor, can be used in such patients, but only with the utmost care

Thyrotoxicosis

Beta blockers mask some of the clinical signs of thyrotoxicosis. Therefore, when Lopresor is administered to patients having, or suspected of developing, thyrotoxicosis, both thyroid and cardiac function should be closely monitored

Oculomucocutaneous syndrome

The full oculomucocutaneous syndrome, has not been reported with Lopresor. However, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases the symptoms cleared when Lopresor treatment was stopped. Patients should be observed carefully for potential ocular effects. If such effects occur, gradual discontinuation of Lopresor should be considered

•       Calcium channel blockers (IV use)

Calcium channel blockers such as verapamil and diltiazem may potentiate the depressant effects of beta blockers on blood pressure, heart rate, cardiac contractility and atrioventricular conduction. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving Lopresor because there is a risk of cardiac arrest in this situation (see section 4.4 “Special Warnings and precautions for use”)

•       Interactions to be considered

 

 

•       Other antihypertensive drugs

The effects of Lopresor and other antihypertensive drugs on blood pressure are usually additive. Patients receiving concurrent treatment with catecholamine depleting drugs, other beta blockers (including those in form of eye drops, such as timolol), or monoamine oxidase (MAO) inhibitors, should be carefully monitored. In addition, possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor

•             Calcium channel blockers (oral use)

Co-administration of a beta-adrenergic antagonist with a calcium channel blocker may produce an additive reduction in myocardial contractility due to negative chronotropic and inotropic effects . Patients taking an oral calcium channel blocker of the verapamil type in combination with Lopresor should be closely monitored

•       Anti-arrhythmic drugs

Beta-blockers may potentiate the negative inotropic effect of anti-arrhythmic agents and their effect on atrial-conduction time. Particularly, in patients with pre-existing sinus node dysfunction, co-administration of amiodarone may result in additive electro-physiologic effects including bradycardia, sinus arrest, and atrioventricular block anti-arrhythmic agents such as quinidine tocainide, procainamide, ajmaline amiodarone, flecainide and disopyramide may potentiate the effects of Lopresor on heart rate and atrioventricular conduction

•       Nitroglycerin

Nitroglycerin may enhance the hypotensive effect of Lopresor

 

Other drugs causing decrease in heart rate

 Concomitant administration of beta-blockers with other drugs known to decrease heart rate such as sphingosine-1-phosphate receptor modulators (e.g. fingolimod) may result in additive heart rate lowering effects.

Other drugs causing decrease in blood pressure

Concomitant administration of beta-blockers with other drugs known to decrease blood pressure such as aldesleukin may result in an enhanced hypotensive effect.

•       General anesthetics

Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see section 4.4 “Special Warnings and precautions for use”)

•       CYP2D6 inhibitors

Potent inhibitors of this enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 will result in the change of phenotype into poor metabolizer (see section 5 “pharmacological properties”). Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically-significant potent inhibitors of CYP2D6 are antidepressants such as fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, desipramine antipsychotics such as chlorpromazine, fluphenazine, haloperidol, thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine.

•       Hydralazine

Co-administration of hydralazine may inhibit pre-systemic metabolism of metoprolol leading to increased concentrations of metoprolol.

•       Digitalis glycosides

Concomitant use of digitalis glycosides may result in excessive bradycardia and/or an increase in atrioventricular conduction time. Monitoring heart rate and PR interval is recommended

•       Sympathomimetics

Co-administration of sympathomimetic drugs such as adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine, phenylpropanolamine, and xanthine derivatives (including antitussives or nose and eye drops) with a beta blocker may enhance the pressor response

 

resulting in hypertension due to mutual inhibition of therapeutic effects However, this is less likely with therapeutic doses of beta1-selective drugs than with non-selective beta-blockers

•       Non-steroidal  anti-inflammatory drugs

Co-administration of non-steroidal anti-inflammatory drugs including COX-2 inhibitors with a beta blocker may decrease the antihypertensive effect of metoprolol possibly as a result of the inhibition of renal prostaglandin synthesis and sodium and fluid retention caused by non- steroidal anti-inflammatory drugs

•       Hepatic enzyme inducers

Enzyme-inducing drugs may affect plasma concentrations of metoprolol. For

example, the plasma concentration of metoprolol is lowered by rifampicin

 

 

•       Anti-adrenergic agents

The antihypertensive effect of alpha-adrenergic blockers such as guanethidine, bethanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta blockers. Beta- adrenergic blockers may also potentiate the postural hypotensive effect of the first dose of prazosin, probably by preventing reflex tachycardia. On the contrary, beta-adrenergic blockers may also potentiate the hypertensive response to discontinuation of clonidine in patients receiving concomitant clonidine and beta-adrenergic blockers If a patient is treated with clonidine and Lopresor concomitantly, and clonidine treatment is to be discontinued, Lopresor should be stopped several days before clonidine is discontinued

•       Antidiabetic drugs and insulin

Beta blockers may interfere with the normal hemodynamic response to hypoglycemia and produce a rise in blood pressure associated with severe bradycardia In diabetic patients who use insulin, beta blocker treatment may be associated with increased or prolonged hypoglycemia. Beta blockers may also antagonise the hypoglycemic effects of sulfonylureas. The risk of either effect is less with a beta1-selective drug such as Lopresor than with a non-selective beta blocker. However, diabetic patients receiving Lopresor should be monitored to ensure that diabetic control is maintained (see section 4.4 “Special Warnings and precautions for use”)

•       Lidocaine (xylocaine)

Metoprolol may reduce the clearance of lidocaine, leading to increased lidocaine effects

•       Prazosin

The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker, including Lopresor

•       Ergot alkaloid

Co-administration with beta blockers may enhance the vasoconstrictive action of ergot alkaloids

•       Dipyridamole

In general, administration of a beta blocker should be withheld before dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection

•       Alcohol

Metoprolol may modify the pharmacokinetic parameters of alcohol

Special populations

•       Hepatic impairment

Metoprolol undergoes substantial hepatic first-pass metabolism, and is mainly eliminated by hepatic metabolism (see section 5 “pharmacological properties”). Therefore, hepatic impairment may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to increased plasma concentrations

•       Geriatric patients

Elderly patients should be treated cautiously. An excessive decrease in blood pressure or pulse rate may reduce the blood supply to vital organs to inadequate levels

Risk summary

There is a limited amount of data on the use of metoprolol in pregnant women. Experience with metoprolol in the first trimester of pregnancy is limited, but no fetal malformations attributable to metoprolol have been reportedThe risk to the fetus/mother is unknown However, beta blockers may reduce placental perfusion Embryotoxicity and/or fetotoxicity in rats and rabbits were noted starting at doses of 50 mg/kg in rats and 25 mg/kg in rabbits, as demonstrated by increases in preimplantation loss

Lopresor should be given to pregnant women only if clearly needed The doctor should be immediately informed, if pregnancy is confirmed

•       Clinical  Considerations

Disease-associated maternal and fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post- partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death

 

•       Dosage regimen adjustments during pregnancy and the postpartum period

The pharmacokinetics of  metoprolol is altered in pregnancy and the clearance is increased by 2-3 fold but no dose adjustment is required

In the case of treatment with Lopresor during pregnancy, the lowest possible dose should be used, and treatment discontinuation should be considered 2 to 3 days before delivery to avoid increased uterine contractility and effects of a beta-blockade in the newborn baby (for example, bradycardia, hypoglycemia)

•       Fetal/Neonatal adverse reactions

Neonates of women with hypertension who are treated with beta-blockers during late pregnancy may be at increased risk for bradycardia and hypoglycemia

•       Animal Data

Reproductive toxicity studies in mice, rats and rabbits did not show any teratogenic potential for metoprolol tartrate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted starting at doses of 50 mg/kg in rats and 25 mg/kg in rabbits, as demonstrated by increases in preimplantation loss, decreases in the number of viable fetuses per dose, and/or decreases in neonatal survival. High doses were associated with some maternal toxicity, and growth delay of the offspring in utero, which was reflected in minimally lower weights at birth

Lactation

•        Risk summary

Metoprolol is secreted into the breast milk: with therapeutic doses, an infant consuming 1 L of breast milk daily would receive a dose of less than 1 mg of metoprolol. Relative infant dose through breast milk is less than 1.0% of maternal weight-adjusted dose Nevertheless, breast-fed infants should be closely observed for signs of beta-blockade

•       Females and males of reproductive potential Infertility

The effects of Lopresor on human fertility have not been studied.

Metoprolol tartrate has been associated with reversible adverse effects on spermatogenesis starting at oral dose levels of 3.5 mg/kg in rats (0.1 times the maximum human dose based on body surface area). However, no effect on reproductive performance was seen in male rats administered metoprolol tartrate at doses ≥50 mg/kg (approximate to the maximum human dose)

Dizziness, fatigue or visual impairment may occur during treatment with Lopresor (see section 4.8 “Undesirable effects”), and may adversely affect the patient’s ability to drive or use machines

Tabulated summary of adverse drug reactions from clinical trials

Adverse drug reactions from clinical trials (Table 7-1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 7-1   :  Adverse drug reactions from clinical trials

Blood and lymphatic system disorders
	Very rare:	thrombocytopenia
Psychiatric disorders
	Rare:	depression, nightmares
	Very rare:	personality disorder, hallucinations
Nervous system disorders
	Common:	dizziness, headache
	Rare:	depressed level of consciousness, somnolence, insomnia, paraesthesia
Eye disorders
	Very rare:	visual impairment(e.g. blurred vision), dry eyes, eye irritation
Ear and labyrinth disorders
	Very rare:	tinnitus, hearing disorders1 (e.g. hypoacusis or deafness)
Cardiac disorders
	Common:	bradycardia
	Rare:	cardiac failure, arrhythmias, palpitation
	Very rare:	conduction disorders, chest pain,
Vascular disorders
	Common:	orthostatic hypotension (occasionally with syncope)
	Rare:	Oedema, Raynaud's phenomenon
	Very rare:	gangrene2
Respiratory, thoracic and mediastinal disorders
	Common:	exertional dyspnoea
	Rare:	bronchospasm3
	Very rare:	rhinitis
Gastrointestinal disorders
	Common:	nausea and vomiting, abdominal pain
	Rare:	diarrhoea or constipation
	Very rare:	dry mouth, retroperitoneal fibrosis
Hepatobiliary disorders
	Very rare:	hepatitis
Skin and subcutaneous tissue disorders
	Rare:	rash (in the form of urticaria, psoriasiform and dystrophic skin lesions)
	Very rare:	photosensitivity reaction, hyperhydrosis, alopecia, worsening of psoriasis
Musculoskeletal and connective tissue disorders
	Rare:	muscle spasms
	Very rare:	arthritis
Reproductive system and breast disorders
	Very rare:	erectile dysfunction, libido disorder ,Peyronie's disease
General disorders and administration site conditions
	Common:	fatigue
Investigations
	Very rare:	weight increase, liver function test abnormal

¹ in doses exceeding those recommended² in patients with pre-existing severe peripheral circulatory disorders

³ which may occur in patients without a history of obstructive lung disease

Adverse drug reactions from spontaneous reports and literature cases (frequency not known)

The following adverse reactions have been derived from post-marketing experience with Lopresor via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Table 7-2 : Adverse drug reactions from spontaneous reports and literature (frequency not known) Nervous system disorders   confusional state Investigations blood triglycerides increased, High Density Lipoprotein (HDL) decreased

To report any side effect(s):

·         Saudi Arabia

-          Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o Toll free phone: 8002490000

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

 

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

 

•    Other GCC States:

-  Please contact the relevant competent authority.

Signs and symptoms

An overdosage of Lopresor may lead to severe hypotension, sinus bradycardia, atrioventricular block, myocardial infarction, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, loss of consciousness (or even coma), convulsions, nausea, vomiting, and cyanosis and death

Concomitant ingestion of alcohol, antihypertensives, quinidine, or barbiturates aggravates the signs and symptoms

The first manifestations of overdose appear 20 minutes to 2 hours after ingestion of Lopresor. The effects of massive overdose may persist for several days, despite declining plasma concentrations

Management

Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted, if appropriate. Even healthy patients who have taken a small overdose should be closely observed for signs of poisoning for at least 4 hours

In the event of a potentially life-threatening oral overdose, vomiting or gastric lavage should be induced (if within 4 hours after ingestion of Lopresor) and/or activated charcoal should be used to remove the drug from the gastrointestinal tract Hemodialysis is unlikely to make a useful contribution to metoprolol elimination

Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care .Thebeta blocker withdrawal phenomenon (see section 4.4 “Special Warnings and precautions for use”) may occur after overdose.

The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac contractility, and cardiac output

Metoprolol lowers elevated blood pressure in the standing and lying position. It also reduces the rise in blood pressure occurring in response to exercise. Treatment results in an initial increase in peripheral vascular resistance, which during long-term administration is normalized or, in some cases, reduced. As with all beta blockers, the precise mechanism of the antihypertensive effect of metoprolol is not fully understood. However, the long-term reduction in blood pressure with metoprolol appears to parallel this gradual decrease in total peripheral resistance.

In patients with angina pectoris, metoprolol reduces the frequency and severity of ischemic episodes and increases physical working capacity. These beneficial effects may be due to decreased myocardial oxygen demand as a result of the reduced heart rate and myocardial contractility.

In patients with supraventricular tachycardia, atrial fibrillation, or ventricular extrasystoles or other ventricular arrhythmias, metoprolol has a regulating effect on the heart rate. Its anti-arrhythmic action is primarily due to inhibition of the automaticity of pacemaker cells and to prolongation of atrioventricular conduction.

In patients with a suspected or confirmed myocardial infarction, metoprolol lowers mortality. This effect may possibly be attributable to a decrease in the incidence of severe ventricular arrhythmias, as well as to limitation of infarct size. Metoprolol has also been shown to reduce the incidence of non-fatal myocardial reinfarction

Through its beta-blocking effect, metoprolol is suitable for the treatment of functional heart disorders with palpitation, for the prevention of migraine, and add-on treatment for hyperthyroidism.

Long-term treatment with metoprolol may reduce insulin sensitivity. However, metoprolol interferes with insulin release and carbohydrate metabolism less than non-selective beta blockers.

In short-term studies, it has been shown that metoprolol may alter the blood lipid profile. It may cause an increase in triglycerides and a decrease in free fatty acids; in some cases, a small decrease in the high-density lipoprotein (HDL) fraction has been observed, although to a lesser extent than with non-selective beta blockers. In one long-term study lasting several years, cholesterol levels were found to be reduced. Pharmacokinetic and pharmacodynamic studies indicate that 30% of maximum beta-1-adrenoreceptor antagonistic activity is essential for minimum pharmacodynamic effect which is observed with about 45 nmol/L metoprolol in plasma

Absorption

Following oral administration of conventional tablets, metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract. The drug is absorbed evenly throughout the gastrointestinal tract. Absorption of metoprolol from Lopresor Retard tablets is slower, but the availability of metoprolol is similar compared with conventional tablets. Peak plasma concentrations are attained after approximately 1.5 to 2 hours with conventional metoprolol tablets, and after approximately 4 to 5 hours with sustained-release tablets. Plasma concentrations of metoprolol increase approximately in proportion with the dose in the 50 mg to 200 mg dose range. Owing to extensive hepatic first-pass metabolism, approximately 50% of a single oral dose of metoprolol reaches the systemic circulation. The extent of pre-systemic elimination differs between individuals because of genetic differences in oxidative metabolism. Although the plasma profiles exhibit wide inter-subject variability, they are reproducible within an individual Following repeated administration, the percentage of the dose systemically available is approximately 40% higher than after a single dose (that is, approximately 70%). This may be due to partial saturation of the first-pass metabolism, or reduced clearance as a result of reduced hepatic blood flow. Ingestion with food may increase the systemic availability of a single oral dose by approximately 20% to 40%

After intravenous injection, metoprolol is very rapidly distributed with a half-life of 5 to 15 min. Within the dose range of 10 to 20 mg, the plasma concentrations rise linearly in relation to the size of the dose. Metoprolol exhibits stereo-specific pharmacokinetics.

Distribution

Metoprolol is extensively and rapidly distributed, with a reported volume of distribution of 3.2 to 5.6 L/kg. The apparent volume of distribution at steady-state (Vss) in extensive metabolizers (4.84 L/kg) is relatively higher than poor metabolizers (2.83 L/kg). The half-life is not dose-dependent  and does not change on repeated dosing. Approximately 10% of metoprolol in plasma is protein bound. Metoprolol crosses the placenta, and is found in breast milk. In patients with hypertension, metoprolol concentrations in cerebrospinal fluid are similar to those in plasma. Metoprolol is not a significant P-glycoprotein substrates indicating that inter-individual variability in pharmacokinetics of metoprolol can be majorly due to CYP2D6 metabolism

Biotransformation / Metabolism

Metoprolol is extensively metabolized by enzymes of the cytochrome P450 system in the liver. The main metabolic pathways of metoprolol are alpha-hydroxylation, O-demethylation, and oxidative deamination. Alpha-hydroxylation of metoprolol is stereo-selective. The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6).

However, the cytochrome P450 2D6 dependent metabolism of metoprolol seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol contribute significantly to its beta-blocking effect

Elimination

The average elimination half-life of metoprolol is 3 to 4 hours; in poor metabolizers the half-life may be 7 to 9 hours. Following single oral administration of 100 mg metoprolol, the median clearances were 31, 168, and 367 L/h in poor metabolizers, extensive metabolizers, and ultra-rapid metabolizers, respectively. The renal clearance of the stereo-isomers does not exhibit stereo-selectivity in renal excretion. Approximately 95% of the dose can be recovered in urine. In most subjects (extensive metabolisers), less than 5% of an oral dose, and less than 10% of an intravenous dose, is excreted as unchanged drug. In poor metabolizers, up to 30% or 40% of oral or intravenous doses, respectively, may be excreted unchanged. The total plasma clearance of metoprolol after intravenous administration is approximately 1 L/min.

Dose proportionality

Metoprolol exhibits saturable pre-systemic metabolism leading to non-proportionate increase in the exposure with increased dose. However, a dose proportionate pharmacokinetics is expected with extended release formulations

Food effect

Food appeared to increase the rate of absorption of metoprolol leading to a slightly higher maximum plasma concentration at earlier time. However, it does not have a significant impact on the clearance or the time at which the maximum peak concentration is observed (T_max).

In order to minimize the effect-variations within the individual, it is recommended that Lopresor should always be taken in standardized relation with food: If the physician asks the patient to take Lopresor either before or with breakfast then the patient should continue taking Lopresor with same dosing schedule during the course of therapy

Special populations

Geriatric patients (>65 years or age or older)       

The geriatric population may show slightly higher plasma concentrations of metoprolol as a combined result of a decreased metabolism of the drug in elderly population and a decreased hepatic blood flow. However, this increase is not clinically-significant or therapeutically- relevant. Metoprolol does not meaningfully accumulate on repeated administration and there is no need to adjust the dose in elderly patients

Patients with renal impairment

Pharmacokinetics of metoprolol is not impacted in patient with renal impairment. However, there is a possibility of accumulation of one of its less active metabolite in patients with a creatinine clearance below 5 mL/min and this accumulation would not influence the beta-blocking properties of metoprolol. Patients with renal impairment may usually be treated with normal doses.

Patients with hepatic impairment

Since the drug is primarily eliminated by hepatic metabolism, hepatic impairment may impact the pharmacokinetics of metoprolol. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h) in patients with liver impairment.

Patients with a portacaval anastomosis

Patients with a portacaval anastomosis had a systemic clearance of an intravenous dose of approximately 0.3 L/min and area under concentration-time curve (AUC) values up to 6-fold higher than those in healthy subjects

Patients with inflammatory disease

Inflammatory disease has no effect on the pharmacokinetics of metoprolol

Patients with hyperthyroidism

Hyperthyroidism may increase the pre-systemic clearance of metoprolol

Ethnic sensitivity

The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizer phenotype. Approximately 7% of Caucasians and less than 1% Orientals are poor metabolizers. CYP2D6 poor metabolizers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolizer with normal CYP2D6 activity

Effect of gender

There is no significant evidence to suggest a possible difference in elimination between the male and the female population, gender-specific recommendations for dosing of metoprolol are not necessary

Clinical studies

No additional clinical studies have been performed.

Non-clinical safety data

Reproductive toxicity

See section 4.6  Pregnancy, lactation and females and males of reproductive potential.

Mutagenicity

Metoprolol tartrate was devoid of mutagenic/genotoxic potential in the bacterial cell system (Ames) test and in vivo assays involving mammalian somatic cells or germinal cells of male mice

Carcinogenicity

Metoprolol tartrate was not carcinogenic in mice and rats after oral administration of doses up to 800 mg/kg for 21 to 24 months

Tablets of 50 mg: Silica aerogel, cellulose, lactose, magnesium stearate, sodium carboxymethyl starch, hydroxypropyl methylcellulose, red iron oxide (E 172), polysorbate 80, talc, titanium dioxide (E 171).

Tablets of 100 mg: Silica aerogel, cellulose, magnesium stearate, sodium carboxymethyl starch, hydroxypropyl methylcellulose, glyceryl polyethylene glycol oxystearate, talc, titanium dioxide (E 171).

Not applicable

36 months

Store below 30 °C.

Protect from moisture and heat

must be kept out of the sight and reach of children.

Information might differ in some countries.

Lopresor 50mg: blisters containing 40 tablets in PVC/PE/PVDC blisters
Lopresor 100mg: blisters containing 20 tablets in PVC/PE/PVDC blisters

There are no specific instructions for use/handling.