LOPRESOR - PACKAGE LEAFLET - LEAFLETS

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Lopresor - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Metoprolol (Metoprolol tartrate)

LOPRESOR 100 mg coated tablets
LOPRESOR 200 mg prolonged-release tablets

Indications Why is Lopresor used? What is it for?

Lopresor contains metoprolol tartrate which belongs to a group of medicines called beta-blockers which work by slowing the heartbeat and lowering blood pressure.

Lopresor is indicated in adults:

to treat high blood pressure (either alone or in combination with other blood pressure lowering medicines, for example diuretics, peripheral vasodilators or ACE inhibitors)
to prevent chest pain caused by reduced oxygen supply to the heart (angina pectoris). To relieve acute seizures, your doctor may prescribe nitroglycerin if needed
in known or suspected heart attack
in prevention after heart attack
in disturbances of heart function which manifest as palpitations (sensation of perceiving the heartbeat)
to prevent headaches (migraines).

Talk to your doctor if you don't feel better or feel worse.

Contraindications When Lopresor should not be used

Do not take Lopresor:

if you are allergic to metoprolol tartrate or any of the other ingredients of this medicine (listed in section 6) or other medicines related to it
if you are allergic to other medicines belonging to the beta-blocker class such as metoprolol
if you suffer from blockage in the electrical conduction of the heart (second and third degree atrioventricular block)
if you have decompensated heart failure, a severe heart disease
if you suffer from a reduction in heart rate, i.e. the number of heart beats per minute (less than 45-50 beats)
if you have a heart disease called "sinus knot syndrome" (characterized by heart rhythm disturbances)
if you suffer from severe blood circulation disorders (peripheral arterial circulation)
if you suffer from low blood pressure with severe reduction in heart function (cardiogenic shock)
if you have untreated cancer of the adrenal gland, a gland located above the kidney which can cause high blood pressure (pheochromocytoma)
if you suffer from low blood pressure
if you have severe bronchial asthma or have a history of severe narrowing of the bronchi which makes breathing difficult
if you have recently had a heart attack or severe heart failure.

Precautions for use What you need to know before taking Lopresor

Talk to your doctor or pharmacist before taking Lopresor.

Tell your doctor if you have or have ever suffered from the following conditions:

respiratory diseases of mild or moderate severity (bronchospastic diseases). Lopresor must be administered at the lowest effective dose and always at the same time as a β2-agonist (see "Do not take Lopresor").
high blood sugar levels (diabetes), especially if you are being treated with insulin or medicines that lower blood sugar levels by mouth (see section "Other medicines and Lopresor"), because this medicine may not make you recognize the symptoms of "hypoglycaemia (low blood sugar) such as rapid heartbeat, dizziness and sweating
congestive heart failure, a disease of the heart
disturbances in the electrical conduction of the heart (first degree atrioventricular block)
heart attack
circulation disorders in the arms and legs (e.g. Raynaud's disease or phenomenon, intermittent claudication)
if you suffer from a known or suspected tumor of the adrenal gland, a gland located above the kidney that can cause a rise in blood pressure (pheochromocytoma), Lopresor should always be given at the same time as an alpha blocker and only after treatment with Lopresor. alphabet blocker has been started (see "Do not take Lopresor").
a type of angina (chest pain) called Prinzmetal's angina
an increase in the function of a gland called the thyroid gland (thyrotoxicosis)
allergy. If you have an allergy and take beta-blockers, the allergic reactions may be more severe than normal
liver problems (liver dysfunction) as your doctor may decide to change your dose.

If during treatment with Lopresor you experience side effects in the eyes (dry eyes and / or occasionally skin rashes under the eye), consult your doctor immediately who may decide to stop the treatment. (See section "Possible side effects. ").

If you are going to have surgery that requires general anesthesia, tell the anesthetist (the doctor who performs the anesthesia) that you are taking Lopresor. The anesthetist will choose the most suitable anesthetic for you in order to reduce any unwanted effects. of the heart during anesthesia. Your doctor may decide to stop treatment with Lopresor before surgery, in which case the withdrawal is gradual and is completed approximately 48 hours before general anesthesia.

Senior citizens

If you are elderly, use this medicine with caution. In fact, an excessive reduction in blood pressure or heart rate can lead to an inadequate blood supply to vital organs (see section 3 "How to take Lopresor").

Children and adolescents

The efficacy and safety in children and adolescents below 18 years of age is limited, therefore Lopresor is not recommended in this population (0-18 years).

Interactions Which drugs or foods can modify the effect of Lopresor

Other medicines and Lopresor

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

Interactions with drugs whose concomitant use is not recommended.

medicines to treat certain heart disorders belonging to the class of calcium channel blockers (given into a vein) such as verapamil and diltiazem. This combination may potentiate the depressant effects of Lopresor on the heart and blood pressure.

Interactions to be considered

medicines that lower blood pressure: medicines that lower the levels of catecholamines in the blood (substances produced by the body that work to control the heart rate); other beta-blockers (including in the form of eye drops); monoamine oxidase (MAO) inhibitors, medicines used to treat depression, even within 14 days after stopping treatment.
medicines to treat certain heart disorders belonging to the class of calcium channel blockers (e.g. verapamil) by mouth
medicines to treat heart rhythm abnormalities (antiarrhythmics such as quinidine, tocainide, procainamide, ajmaline, amiodarone, flecainide, disopyramide and propafenone)
nitroglycerin, a medicine used to treat angina
medicines to induce anesthesia during surgery (general and local anesthetics such as lidocaine) see also the section "Warnings and precautions".
medicines to treat depression (fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, desipramine)
medicines to treat certain mental disorders (antipsychotics such as chlorpromazine, fluphenazine, haloperidol, thioridazine)
medicines used to treat the HIV virus, antiretrovirals such as ritonavir
medicines to treat allergies (antihistamines such as diphenhydramine)
medicines to treat malaria (hydroxychloroquine or quinidine)
medicines to treat fungal infections (antifungals such as terbinafine)
hydralazine and prazosin (medicines used to treat high blood pressure)
medicines to treat certain heart disorders belonging to the class of digitalis glycosides.
medicines used to treat certain breathing problems (such as asthma and cough) or to clear the nose (nasal drops) or to treat certain eye disorders (eye drops) for example: adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine, phenylpropanolamine , xanthine derivatives
medicines to treat inflammation and pain (non-steroidal anti-inflammatory drugs)
rifampicin, an antibiotic
medicines belonging to the alpha-adrenergic blocker class (guanethidine, betanidine, reserpine, alpha-amethyldopa or clonidine), used to treat diseases such as benign prostatic hypertrophy (enlarged prostate), urinary retention (inability of the bladder to empty completely) and high blood pressure
medicines to reduce blood sugar levels (antidiabetics and insulin)
medicines used to treat migraine (ergot alkaloids)
Dipyridamole. In general, administration of a beta-blocker should be discontinued prior to a dipyridamole test, closely monitoring heart rate after dipyridamole injection.

Lopresor with food, drink and alcohol

The use of alcohol during treatment is not recommended.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant, think you may be pregnant or are planning to become pregnant, or if you are breast-feeding, talk to your doctor or pharmacist before starting treatment with this medicine.

Pregnancy

If you are pregnant, your doctor will only prescribe this medicine if absolutely necessary. In case of treatment with Lopresor during pregnancy, your doctor will prescribe the lowest possible dose and will ask you to stop the therapy at least 2 or 3 days before the birth, to avoid effects on the unborn baby (e.g. bradycardia, hypoglycaemia).

Feeding time

Lopresor passes into breast milk, so the use of this medicine is not recommended if you are breastfeeding.

Driving and using machines

Dizziness, fatigue or visual disturbances may occur while taking Lopresor. If this occurs, do not drive or use any tools or machinery.

Lopresor 100 mg film-coated tablets contain castor oil

It can cause stomach upset and diarrhea.

For those who play sports:

For those who carry out sporting activities, the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

Dosage and method of use How to use Lopresor: Dosage

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

LIKE

Always take the tablets with a glass of water and do not chew them.

Take Lopresor regularly with meals. If your doctor has advised you to take

Lopresor either before or during breakfast, continue to take Lopresor with the same schedule for the duration of the treatment.

Lopresor 100 mg film-coated tablets

take this medicine on an empty stomach.

Lopresor 200 mg prolonged-release tablets

take this medicine with or without food, according to your preference.

HOW MUCH

To treat high blood pressure

Lopresor 100 mg film-coated tablets:

100-200 mg per day, either as a single administration (1 or 2 tablets in the morning depending on the prescribed dose) or in 2 divided doses (one tablet in the morning and one in the evening). If necessary, your doctor may also prescribe another medicine to lower your blood pressure.

Lopresor 200 mg prolonged-release tablets:

1 tablet in the morning.

To prevent chest pain caused by reduced oxygen supply to the heart (angina pectoris)

Lopresor 100 mg film-coated tablets:

100-200 mg per day, in 2 divided doses. If necessary, the daily dosage can be increased to 400 mg

Lopresor 200 mg prolonged-release tablets:

1 tablet in the morning.During the withdrawal phase of the treatment, your doctor will keep you under close supervision. Your doctor will reduce your dose gradually over a period of 1 to 3 weeks and will prescribe replacement therapy if necessary.

Infarction of the heart

In the acute phase, the doctor will adjust the dosage based on your physical condition. Maintenance therapy: the oral dose is 200 mg per day, in two divided doses. The treatment should be continued for at least 3 months.

In disturbances of heart function that manifest themselves with palpitations (sensation of perceiving the heartbeat) and Prevention of headaches (migraines)

Lopresor 100 mg film-coated tablets:

100 mg per day, given once in the morning (1 tablet in the morning); if necessary, the daily dosage can be increased to 200 mg, administered in two divided doses (1 tablet in the morning and one in the evening).

Lopresor 200 mg prolonged-release tablets:

1 tablet per day, in the morning.

Use in patients with impaired liver function

If you have impaired liver function, your doctor will prescribe Lopresor starting with low doses and will increase the dose cautiously according to your response to the medicine.

Elderly (> 65 years)

If you are over 65, this medicine will be prescribed to you with caution due to the increased likelihood of side effects. In particular, your doctor will regularly check your blood pressure, and the rate of your heartbeat (see "Warnings and precautions").

Use in children and adolescents

The use of this medicine is not recommended in children and adolescents under 18 years of age.

Overdose What to do if you have taken too much Lopresor

If you take more Lopresor than you should

If you take too much of this medicine, tell your doctor or go to a hospital straight away. While waiting for the doctor, within 4 hours after ingestion, it may be useful to induce vomiting and / or take activated charcoal to remove the medicine from the stomach and intestines. In any case, after excessive intake of beta-blockers, he must always be monitored in hospital.

An overdose of this medicine can cause the following symptoms:

excessive reduction in blood pressure
reduced number of heart beats (sinus bradycardia)
difficulty of the heart in pumping blood to the body due to an alteration in the electrical conduction system of the heart (atrioventricular block)
severe heart disease (heart failure)
decrease in blood pressure with severe reduction in heart function (cardiogenic shock)
cardiac arrest
narrowing of the bronchi and difficulty in breathing (bronchospasm)
deterioration of consciousness (or even coma)
convulsions
nausea
He retched
bluish discoloration of the body (cyanosis)
death.

Taking alcohol, medicines to lower blood pressure, quinidine (medicine to treat heart rhythm disturbances), or barbiturates (medicines to treat epilepsy) at the same time aggravates the signs and symptoms. The first manifestations of excessive drug intake occur 20 minutes to 2 hours after administration of the drug. The effects can also persist for several days.

If you forget to take Lopresor

If you forget to take a tablet, do not take a double dose to make up for a forgotten tablet.

If you stop taking Lopresor

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Abrupt discontinuation of treatment

Do not stop treatment with Lopresor abruptly, especially if you have diseases due to a reduced supply of oxygen to the heart (ischemic), such as angina pectoris (chest pain). To prevent angina pectoris from getting worse, your doctor will reduce these. dosing gradually over a period of 1 to 3 weeks and will prescribe replacement therapy if necessary. Your doctor will keep you under close surveillance while you are stopping treatment.

Side Effects What are the side effects of Lopresor

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience the following side effects of the eyes (dry eyes and / or occasionally skin rashes under the eye) during treatment with Lopresor, contact your doctor who may STOP treatment with this medicine.

In addition, you may experience the following side effects:

Common (may affect up to 1 in 10 people)

low blood pressure when moving from sitting to standing (orthostatic hypotension occasionally with syncope)
nausea
He retched
pain in the abdomen
fatigue
difficulty in breathing following physical exertion (exertional dyspnea)
slow heart rate (bradycardia)
dizziness
headache.

Rare (may affect up to 1 in 1000 people)

diarrhea
constipation
skin rashes (in the form of hives, skin lesions)
muscle cramps
bronchospasm (even if you have not suffered from obstructive lung disease in the past)
swelling (edema)
pain in the fingers and toes that turn first whitish then bluish and finally reddish (Raynaud's phenomenon)
heart disease (heart failure)
changes in the rhythm of the heart
perception of heartbeat (palpitations)
reduced level of consciousness
sleepiness or insomnia
tingling in the arms and legs (paraesthesia)
depression
nightmares.

Very Rare (may affect up to 1 in 10,000 people)

weight gain
abnormalities in liver function tests
erectile dysfunction
impaired sexual desire
Peyronie's disease (penile disease)
joint inflammation (arthritis)
light sensitivity reactions (photosensitivity)
excessive sweating
hair loss and hair loss (alopecia)
worsening of psoriasis (skin disease)
severe liver disease (hepatitis)
dryness of the mucous membrane of the mouth
retroperitoneal fibrosis (inflammation of the abdomen)
irritation and inflammation of the lining of the nose (rhinitis)
gangrene (bluish or greenish skin on the hands or feet) if you suffer from severe disorders of the peripheral blood circulation
reduction in the number of platelets in the blood (thrombocytopenia)
personality disorders
hallucinations
reduced vision (e.g. blurred vision)
irritation
ringing in the ears (tinnitus)
hearing disorders in case of exceeding the recommended doses (eg reduced hearing or deafness)
chest pain.

In addition, the following side effects may occur, the frequency of which cannot be determined:

Disorders of the nervous system

confusional state

Metabolism and nutrition disorders

increase in triglycerides (fats) in the blood
reduction of HDL cholesterol in the blood.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Lopresor 100 mg film-coated tablets

Do not store Lopresor 100 mg film-coated tablets above 30 ° C.

Store in the original package to protect the medicine from moisture.

Lopresor 200 mg prolonged-release tablets

This medicine does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP.

The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Lopresor contains

Lopresor 100 mg film-coated tablets

Each film-coated tablet contains:

The active ingredient is metoprolol tartrate 100 mg.

The other ingredients are: sodium starch carboxymethyl A, colloidal anhydrous silica, magnesium stearate, microcrystalline cellulose, hypromellose, hydrogenated polyhydroxy castor oil, talc, titanium dioxide.

Lopresor 200 mg prolonged-release tablets

Each prolonged-release tablet contains:

The active ingredient is: metoprolol tartrate 200 mg.
The other ingredients are: colloidal anhydrous silica, microcrystalline cellulose, dibasic calcium phosphate dihydrate, polyacrylate dispersion 30%, magnesium stearate, glyceryl palmitate stearate, hypromellose, polysorbate 80, talc, titanium dioxide, yellow iron oxide.

Description of what Lopresor looks like and contents of the pack

Tablets for oral use.

Lopresor 100 mg comes in round, white film-coated tablets packed in blisters of 30 tablets
Lopresor 200 mg comes in round and yellow prolonged-release tablets packed in blisters of 28 tablets.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Lopresor can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER O 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

LOPRESOR

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Lopresor 100 mg film-coated tablets

Each film-coated tablet contains:

Active ingredient: metoprolol tartrate 100 mg.

Lopresor 200 mg prolonged-release tablets

Each prolonged-release tablet contains:

Active ingredient: metoprolol tartrate 200 mg.

For the full list of excipients see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets.

Prolonged-release tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Arterial hypertension: either alone or in combination with other antihypertensive drugs, for example diuretics, peripheral vasodilators or ACE inhibitors.

Angina pectoris: long-term prophylaxis. To relieve acute crises, nitroglycerin should be used if necessary.

Overt or suspected myocardial infarction, as secondary prevention after myocardial infarction.

Functional heart disorders with palpitations.

Prevention of migraine.

04.2 Posology and method of administration

Dosage

General population

It is advisable to individualize the posology and to follow the following dosing schedule.

Hypertension

Lopresor 100 mg film-coated tablets: 100-200 mg per day, either as a single administration, in the morning, or in 2 divided doses (morning and evening).

Lopresor 200 mg prolonged-release tablets: 1 tablet in the morning.

Angina pectoris

Lopresor 100 mg film-coated tablets: 100-200 mg per day, in 2 divided doses. If necessary, the dosage can be increased to 400 mg.

Lopresor 200 mg prolonged-release tablets: 1 tablet in the morning

Heart attack

Acute phase: The recommended dosage can be adapted based on the patient's haemodynamic status.

Maintenance therapy: The oral maintenance dose is 200 mg per day, in two divided doses. The treatment should be continued for at least 3 months.

Functional heart disorders with palpitations and migraine prevention

Lopresor 100 mg film-coated tablets: 100 mg per day, given once in the morning; if necessary, the daily dosage can be increased to 200 mg, given in two divided doses (morning and evening).

Lopresor 200 mg prolonged-release tablets: 1 tablet, given once in the morning.

Pediatric population

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

Kidney failure

No dosage adjustments of Lopresor are required in patients with impaired renal function.

Hepatic insufficiency

Blood levels of metoprolol may substantially increase in patients with impaired hepatic function. Therefore, Lopresor 100 mg film-coated tablets or Lopresor 200 mg prolonged-release tablets should be administered starting with low doses and increasing doses with caution according to the clinical response (see sections 4.4 and 5.2).

Elderly (> 65 years)

No dose adjustments of Lopresor are required in elderly patients, but the drug should be administered with caution due to the increased likelihood of adverse events. In particular, such patients should be monitored for excessive reduction in blood pressure or heart rate (see section 4.4).

Method of administration

The tablets should not be chewed and should be taken with a glass of water.

Lopresor should always be taken in regular relation to meals. If the doctor advises the patient to take Lopresor either before or during breakfast, the patient should continue to take Lopresor with the same schedule for the duration of the treatment.

Lopresor 200 mg prolonged-release tablets it can be taken on a full or empty stomach, preferably in the morning.

Lopresor 100 mg film-coated tablets it must be taken on an empty stomach.

04.3 Contraindications

• Known hypersensitivity to the active substance, to drugs related to it, or to any of the excipients;

• Hypersensitivity to other beta-blockers (cross-sensitivity between beta-blockers may occur);

• Second or third degree atrioventricular block;

• Decompensated heart failure, clinically relevant sinus bradycardia (heart rate less than 45-50 beats / minute);

• Sinus node syndrome;

• Severe disorders of the peripheral arterial circulation;

• Cardiogenic shock;

• Untreated pheochromocytoma (see section 4.4);

• Hypotension;

• Severe bronchial asthma or a history of severe bronchospasm.

• The use of Lopresor is contraindicated in heart failure patients with heart rate less than 45-50 beats / minute, P-R interval greater than 0.24 seconds, systolic blood pressure less than 100 mmHg and / or severe heart failure.

04.4 Special warnings and appropriate precautions for use

Bronchospastic affections

Generally beta-blockers, including Lopresor, should not be given to patients with bronchospastic conditions. However, due to the relative cardioselectivity of metoprolol, Lopresor can be administered with caution to patients with mild or moderate bronchospastic disease in cases where other suitable drugs are not tolerated or have proved ineffective.

However, since β1-selectivity is not absolute, a β2-agonist should be administered concurrently and the lowest possible dose of Lopresor used.

Lopresor is contraindicated in severe bronchial asthma and in patients with a history of severe bronchospasm (see section 4.3).

Diabetic patients

Lopresor should be used with caution in patients with diabetes mellitus, especially those treated with insulin or oral hypoglycemic agents (see section 4.5). Diabetic patients should be advised that beta-blockers, including Lopresor, can mask hypoglycemic tachycardia; however, other manifestations of hypoglycemia, such as dizziness and sweating, may not be significantly suppressed and sweating may also be increased.

Cardiovascular system

In patients with untreated congestive heart failure (see section 4.3), beta-blockers, including Lopresor, should not be used. The use of a beta blocker can only be considered after having adequately treated and stabilized the heart failure.

Due to their negative effect on atrioventricular conduction, beta-blockers, including Lopresor, should only be used with caution in patients with first degree atrioventricular block (see section 4.3). If the patient experiences progressive bradycardia (heart rate less than 50-55 beats / minute), the dosage should be gradually reduced or the treatment discontinued (see section 4.3).

Peripheral circulatory disorders

Lopresor should be used with caution in patients with peripheral arterial circulatory disorders (e.g., Raynaud's disease or phenomenon, intermittent claudication), as treatment with beta-blockers can aggravate these conditions (see section 4.3).

Pheochromocytoma

In patients with known or suspected pheochromocytoma, Lopresor should always be given in combination with an alpha blocker and only after alpha blocker treatment has been started (see section 4.3).

Anesthesia and Surgery

Chronic beta-blocker therapy should not be routinely discontinued prior to major surgery. The heart's reduced ability to respond to adrenergic stimulation may increase the risks of general anesthesia and surgical procedures. Before any surgery requiring general anesthesia, the anesthetist should be informed that the patient is being treated with a beta blocker. An anesthetic with the least possible cardiodepressive effect should be used (see section 4.5). If discontinuation of the beta blocker, including Lopresor, is thought to be necessary prior to surgery, withdrawal should occur gradually and complete approximately 48 hours prior to general anesthesia.

Abrupt discontinuation of treatment

Abrupt discontinuation of Lopresor treatment should be avoided, especially in patients with ischemic heart disease. To prevent an exacerbation of angina pectoris, the dosage should be reduced gradually over a period of 1 to 3 weeks and, if necessary, replacement therapy should be initiated at the same time. The patient should be kept under close medical supervision during the withdrawal.

Anaphylactic reactions

In patients taking beta-blockers, anaphylactic reactions caused by other agents can be particularly severe and resist normal doses of adrenaline. Whenever possible, the use of beta blockers, including Lopresor, should be avoided in patients 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 (a variant of angina pectoris). Relatively selective beta1-blockers, such as Lopresor, can be used in such patients, but only with extreme caution.

Thyrotoxicosis

Beta blockers mask some of the clinical symptoms of thyrotoxicosis. Therefore, when administering Lopresor to patients with known or suspected thyrotoxicosis, both thyroid and cardiac function should be closely monitored.

Oculomucocutaneous syndrome

Oculomucocutaneous syndrome in its complete variant has not been reported with Lopresor. However, partial manifestations of this syndrome (dry eyes and / or occasionally skin rash) have also been described with Lopresor. In most cases the symptoms disappeared upon discontinuation of Lopresor treatment. Patients should be carefully observed for potential ocular effects. If such effects occur, consideration should be given to discontinuing Lopresor.

Calcium channel blockers (oral and intravenous use)

Patients on oral therapy with a calcium channel blocker of the verapamil type in combination with Lopresor should be carefully monitored. Furthermore, calcium channel blockers of the verapamil (phenylalkylamines) type should not be administered intravenously in patients receiving Lopresor due to the risk of cardiac arrest in this situation (see section 4.5).

Hepatic insufficiency

Metoprolol undergoes significant hepatic first pass metabolism and is eliminated primarily via hepatic metabolism (see section 5.2). Therefore, hepatic insufficiency may increase the systemic bioavailability of metoprolol and reduce its total clearance, leading to an increase in its plasma concentrations.

Elderly Elderly patients should be treated with caution. In fact, an excessive reduction in blood pressure or heart rate can cause inadequate blood supply to vital organs.

04.5 Interactions with other medicinal products and other forms of interaction

Interactions with drugs whose concomitant use is not recommended

The following drugs may increase the effects or plasma concentrations of metoprolol.

Calcium channel blockers (intravenous use)

Calcium antagonists of the verapamil and diltiazem type may potentiate the depressant effects of beta-blockers on blood pressure, heart rate and contractility, and atrioventricular conduction. Calcium antagonists of the verapamil (phenylalkylamines) type should not be administered intravenously to patients receiving Lopresor, as there is a risk of cardiac arrest.

Interactions to be considered

Effects of other drugs on metoprolol

Other antihypertensive medicines

The effect of Lopresor and other antihypertensive drugs on blood pressure is generally additive. Patients concomitantly treated with catecholamine-depleting drugs, other beta-blockers (including eye drops), or monoamine oxidase (MAO) inhibitors In addition, significant hypertension can theoretically occur up to 14 days after discontinuation of concomitant administration of an irreversible MAO inhibitor.

Calcium channel blockers (oral use)

Concomitant administration of a beta-blocker with a calcium channel blocker may result in an additive reduction in myocardial contractility due to negative inotropic and chronotropic effects. Patients on oral therapy with a calcium channel blocker of the verapamil type in combination with Lopresor should be carefully monitored.

Antiarrhythmics

Beta-blockers may potentiate the negative inotropic effect of antiarrhythmics and their effect on atrial conduction time. In particular, in patients with pre-existing sinus node dysfunction, concomitant administration of amiodarone may lead to additive electrophysiological effects including bradycardia, sinus arrest and atrioventricular block. Antiarrhythmics such as quinidine, tocainide, procainamide, ajmaline, amiodarone, flecainide and disopyramide can potentiate the effect of Lopresor on heart rate and atrioventricular conduction.

Nitroglycerin

Nitroglycerin may increase the hypotensive effect of Lopresor.

General anesthetics

Some inhalation anesthetics may enhance the cardiodepressive effect of beta-blockers (see section 4.4).

CYP2D6 inhibitors

Strong inhibitors of this enzyme can increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would result in a change in the phenotype in poor metaboliser (see section 5.2.). Caution should be exercised when metoprolol is co-administered with potent CYP2D6 inhibitors. Potent known inhibitors of CYP2D6, clinically significant, 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

Concomitant administration of hydralazine may inhibit the pre-systemic metabolism of metoprolol resulting in an increase in the concentration of metoprolol.

Digitalis glycosides

Simultaneous use of digitalis glycosides may cause excessive bradycardia and / or prolongation of atrioventricular conduction time. Monitoring of heart rate and PR interval on ECG is recommended.

Sympathomimetics

The concomitant administration with a beta-blocker of substances with sympathomimetic activity, such as adrenaline, noradrenaline, isoprenaline, ephedrine, phenylephrine, phenylpropanolamine and xanthine derivatives contained in antitussive products or in nasal and ophthalmic drops, can increase the blood pressure response causing hypertension by mutual inhibition of the therapeutic effects. This is less likely with therapeutic doses of β1-selective drugs than with non-cardioselective beta-blockers.

Non-steroidal anti-inflammatory drugs

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

Inducers of liver enzymes

Enzyme inducers can affect plasma levels of metoprolol. For example, the plasma concentration of metoprolol is lowered by rifampicin.

Effects of metoprolol on other drugs

Antiadrenergic medicines

The antihypertensive effect of alpha-adrenergic blockers such as guanethidine, betanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta-blockers. Beta-adrenergic blockers may also enhance the postural hypotensive effect of the first administration of prazosin, possibly preventing reflex tachycardia. Conversely, beta-adrenergic blockers may also potentiate the hypertensive response to clonidine withdrawal as in patients taking concomitant clonidine and beta-blockers. If a patient is treated concurrently with clonidine and Lopresor and the clonidine treatment must be discontinued, Lopresor therapy must be stopped several days before clonidine.

Antidiabetics and insulin

Beta-blockers may interfere with the usual haemodynamic response to hypoglycaemia and lead to an increase in blood pressure associated with severe bradycardia. In diabetic patients using insulin, treatment with beta-blockers may be associated with more pronounced or prolonged episodes of hypoglycaemia. Beta blockers can also antagonize the hypoglycemic effect of sulfonylureas. The risk of these effects is lower with a β1-selective drug such as Lopresor than with non-cardioselective beta-blockers. However, diabetic patients receiving Lopresor should be closely monitored to ensure diabetes control (see section 4.4).

Lidocaine (xylocaine)

Metoprolol can reduce the clearance of lidocaine, causing an increase in the effects of lidocaine.

Prazosin

The acute postural hypotension that may follow the first administration of prazosin may be accentuated in patients already treated with a beta-blocker, including Lopresor 100 mg film-coated tablets or Lopresor 200 mg prolonged-release tablets.

Ergot alkaloids

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

Dipyridamole

In general, administration of a beta-blocker should be discontinued prior to a dipyridamole test, closely monitoring heart rate after dipyridamole injection.

Alcohol

Metoprolol can modify the pharmacokinetic parameters of alcohol.

04.6 Pregnancy and lactation

Pregnancy

There are only limited data on the use of metoprolol in pregnant women. Experience with metoprolol in the first trimester of pregnancy is limited, but no malformations attributable to metoprolol have been reported to date. However, beta-blockers can reduce placental perfusion. Limited animal studies indicate no direct or indirect effects of reproductive toxicity (see section 5.3). The maternal-fetal risk is unknown.

For the above, Lopresor should only be administered to pregnant women if there is a clear need. In case of treatment with Lopresor during pregnancy, the lowest possible dose should be used and therapy should be suspended at least 2 or 3 days before delivery, to avoid an increase in uterine contractility and the effects of beta blockade in the unborn child (e.g. . bradycardia, hypoglycemia).

Breastfeeding

Small amounts of metoprolol are excreted in breast milk: at therapeutic doses an infant taking 1 liter of breast milk per day would receive a metoprolol dose of less than 1 mg. However, during lactation it is advisable to keep the newborn under close control for manifestations and symptoms of beta-blockade.

Fertility

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

Metoprolol tartrate exhibited effects on rat spermatogenesis at therapeutic doses, but there was no effect on conception rate at much higher doses in animal fertility studies (see section 5.3).

04.7 Effects on ability to drive and use machines

Dizziness, fatigue or visual disturbances may occur during treatment with Lopresor (see section 4.8) which may adversely affect the ability to drive and use machines.

04.8 Undesirable effects

Adverse reactions observed in clinical trials are listed by MedDRA organ class and systems. Within each class, adverse reactions are sorted by frequency, with the most frequent reaction cited first. Within each frequency group, adverse reactions are presented in order of decreasing severity. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: very common (≥1 / 10); common (≥1 / 100 y

Disorders of the blood and lymphatic system

Very rare: thrombocytopenia.

Psychiatric disorders

Rare: depression, nightmares.

Very rare: personality disorders, hallucinations

Disorders of the nervous system

Common: dizziness, headache.

Rare: reduced level of consciousness, drowsiness or insomnia, paraesthesia.

Eye disorders

Very rare: visual impairment (e.g. blurred vision), irritation, dry eyes.

Ear and labyrinth disorders

Very rare: tinnitus, hearing disturbances1 (e.g. hearing loss or deafness)

Heart ailments

Common: bradycardia.

Rare: heart failure, cardiac arrhythmias, palpitations.

Very rare: conduction disturbances, chest pain.

Vascular disorders

Common: orthostatic hypotension (occasionally with syncope).

Rare: edema, Raynaud's phenomenon.

Very rare: gangrene2

Respiratory, thoracic and mediastinal disorders

Common: exertional dyspnea.

Rare: bronchospasm 3.

Very rare: rhinitis.

Gastrointestinal disorders

Common: nausea, vomiting, abdominal pain.

Rare: diarrhea, constipation.

Very rare: dry mouth, retroperitoneal fibrosis 4

Hepatobiliary disorders

Very rare: hepatitis.

Disorders of the skin and subcutaneous tissue

Rare: rash (in the form of urticaria, psoriasiform and dystrophic skin lesions).

Very rare: photosensitivity reactions, hyperhidrosis, alopecia, worsening of psoriasis.

Musculoskeletal and connective tissue disorders

Rare: muscle cramps

Very rare: arthritis.

Disorders of the reproductive system and breast

Very rare: erectile dysfunction, libido disturbance, Peyronie's disease 4.

General and administration site disorders

Common: fatigue

Diagnostic tests

Very rare: weight gain, liver function test abnormalities.

1 in doses higher than those recommended;

2 in patients with pre-existing peripheral circulatory diseases;

3 can occur in patients with no history of obstructive pulmonary disease;

4 the relationship with Lopresor has not been definitively established.

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

The following adverse reactions have been derived from post-marketing experience of Lopresor 100 mg film-coated tablets or Lopresor 200 mg prolonged-release tablets, from spontaneous and literature reports. not known and are subject to confusion factors, it is not possible to reliably estimate their frequency which is therefore defined as "not known".

Adverse reactions are listed by MedDRA organ class and systems. Within each class, adverse reactions are presented in order of decreasing severity.

Disorders of the nervous system

Confusional state

Diagnostic tests

Hypertriglyceridemia, reduced HDL.

04.9 Overdose

Signs and symptoms

An overdose of the drug can lead to severe hypotension, sinus bradycardia, atrioventricular block, myocardial infarction, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, deterioration of consciousness (or even coma), seizures, nausea, vomiting, cyanosis and death.

The simultaneous intake of alcohol, antihypertensives, quinidine, barbiturates aggravates the signs and symptoms. The first manifestations of overdose occur from 20 minutes to 2 hours after the administration of the drug. The effects of a massive overdose can persist for several days, despite the decline in plasma concentrations.

Treatment

Patients with overdose of beta-blockers must always be hospitalized in order to monitor vital functions (cardiac function, blood gas analysis, biochemical parameters). If appropriate, emergency supportive measures, such as artificial ventilation or heart rate regulation, should be instituted. Although apparently in good condition, patients who have taken doses that cause a modest overdose should be closely observed for at least 4 hours for evidence of symptoms of poisoning.

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

Other clinical manifestations of overdose should be managed symptomatically on the basis of modern intensive care systems.

Beta blocker withdrawal may occur after an episode of overdose (see section 4.4).

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: cardioselective, unassociated beta-blockers

ATC code C07AB02

Metoprolol is a cardioselective beta-blocker that acts on β1-adrenergic receptors, mainly located in the heart, at lower doses than those that stimulate the β2-receptors, mainly located in the bronchi and peripheral vessels. Metoprolol has no membrane stabilizing effect, nor does it exhibit partial agonist activity (ISA).

The stimulating effect of catecholamines on the heart is reduced or inhibited by metoprolol. This causes a decrease in heart rate, contractility and output.

Metoprolol lowers high blood pressure both in ortho- and supine position. It also reduces the extent of blood pressure increases that occur in response to physical exercise. Treatment with metoprolol causes an initial increase in peripheral vascular resistance, which in the course of of long-term therapies normalizes or even decreases. As with all beta-blockers, the precise mechanism of the antihypertensive effect of metoprolol is not fully known. However, the long-term reduction in blood pressure observed with metoprolol appears to be directly proportional to the gradual reduction in total peripheral resistance.

In angina pectoris, metoprolol reduces the frequency and severity of ischemic attacks and increases exercise tolerance. These beneficial effects may be due to reduced myocardial oxygen demand, as a result of reduced heart rate and myocardial contractility.

In case of supraventricular tachycardia, atrial fibrillation or ventricular extrasystoles or other ventricular arrhythmias, metoprolol has a regulating effect on heart rate. Its antiarrhythmic action is mainly due to the inhibition of the automatism of the sinoatrial node and to the prolongation of the atrioventricular conduction time.

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

Thanks to its beta-blocking effect, metoprolol is indicated for the treatment of functional heart disorders with palpitations, for the prevention of migraine and for use in hyperthyroidism as an additional drug.

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

In short-term studies, it has been shown that metoprolol can exert an "influence on blood lipids, causing an increase in triglycerides and a decrease in free fatty acids; in some cases a small decrease in the HDL fraction has been observed, although to a lesser extent. amount compared to non-selective beta-blockers In a long-term study, lasting several years, cholesterol levels were reduced.

Pharmacokinetic and pharmacodynamic studies indicate that 30% of maximum beta-1-adrenoceptor antagonistic activity is essential for a minimal pharmacodynamic effect which is observed with approximately 45 nmol / L of metoprolol in plasma.

05.2 Pharmacokinetic properties

Absorption

After oral administration of conventional tablets, metoprolol is absorbed rapidly, evenly and almost completely along the intestinal tract. The absorption of metoprolol from the Lopresor 200 mg prolonged-release tablets it is slower, but the bioavailability of metoprolol is similar to that obtained with conventional tablets. Peak plasma concentrations are reached after approx. 1.5-2 hours. with Lopresor 100 mg coated tablets and after 4-5 hours approx. with Lopresor 200 mg prolonged-release tablets. Plasma concentrations of metoprolol increase almost dose proportionally over the range of 50-200 mg.

Due to massive hepatic first pass elimination, only about 50% of a single oral dose of metoprolol reaches the systemic circulation. The extent of pre-systemic elimination differs at the individual level, due to genetic differences in oxidative metabolism. Although plasma profiles have a "wide intersubjective variability, they are well reproducible in a single individual.

Following repeated administration, the percentage of the systemically available dose is approximately 40% higher. than that obtained with a single dose (i.e. 70% approx.). This may be due to partial saturation of first pass metabolism or to reduced clearance as a result of reduced hepatic blood flow. Simultaneous ingestion of food can increase the systemic bioavailability of a single oral dose by approximately 20-40%.

Distribution

Metoprolol is extensively and rapidly distributed, with a volume of distribution of 3.2-5.6 l / kg. The apparent volume of distribution at equilibrium (Vss) in heavy metabolisers (4.84 L / kg) is relatively higher than that in poor metabolisers (2.83 L / kg). The half-life is not dose dependent and does not change in case of repeated administration. 10% approx. of plasma metoprolol is bound to proteins. Metoprolol crosses the placenta and is found in breast milk (see section 4.6). In patients with hypertension, concentrations of metoprolol in CSF are similar to those in plasma.

Metoprolol is not a significant substrate for P-glycoproteins, suggesting that the inter-individual pharmacokinetic variability of metoprolol is mainly due to CYP2D6 metabolism.

Metabolism

Metoprolol is extensively metabolised by hepatic enzymes of the cytochrome P450 system. The main metabolic pathways of metoprolol are alpha-hydroxylation, O-demethylation and oxidative deamination. The alpha-hydroxylation of metoprolol is stereo-selective. The oxidative metabolism of metoprolol is genetically controlled with an important contribution from the 2D6 isoform of the polymorphic cytochrome P450. However, cytochrome P450 2D6-dependent metabolism of metoprolol appears to have little or no effect on drug safety and tolerability. No metabolites of metoprolol contribute significantly to its beta-blocking effect.

Proportionality of the dose

Metoprolol exhibits saturable pre-systemic metabolism which, with increasing dose, leads to a non-proportional increase in exposure.

Elimination

The mean elimination half-life of metoprolol is 3-4 hours; in slow metabolising subjects it can be 7-9 hours. After single oral administration of 100 mg metoprolol the median clearance was 31, 168 and 367 L / h, respectively. in poor metabolisers, heavy metabolisers and ultra-rapid metabolisers. Renal clearance of stereoisomers does not show stereo-selectivity in renal excretion.About 95% of an oral dose is excreted in the urine. The amount of drug eliminated in unchanged form is, in the majority of subjects (extensively metabolised), less than about 5%, but can reach 30% in subjects with slow metabolization.

Effects of food

Food intake appears to increase the rate of absorption of metoprolol resulting in a slightly higher maximum plasma concentration in a shorter time. However, this has no significant impact on clearance or the time at which maximum concentration (Tmax) is observed.

In order to minimize the intraindividual variability of the effect, it is recommended to take Lopresor in constant relationship with food (see section 4.2).

Pharmacokinetics in special patient groups

Geriatric patients

In the geriatric population, a slightly higher maximum plasma concentration of metoprolol may be observed as a result of reduced drug metabolism in the elderly patient associated with reduced blood flow to the liver. However, this increase is not clinically significant or therapeutically relevant. Metoprolol does not accumulate upon repeated administration and there is no need for dosage adjustments in the elderly population.

Patients with impaired renal function

The pharmacokinetics of metoprolol are not affected in patients with impaired renal function. However, there is the possibility of accumulation of a less active metabolite in patients with a creatinine clearance of less than 5 mL / min, but this accumulation does not affect the beta-blocking properties of the drug.

Patients with impaired renal function can usually be treated with normal dosages.

Patients with impaired hepatic function

As the drug is mainly cleared by hepatic metabolism, hepatic impairment may affect the pharmacokinetics of metoprolol. The elimination half-life of metoprolol is considerably prolonged, based on severity (up to 7.2 h), in these patients (see section 4.2).

Patients with porta-cava anastomosis

Patients with porta-cava anastomosis have a systemic clearance of approx. 0.3 l / min and AUC values up to 6 times higher than in healthy volunteers.

Patients with inflammatory diseases

Inflammatory diseases do not affect the pharmacokinetics of metoprolol.

Patients with hyperthyroidism

Hyperthyroidism may increase the pre-systemic clearance of metoprolol.

Ethnic sensitivity

The oxidative metabolism of metoprolol is genetically controlled with an important contribution of the 2D6 isoform of the polymorphic cytochrome P450.

There are significant ethnic differences in the prevalence of the "poor metabolisers" (PM) phenotype. Approximately 7% of Caucasians and less than 1% of Orientals are PMs. Poor CYP2D6 metabolisers have plasma concentrations of metoprolol several times higher than "good metabolisers" with normal CYP2D6 activity.

Gender effects

There is no significant evidence to suggest possible elimination differences between male and female populations, no gender-specific dosage recommendations are needed for metoprolol.

05.3 Preclinical safety data

Reproductive toxicity

Reproductive toxicity studies in mice, rats and rabbits revealed no teratogenic potential of metoprolol tartrate. Embryotoxicity and / or fetotoxicity in rats and rabbits were observed from doses of 50 mg / kg in rats and 25 mg / kg in rabbits, as demonstrated by pre-implantation losses, reduction in the number of viable fetuses per mare and / or reduction in neonatal survival. High doses have been associated with some maternal toxicity and growth retardation of the offspring, in utero, as shown by minimal weight deficit at birth. Metoprolol tartrate was associated with reversible adverse effects on spermatogenesis from oral doses of 3.5 mg / kg in rats, although other studies did not show any effect of metoprolol tartrate on reproductive performance in male rats.

Mutagenicity

In the Ames test with bacterial cells, and in the in vivo tests with mammalian somatic cells or male mouse germ cells, metoprolol tartrate was found to be devoid of mutagenic / genotoxic potential.

Carcinogenicity

After oral administration of doses up to 800 mg / kg for 21-24 months, metoprolol tartrate was not carcinogenic in mice and rats.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Lopresor 100 mg film-coated tablets

Sodium starch A, colloidal anhydrous silica, magnesium stearate, microcrystalline cellulose, hypromellose, hydrogenated polyhydric castor oil, talc, titanium dioxide.

Lopresor 200 mg prolonged-release tablets

Colloidal anhydrous silica, microcrystalline cellulose, dibasic calcium phosphate dihydrate, polyacrylate dispersion 30%, magnesium stearate, glyceryl palmitate stearate, hypromellose, polysorbate 80, talc, titanium dioxide, yellow iron oxide.