SEQUACOR - PACKAGE LEAFLET - LEAFLETS

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Sequacor - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Bisoprolol (Bisoprolol fumarate)

Sequacor 1.25 mg film-coated tablets
Sequacor 2.5 mg film-coated tablets
Sequacor 3.75 mg film-coated tablets
Sequacor 5 mg film-coated tablets
Sequacor 7.5 mg film-coated tablets
Sequacor 10 mg film-coated tablets

Why is Sequacor used? What is it for?

The active ingredient contained in Sequacor is bisoprolol. Bisoprolol belongs to a group of drugs known as beta blockers. These drugs work by affecting the body's response to certain nerve impulses, especially in the heart. Consequently, bisoprolol slows the heartbeat rate and allows the heart to circulate blood more easily throughout the body.

Heart failure occurs when the heart muscle weakens and is no longer able to pump enough blood to meet the body's needs. Sequacor is indicated in the treatment of stable chronic heart failure. It is usually used in combination with other medicines indicated to treat this condition (such as ACE inhibitors, diuretics and cardiac glycosides).

Contraindications When Sequacor should not be used

Do not take Sequacor if any of the following apply to you:

Allergy (hypersensitivity) to bisoprolol or to any of the components (see section 6 "What Sequacor contains");
Severe asthma
Severe circulatory problems in the extremities (such as Raynaud's Syndrome) resulting in tingling in the toes and hands, which may turn pale or blue
Untreated pheochromocytoma which is a rare tumor of the adrenal gland;
Metabolic acidosis, which is a condition in which there is an increase in acids in the blood.

Do not take Sequacor if you suffer from any of the following heart problems:

Acute heart failure;
Worsening of heart failure requiring intravenous administration of drugs that increase the strength of contraction of the heart;
Slow heartbeat
Low pressure;
Certain heart conditions that cause a slow heart rate or an irregular heartbeat;
Cardiogenic shock, which is a severe acute heart condition that causes a lowering of blood pressure and circulatory failure.

Precautions for use What you need to know before taking Sequacor

If you suffer from any of the following conditions tell your doctor before taking Sequacor; he / she may wish to act with caution (e.g. prescribe additional treatment or perform more frequent checks):

Diabetes;
Strict fasting;
Certain heart diseases such as heart rhythm disturbances or severe chest pain at rest (Prinzmetal's angina);
Kidney or liver problems
Circulatory disorders in the extremities of lesser severity;
Chronic lung disease or minor asthma
History of skin peeling (psoriasis)
Adrenal gland tumor (pheochromocytoma);
Thyroid disorders.

Also tell your doctor if you are going to have:

to desensitizing therapy (for example to prevent hay fever), since Sequacor may make the onset of an allergic reaction more likely or this reaction may manifest itself in a more severe form;
to anesthesia (e.g. for surgery), as Sequacor can influence your body's reactions in this situation.

Tell your doctor immediately if you have chronic lung disease or minor asthma if you start to experience new difficulty in breathing, coughing, wheezing after exercise, etc. when using Sequacor.

Children and adolescents

The use of Sequacor is not recommended in children and adolescents. For those who carry out sporting activities: the use of the drug without therapeutic need constitutes doping and can in any case determine positive anti-doping tests.

Interactions Which drugs or foods can modify the effect of Sequacor

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

Do not take the following medicines at the same time as Sequacor unless your doctor has specific instructions:

some medicines used to treat an abnormal or irregular heartbeat (Class I antiarrhythmics such as quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone);
some medicines used to treat high blood pressure, angina pectoris or irregular heartbeat (calcium channel blockers such as verapamil and diltiazem);
some medicines used to treat hypertension such as clonidine, methyldopa, moxonodine, rilmenidine. However, do not stop taking these medicines without first consulting with your doctor.

Consult your doctor before taking the following medicines at the same time as Sequacor; your doctor may find it necessary to check your condition more frequently:

some medicines used to treat hypertension or angina pectoris (dihydropyridine calcium channel blockers such as felodipine and amlodipine);
some medicines used to treat irregular or abnormal heart beat (class III antiarrhythmic drugs such as amiodarone);
topical beta-blockers (such as timolol-based eye drops for the treatment of glaucoma);
some medicines used to treat Alzheimer's disease or glaucoma (parasympathomimetics such as tacrine or carbachol) or medicines used to treat acute heart problems (sympathomimetics such as isoprenaline or dobutamine);
antidiabetic medicines including insulin;
anesthetics (for example, during surgery);
digitalis, used to treat heart failure;
non-steroidal anti-inflammatory drugs (NSAIDs) to treat arthritis, pain or inflammation (eg ibuprofen or diclofenac);
any medicine that can lower blood pressure, whether this effect is intended or not, such as antihypertensives, some medicines for the treatment of depression (tricyclic antidepressants such as "imipramine or" amitriptyline), some drugs for the treatment of epilepsy or used during anesthesia (barbiturates such as phenobarbital) or some drugs for the treatment of psychotic disorders characterized by loss of contact with reality (phenothiazines such as levomepromazine);
mefloquine for the prevention or treatment of malaria;
antidepressants called monoamine oxidase inhibitors (except MAO-B inhibitors) as well as meclobemide.

Warnings It is important to know that:

Pregnancy and breastfeeding

Pregnancy

Using Sequacor during pregnancy could harm your baby. Tell your doctor if you are pregnant or planning to become pregnant. Your doctor will decide whether you can take Sequacor during pregnancy.

Feeding time

It is not known whether bisoprolol passes into breast milk. Breast-feeding is therefore not recommended during therapy with Sequacor.

Driving and using machines

Your ability to drive or operate machinery may be impaired depending on your degree of tolerance to the medicine. Be particularly cautious at the beginning of treatment, when increasing the dose or when the medicine is changed and also in the case of simultaneous alcohol intake.

Dosage and method of use How to use Sequacor: Dosage

Always take this medicine exactly as your doctor has told you. If you are unsure, ask your doctor or pharmacist.

Treatment with Sequacor should take place under regular medical supervision. Particularly at the beginning of the treatment, and in the phase of increasing the dose and at the end of the treatment.

Take the tablet with some water in the morning, with or without food. Do not crush or chew the tablet. The scored tablets can be divided into two equal doses.

Sequacor treatment is usually a long-lasting treatment.

Adults, including the elderly:

Treatment with bisoprolol should be started with a low dose and gradually increased. Your doctor will decide how to increase the dose. Normally this will happen in the following way:

1.25 mg bisoprolol once daily for one week;
2.5 mg bisoprolol once daily for one week;
3.75 mg bisoprolol once daily for one week;
5 mg bisoprolol once daily for four weeks;
7.5 mg bisoprolol once daily for four weeks;
10 mg bisoprolol once daily as a maintenance (long-term) dose.

The maximum recommended daily dose is 10 mg bisoprolol.

Depending on your degree of tolerance to the drug, your doctor may decide to extend the intervals between dose increases. If your condition worsens or if you can no longer tolerate the drug, it may be necessary to reduce the dose again or to discontinue treatment. A maintenance dose of bisoprolol of less than 10 mg may be sufficient in some patients.

Your doctor will tell you what to do.

If you have to stop treatment permanently, your doctor will usually advise you to reduce the dose gradually; otherwise, his condition could worsen.

If you forget to take Sequacor

Do not take a double dose to make up for a forgotten dose. Take your usual dose the next morning.

If you stop taking Sequacor

Do not stop taking Sequacor unless your doctor tells you to. Otherwise, your condition can seriously worsen. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Sequacor

If you have taken more Sequacor tablets than you should, tell your doctor immediately. Your doctor will decide what measures to take.

Symptoms of an overdose can include: slow heart rate, severe breathing difficulties, dizziness or tremor (due to decreased blood sugar).

Side Effects What are the side effects of Sequacor

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

To prevent serious reactions, contact your doctor immediately if the side effect is serious, has come on suddenly or gets worse quickly.

The most serious side effects relate to heart function:

slow heart rate (may affect more than 1 in 10 people)
worsening of heart failure (may affect up to 1 in 10 people)
slow or irregular heartbeat (may affect up to 1 in 100 people)

If you feel dizzy or faint or have difficulty breathing, contact your doctor as soon as possible.

Other side effects are listed below based on how frequently they have occurred:

Common (may affect up to 1 in 10 people):

Tiredness, feeling of weakness, dizziness, headache;
Feeling cold or numb in the hands or feet
Low pressure;
Gastric or intestinal problems such as nausea, vomiting, diarrhea or constipation.

Uncommon (may affect up to 1 in 100 people):

Sleep disorders;
Depression;
Dizziness when standing up
Breathing problems in patients with asthma or chronic lung disease;
Muscle weakness, muscle cramps.

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

Hearing problems
Allergic rhinitis;
Reduced lacrimation;
Inflammatory process of the liver which can cause yellowing of the skin or the sphere of the eye;
Abnormal results of some blood tests for liver function or abnormal concentration of fat;
Allergic-like reactions such as itching, flushing, rash;
Impaired erection;
Nightmares, hallucinations;
Fainting (syncope)

Very rare (may affect up to 1 in 10,000 people) (affects less than 1 in 10,000 people):

Eye irritation and redness (conjunctivitis);
Hair loss
Onset or worsening of skin peeling (psoriasis); psoriasis in the form of a rash.

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.

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 the month.

Sequacor 1.25 mg film-coated tablets:

Sequacor 2.5 mg film-coated tablets:

Sequacor 3.75 mg film-coated tablets:

Store at a temperature not exceeding 25 ° C.

Sequacor 5 mg film-coated tablets:

Sequacor 7.5 mg film-coated tablets:

Sequacor 10 mg film-coated tablets:

Store at a temperature not exceeding 30 ° C.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Sequacor contains

Sequacor 1.25 mg film-coated tablets

The active ingredient is bisoprolol fumarate. Each film-coated tablet contains 1.25 mg
The other ingredients are:

Tablet core: anhydrous colloidal silica; magnesium stearate; crospovidone; pregelatinised maize starch; cornstarch; microcrystalline cellulose; calcium hydrogen phosphate (anhydrous).

Coating: dimethicone; talc; macrogol 400; titanium dioxide (E171); hypromellose.

Sequacor 2.5 mg film-coated tablets

The active ingredient is bisoprolol fumarate. Each film-coated tablet contains 2.5 mg
The other ingredients are:

Tablet core: anhydrous colloidal silica; magnesium stearate; crospovidone; cornstarch; microcrystalline cellulose; calcium hydrogen phosphate (anhydrous).

Coating: dimethicone; macrogol 400; titanium dioxide (E171); hypromellose.

Sequacor 3.75 mg film-coated tablets

The active ingredient is bisoprolol fumarate. Each film-coated tablet contains 3.75 mg
The other ingredients are:

Tablet core: anhydrous colloidal silica; magnesium stearate; crospovidone; cornstarch; microcrystalline cellulose; calcium hydrogen phosphate (anhydrous).

Coating: yellow iron oxide (E172); dimethicone; macrogol 400; titanium dioxide (E171); hypromellose.

Sequacor 5 mg film-coated tablets

The active ingredient is bisoprolol fumarate. Each film-coated tablet contains 5 mg
The other ingredients are:

Tablet core: anhydrous colloidal silica; magnesium stearate; crospovidone; cornstarch; microcrystalline cellulose; calcium hydrogen phosphate (anhydrous).

Coating: yellow iron oxide (E172), dimethicone, macrogol 400, titanium dioxide (E171), hypromellose.

Sequacor 7.5 mg film-coated tablets

The active ingredient is bisoprolol fumarate. Each film-coated tablet contains 7.5 mg
The other ingredients are: Tablet core: anhydrous colloidal silica; magnesium stearate; crospovidone; cornstarch; microcrystalline cellulose; calcium hydrogen phosphate (anhydrous). Coating: yellow iron oxide (E172); dimethicone; macrogol 400; titanium dioxide (E171); hypromellose.

Sequacor 10 mg film-coated tablets

The active ingredient is bisoprolol fumarate. Each film-coated tablet contains 10 mg
The other ingredients are:

Tablet core: anhydrous colloidal silica; magnesium stearate; crospovidone; cornstarch; microcrystalline cellulose; calcium hydrogen phosphate (anhydrous).

Coating: red iron oxide (E172); yellow iron oxide (E172); dimethicone; macrogol 400; titanium dioxide (E171); hypromellose.

What Sequacor looks like and contents of the pack

Sequacor 1.25 mg film-coated tablets are round and white in color.

Sequacor 2.5 mg film-coated tablets are heart-shaped, white and scored on both sides.

Sequacor 3.75 mg film-coated tablets are heart-shaped, cream-white and scored on both sides.

Sequacor 5 mg film-coated tablets are heart-shaped, white to yellowish tablets with a score line on both sides.

Sequacor 7.5 mg film-coated tablets are heart-shaped, light yellow and scored on both sides.

Sequacor 10 mg film-coated tablets are pale orange to light orange heart-shaped tablets with a score line on both sides.

Each pack contains 20, 28, 30, 50, 56, 60, 90, or 100 tablets.

Not all pack sizes may be marketed.

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 Sequacor is available 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 the 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 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 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 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

SEQUACOR TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

SEQUACOR 1.25 mg Each tablet contains 1.25 mg bisoprolol fumarate

SEQUACOR 2.5 mg Each tablet contains 2.5 mg bisoprolol fumarate

SEQUACOR 3.75 mg Each tablet contains 3.75 mg bisoprolol fumarate

SEQUACOR 5 mg Each tablet contains 5 mg bisoprolol fumarate

SEQUACOR 7.5 mg Each tablet contains 7.5 mg bisoprolol fumarate

SEQUACOR 10 mg Each tablet contains 10 mg bisoprolol fumarate

Excipients: see paragraph 6.1

03.0 PHARMACEUTICAL FORM -

Film-coated tablets:

SEQUACOR 1.25 mg White, round, film-coated tablets SEQUACOR 2.5 mg White, heart-shaped, film-coated tablets with score line SEQUACOR 3.75 mg Cream-white, heart-shaped, film-coated tablet with score line SEQUACOR 5 mg White to yellowish white, heart-shaped, film-coated tablets with score line SEQUACOR 7.5 mg Light yellow, heart-shaped, film-coated tablets with score line SEQUACOR 10 mg Pale orange to light orange, heart-shaped, film-coated tablets with score line

The scored tablets can be divided into two equal doses.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Treatment of chronic, stable heart failure with reduced left ventricular systolic function, in combination with ACE inhibitors, diuretics and possibly cardioactive glycosides.

(For further information see section 5.1).

04.2 Posology and method of administration -

The standard treatment of chronic heart failure involves the use of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocker, diuretics and, when necessary, cardiac glycosides.

Patients must be stable (without acute failure) when bisoprolol treatment is initiated.

It is recommended that the physician has clinical experience in the treatment of chronic heart failure.

During the titration phase and immediately thereafter, transient phenomena of worsening of heart failure, hypotension or bradycardia may occur.

Dosage

Titration phase

Treatment of chronic, stable heart failure with bisoprolol requires a dose titration step.

Treatment with bisoprolol should begin with a low dose to be gradually increased according to the following schedule:

- 1.25 mg once daily for 1 week, if well tolerated increase to

- 2.5 mg once daily for the following week, if well tolerated increase to

- 3.75 mg once daily for the following week, if well tolerated increase to

- 5 mg once a day for the next 4 weeks, if well tolerated increase to

- 7.5 mg once daily for the next 4 weeks, if well tolerated increase to

- 10 mg once daily for maintenance therapy

The maximum recommended dose is 10 mg once a day.

During the titration phase, careful monitoring of vital signs (heart rate, blood pressure) and symptoms indicative of worsening heart failure is recommended. Symptoms may appear as early as the first day of treatment.

Treatment modification:

If the maximum recommended dose is not well tolerated consider a gradual dose reduction.

It is recommended that the dosage of concomitant therapy be re-examined in case of transient worsening of heart failure, hypotension or bradycardia. It may also be necessary to temporarily reduce the dose of bisoprolol or to consider discontinuing it.

Reintroduction and / or an increase in bisoprolol dosage should always be considered only when the patient is stable again.

In case of discontinuation of the drug a gradual reduction of the dose is recommended as a sudden withdrawal could cause an acute deterioration of the patient's condition.

Treatment of chronic, stable heart failure with bisoprolol is generally a long-term treatment.

Impaired renal or hepatic function

There is no information regarding the pharmacokinetics of bisoprolol in patients with chronic heart failure and impaired hepatic or renal function.

Dosage increases in these patients should be made with greater caution.

Senior citizens

No dose adjustments are required.

Pediatric population

There is no pediatric experience with bisoprolol, therefore its use is not recommended in pediatric patients.

Method of administration

Bisoprolol tablets should be taken in the morning and can be taken with food. They must be swallowed with liquid and not chewed.

04.3 Contraindications -

Bisoprolol is contraindicated in patients with chronic heart failure in the presence of:

• acute heart failure or episodes of decompensated heart failure requiring intravenous inotropic therapy;

• cardiogenic shock;

• second or third degree atrioventricular (AV) block

• sick sinus syndrome;

• sino-atrial block;

• symptomatic bradycardia;

• symptomatic hypotension

• severe bronchial asthma or severe obstructive and chronic lung disease;

• severe form of peripheral arterial occlusion and Raynaud's syndrome;

• untreated pheochromocytoma (see section 4.4);

• metabolic acidosis;

• hypersensitivity to bisoprolol or to any of the excipients (listed in section 6.1).

04.4 Special warnings and appropriate precautions for use -

Treatment of stable chronic heart failure with bisoprolol must be initiated with a special titration step.

Discontinuation of bisoprolol therapy, especially in patients with ischemic heart disease, should not be done abruptly unless necessary, as this may transiently aggravate the heart condition.

The initiation and cessation of bisoprolol treatment requires regular monitoring.

There is no therapeutic experience with bisoprolol in heart failure in patients with the following diseases and conditions:

• insulin dependent diabetes mellitus (type I);

• severe impairment of renal function;

• severe impairment of liver function;

• restrictive myocardiopathy;

• congenital heart disease;

• hemodynamically significant organic valve diseases;

• myocardial infarction (within the previous 3 months).

Bisoprolol should be used with caution in case of:

• bronchospasm (bronchial asthma, obstructive airway diseases);

• diabetes mellitus with unstable blood sugar; symptoms of hypoglycemia can be masked;

• strict fasting;

• ongoing desensitizing therapy; As with other beta-blockers, bisoprolol can increase both sensitivity to allergens and the severity of anaphylactic reactions. Treatment with adrenaline does not always produce the expected therapeutic effect.

• 1st degree atrioventricular block;

• Prinzmetal's angina;

• peripheral arterial occlusion (worsening of symptoms may occur especially at the start of therapy)

• general anesthesia

In patients undergoing general anesthesia, beta-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and in the postoperative period. It is currently recommended that any maintenance beta-blocker treatment be continued in the peri-operative period. The anesthetist should be advised of the use of the beta blocker due to potential interactions with other drugs which may cause bradyarrhythmias, alleviation of reflex tachycardia and decreased ability to reflexively compensate for blood loss.

If it is deemed necessary to discontinue beta-blocker therapy prior to surgery, discontinuation should be done gradually and completed approximately 48 hours prior to anesthesia.

The combination of bisoprolol with calcium channel blockers of the verapamil or diltiazem type, with class I antiarrhythmic drugs and centrally acting antihypertensive drugs, is generally not recommended; for details refer to paragraph 4.5.

In bronchial asthma or other chronic obstructive pulmonary diseases that can cause symptoms, concomitant therapy with bronchodilators should be given.

In individual cases, in patients with asthma, an increase in airway resistance may occur, therefore an increase in the dose of beta2 stimulants may be necessary.

In patients with psoriasis or a family history of psoriasis, the benefit-risk balance should be carefully evaluated before administration of beta-blockers (bisoprolol).

In patients with pheochromocytoma bisoprolol should not be administered separately by an alpha blocker.

Symptoms of thyrotoxicosis may be masked during bisoprolol therapy.

04.5 Interactions with other medicinal products and other forms of interaction -

Combinations not recommended

Calcium channel blockers of the verapamil type and to a lesser extent of the diltiazem type: negative influence on contractility and atrio-ventricular conduction.

Intravenous administration of verapamil in patients on beta-blocker treatment may lead to marked hypotension and atrioventricular block.

Class I antiarrhythmic drugs (eg quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): the effect on atrioventricular conduction time can be potentiated and the negative inotropic effect can be increased.

Centrally acting antihypertensive drugs such as clonidine and others (eg, methyldopa, moxonidine, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in central sympathetic tone (decreased rate and stroke cardiac, vasodilation). Abrupt discontinuation, particularly if prior to discontinuation of the beta-blocker, may increase the risk of "rebound hypertension".

Combinations to be used with caution

Dihydropyridine calcium channel blockers, such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension and the risk of further deterioration of the functional status of the ventricular pump in patients with heart failure cannot be excluded.

Class III antiarrhythmic drugs (eg amiodarone): the effect on atrio-ventricular conduction time can be potentiated.

Topical beta-blockers (e.g. eye drops for the treatment of glaucoma) may have an additive effect to the systemic effects of bisoprolol.

Parasympathomimetic Drugs: Concomitant use may increase atrioventricular conduction time and the risk of bradycardia.

Insulin and oral antidiabetics: increased blood glucose lowering effect. Blockade of beta receptors may mask the onset of hypoglycaemic symptoms.

Anesthetic agents: Attenuation of reflex tachycardia and increased risk of hypotension (for more information on general anesthesia see also section 4.4).

Digitalis glycosides: reduced heart rate, increased atrio-ventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.

Beta agents-sympathomimetics (such as isoprenaline, dobutamine): the combination with bisoprolol can reduce the effect of these drugs.

Sympathomimetics that activate both beta- and alpha-adrenoceptors (such as norepinephrine, adrenaline): combination with bisoprolol may unmask the vasoconstrictive effects of these alpha-mediated agents, leading to increased blood pressure and worsening of claudication intermittent. Such interactions are considered more likely with non-selective beta-blockers.

Concomitant use of antihypertensive agents as well as other drugs with a potential blood pressure lowering effect (such as tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.

Associations to be taken into consideration

Mefloquine: increased risk of bradycardia.

Monoamine oxidase inhibitors (except MAO B inhibitors): increased hypotensive effect of beta-blockers but also risk of hypertensive crisis.

04.6 Pregnancy and breastfeeding -

Pregnancy

Bisoprolol has pharmacological effects which may lead to harmful effects during pregnancy and / or in the fetus / newborn. In general, beta-blockers reduce placental perfusion, which is associated with fetal growth retardation, intrauterine death, abortion or premature birth. Undesirable effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and neonate. If beta-blocker therapy is required, selective beta-1 blockers are preferable. Bisoprolol should not be used during pregnancy unless clearly necessary. In this case, monitor the utero-placental blood flow and fetal growth. Consider alternative therapies in case of harmful effects on pregnancy and the fetus. The newborn should be closely monitored. Symptoms of hypoglycemia and bradycardia generally occur within the first three days.

Breastfeeding

It is not known whether the drug is excreted in breast milk. Therefore, breastfeeding is not recommended during bisoprolol therapy.

04.7 Effects on ability to drive and use machines -

In a clinical study, in patients with coronary artery disease, bisoprolol was found not to adversely affect the ability to drive. However, due to individual variations in drug reactions, the ability to drive and use machines may be affected. This must be considered in particular at the start of therapy, in the event of a change in therapy and in the case of simultaneous alcohol intake.

04.8 Undesirable effects -

Frequency terminology definitions:

Very common (≥ 1/10)

Common (≥1 / 100,

Uncommon (≥ 1 / 1,000 to

Rare (≥ 1 / 10,000,

Very rare (

Cardiac pathologies:

Very common: bradycardia

Common: worsening of heart failure

Uncommon: atrioventricular conduction disturbances.

Laboratory tests:

Rare: Increased triglycerides, increased liver enzymes (ALAT, ASAT).

Nervous System Pathologies:

Common: dizziness, headache

Rare: syncope.

Eye disorders:

Rare: reduced lacrimation (to be taken into account if wearing contact lenses)

Very rare: conjunctivitis.

Ear and labyrinth disorders:

Rare: hearing disorders.

Respiratory, thoracic and mediastinal disorders:

Uncommon: bronchospasm in patients with bronchial asthma or a history of obstructive respiratory disease

Rare: allergic rhinitis.

Gastrointestinal disorders:

Common: gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (itching, redness, rash)

Very rare: alopecia.Beta blockers could cause or worsen psoriasis or induce pseudo-psoriatic rashes.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle weakness and cramps.

Vascular pathologies:

Common: feeling of cold or tingling in the extremities; hypotension

Uncommon: orthostatic hypotension.

Systemic pathologies:

Common: asthenia, fatigue.

Hepatobiliary disorders:

Rare: hepatitis.

Diseases of the reproductive system and breast:

Rare: disorders of male sexual function.

Psychiatric disorders:

Uncommon: sleep disturbances, depression

Rare: nightmares, hallucinations.

04.9 Overdose -

Following overdose (e.g. a daily dose of 15 mg instead of 7.5 mg), third degree A-V block, bradycardia, and dizziness have been reported. In general, the most common symptoms expected in the event of an overdose of a beta-blocker are: bradycardia, hypotension, bronchospasm, acute heart failure and hypoglycaemia. Few cases of overdose with bisoprolol (maximum dose: 2000 mg) have been reported to date in patients with hypertension and / or coronary artery disease who have experienced bradycardia and / or hypotension; all patients recovered. There is "a" large individual variability in sensitivity to a single high dose of bisoprolol and heart failure patients are likely to be very sensitive. It is therefore mandatory to start the therapy of these patients with a gradual titration according to the scheme reported in section 4.2.

In the event of an overdose, bisoprolol treatment should be discontinued and supportive and symptomatic therapy instituted. Limited data suggest that bisoprolol is difficult to dialyzable. Based on the expected pharmacological actions and recommendations of other beta-blockers, the following general measures should be considered when clinically required.

- Bradycardia: administer intravenous atropine. If the response is inadequate, isoprenaline or another drug with positive chronotropic properties may be administered with caution. In some circumstances it may be necessary to insert a transvenous pacemaker.

- Hypotension: intravenous fluids and vasopressor agents should be administered. Intravenous administration of glucagon may be helpful.

- Atrioventricular block (degree II or III): Patients should be monitored closely and treated with isoprenaline infusion or a transvenous pacemaker may need to be introduced.

- Acute worsening of heart failure: administer intravenous diuretics, inotropic drugs, vasodilators.

- Bronchospasm: Administer bronchodilators such as isoprenaline, beta-2 sympathomimetic drugs and / or aminophylline.

- Hypoglycemia: administer an intravenous glucose solution.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: beta-blocking agents, selective, ATC code: C07AB07

Bisoprolol is a highly selective beta-blocker for beta-1 receptors, lacking intrinsic sympathomimetic activity (ISA) and significant membrane stabilizing activity. It has a low affinity for beta-2 receptors of bronchial and vascular smooth muscle as well as for beta-2 receptors that regulate metabolism. Consequently, bisoprolol is generally not expected to affect airway resistance and beta-2 receptor mediated metabolic effects.

The selectivity of bisoprolol towards beta-1 receptors is not dose dependent.

A total of 2647 patients were included in the CIBIS II clinical trial.

83% (n = 2202 patients) were NYHA class III patients, while 17% (n = 445 patients) were NYHA class IV. The patients had stable, symptomatic heart failure (ejection fraction? 35 %, based on echocardiography). Total mortality decreased from 17.3% to 11.8% (relative reduction of 34%).

In addition, a reduction in sudden deaths (3.6% vs 6.3%, with a relative reduction of 44%) and a reduced number of heart failure episodes requiring hospitalization (12% vs 17.6%, relative reduction of 36%).

Finally, a significant improvement in functional status was shown in patients (NYHA class). During the initial and titration phase of bisoprolol there were hospitalizations due to bradycardia (0.53%), hypotension (0.23%) and acute decompensation (4.97%), but in a similar percentage to the placebo group (0 %, 0.3% and 6.74%).

During the entire study period the number of strokes fatal and disabling was 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III clinical trial involved 1010 patients aged ≥65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35% who had not previously been treated with ACE inhibitors, beta-blockers or angiotensin receptor blockers. Patients were treated initially for 6 months with either bisoprolol or enalapril and then for up to 24 months with a combination of bisoprolol and enalapril.

There was a trend of higher frequency of worsening of chronic heart failure when bisoprolol was used in the initial 6-month treatment. Non-inferiority of treatment with bisoprolol used first compared to enalapril used first was not demonstrated in the "analyses per-protocol, although the two strategies for initiating chronic heart failure treatment demonstrated similar results at the end of treatment for the combined primary end-point of death and hospitalization (32.4% in the group initially treated with bisoprolol versus 33, 11% in the enalapril group, population per-protocol). The study shows that bisoprolol can also be used in elderly patients with mild to moderate chronic heart failure.

Bisoprolol is also used for the treatment of hypertension and angina.

Acute administration of bisoprolol in patients with coronary artery disease without chronic heart failure reduces heart rate, systolic output and consequently cardiac output and oxygen consumption. In chronic administration the high initial peripheral resistance decreases.

05.2 "Pharmacokinetic properties -

Absorption

The absorption and bioavailability of bisoprolol after oral administration reaches 90%.

Distribution

The volume of distribution is 3.5 l / kg. The plasma protein binding of bisoprolol is approximately 30%.

Biotransformation and Elimination

Bisoprolol is eliminated from the body by two routes: about 50% is transformed into inactive metabolites in the liver, then eliminated by the kidney; while the remaining 50% is excreted unchanged by the kidney.

Total clearance is approximately 15 l / h. The plasma half-life of 10-12 hours allows 24 hours of therapeutic efficacy after once daily administration.

Linearity

The kinetics of bisoprolol are linear and independent of age.

Special Population

Since excretion occurs equally in the kidney and liver, no dosage adjustment is normally required in patients with impaired liver function or renal insufficiency. Pharmacokinetic parameters in patients with chronic, stable and compromised heart failure hepatic or renal function have not yet been studied.

Plasma levels and half-life of bisoprolol in patients with chronic, stable heart failure (NYHA class III) are prolonged compared to healthy volunteers.

The maximum plasma concentration at the steady state is 64 ± 21 ng / ml for a daily dose of 10 mg and the half-life is 17 ± 5 hours.

05.3 Preclinical safety data -

Non-clinical data reveal no particular risk for humans based on studies on safety, repeated dose toxicity, genotoxicity and carcinogenic potential.

Like other beta-blockers bisoprolol caused toxicity in pregnancy (decreased food intake or weight loss) and embryo-fetal toxicity (increased incidence of resorption, decreased birth weight and delayed physical development) at high doses. but it showed no teratogenic effects.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

SEQUACOR 1.25 mg

Tablet: anhydrous colloidal silica, magnesium stearate, crospovidone, pregelatinised maize starch, maize starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate.

coating film: dimethicone, talc, macrogol 400, titanium dioxide (E 171), hypromellose.

SEQUACOR 2.5 mg