Bisoprolol - Generic Drug - Package Leaflet

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

Active ingredients: Bisoprolol (Bisoprolol Fumarate)

Bisoprolol Mylan 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg or 10 mg film-coated tablets

Why is Bisoprolol - Generic Drug used? What is it for?

Bisoprolol belongs to a class of medicines called beta-blockers. Beta blockers protect the heart from excessive activity.

Bisoprolol Mylan 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg tablets is used in combination with other medicines to treat stable heart failure. Heart failure occurs when the heart muscle is too weak to pump blood properly.

This causes difficulty in breathing and swelling. Bisoprolol lowers the heart rate and makes the heart more efficient at pumping blood around. Bisoprolol Mylan 5 mg and 10 mg tablets are also used to treat high blood pressure and angina pectoris (chest pain caused by blockages in the arteries that supply the heart muscle).

Contraindications When Bisoprolol - Generic Drug should not be used

Do not take Bisoprolol Mylan if you:

  • you are allergic (hypersensitive) to bisoprolol or any of the other ingredients of Bisoprolol Mylan tablets.
  • suffer from severe asthma or severe chronic lung disease
  • have a slow or irregular heartbeat (less than 60 beats per minute). Ask your doctor if you are not sure
  • have very low blood pressure
  • suffer from severe circulatory problems (which can cause tingling or a pale or bluish color in the fingers and toes)
  • suffer from "heart failure that suddenly gets worse and / or that may require treatment in hospital
  • have excess acid in the blood, a condition known as metabolic acidosis
  • have untreated pheochromocytoma, a rare tumor of the adrenal glands.

Precautions for use What you need to know before taking Bisoprolol - Generic Drug

Tell your doctor before you start taking this medicine if:

  • suffer from asthma or chronic lung disease
  • suffer from diabetes. Bisoprolol can hide the symptoms of low blood sugar
  • does not eat solid foods
  • are being treated for hypersensitivity reactions (allergies). Bisoprolol can make your allergy worse or make it more difficult to treat
  • have heart problems
  • have liver or kidney problems
  • has circulation problems in the limbs
  • you must undergo "general anesthesia for surgery, in which case please tell your doctor that you are taking bisoprolol
  • you are taking verapamil or diltiazem, medicines used to treat heart disease. Concomitant use is not recommended, see also section "Taking other medicines"
  • have (or have had) psoriasis (a "recurring rash)
  • suffer from foecromocytoma (a rare tumor of the adrenal glands). Your doctor will need to treat this disease before prescribing Bisoprolol Mylan for you
  • have thyroid problems. These tablets can hide the symptoms of an overactive thyroid.

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.

Interactions Which drugs or foods can modify the effect of Bisoprolol - Generic Drug

Tell your doctor if you are taking any of the following medicines as they may interact with Bisoprolol Mylan:

  • medicines to control hypertension or for heart problems (such as amiodarone, amlodipine, clonidine, digitalis glucosides, diltiazem, disopyramide, felodipine, flecainide, lidocaine, methyldopa, moxonidine, phenytoin, propafenone, quinidine, rilmenidine, verapamil).
  • medicines for depression, such as imipramine, amitriptyline, moclobemide
  • medicines to treat mental disorders, eg. phenothiazines, such as levopromazine
  • medicines used for anesthesia during surgery (see also "Take special care with Bisoprolol Mylan")
  • medicines used to treat epilepsy, eg barbiturates, such as phenobarbital
  • some analgesics (e.g. acetylsalicylic acid, diclofenac, indomethacin, ibuprofen, naproxen)
  • medicines for asthma or used for a stuffy nose
  • medicines used for certain types of eye disorders, such as glaucoma (increased pressure in the eye) or used to widen the pupil of the eye
  • some medicines used to treat shock (e.g. adrenaline, dobutamine, noradrenaline)
  • mefloquine, a medicine used for malaria.
  • all of these medicines as well as bisoprolol can affect blood pressure and / or heart function
  • rifampicin, to treat infections
  • medicines to treat severe headaches or migraines (ergotamine and derivatives).

Tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Taking Bisoprolol Mylan with food and drink

Bisoprolol Mylan should be taken in the morning, including with food. The tablets must be swallowed with liquid and must not be chewed.

Warnings It is important to know that:

Pregnancy and breastfeeding

Bisoprolol Mylan may be dangerous in pregnancy and / or the baby (increased chance of premature birth, miscarriage, developmental delay, low blood glucose and reduced heart rate in the baby).

Therefore you should not use this medicine during pregnancy.

It is unknown whether bisoprolol is excreted in breast milk. Therefore, breastfeeding while using this medicine is not recommended.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

The use of Bisoprolol Mylan can sometimes cause dizziness or tiredness (see "Possible side effects"). If you suffer from these side effects, you should not use vehicles and / or machines. These side effects are more likely to occur early in the day. treatment or change of dosage.

Important information about some of the ingredients of Bisoprolol Mylan

1.25mg, 2.5mg, 3.75mg, 5mg, 7.5mg, 10mg tablets

They contain lactose. If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicine.

5 mg and 7.5 mg tablets

They contain tartrazine (E102), can cause allergic reactions.

10 mg tablets

They contain the dye "Sunset Yellow" (E110): it can cause allergic reactions.

Dose, Method and Time of Administration How to use Bisoprolol - Generic Drug: Posology

Always take Bisoprolol Mylan tablets exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

  • Swallow the tablets with a glass of water
  • The tablets should not be chewed.

Adults

Chest pain and high blood pressure (angina and hypertension)

Your doctor will start treatment with the lowest possible dose (5 mg). Your doctor will monitor you closely at the start of treatment. Your doctor will increase your dose to get the best possible dose.

The maximum recommended dose is 20 mg once a day.

Patients with kidney disease

Patients with severe kidney disease should not exceed 10 mg bisoprolol once daily. Consult your doctor before starting to take this medicine.

Patients with liver disease

Patients with severe liver disease should not exceed 10 mg bisoprolol once daily. Consult your doctor before starting to use this medicine.

Heart failure

Before starting the use of Bisoprolol Mylan you must already be treated with other medicines for heart failure, including an ACE inhibitor, a diuretic and (as an additional option) a cardiac glucoside.

Treatment with Bisoprolol Mylan should start at a low dose and gradually increase. Your doctor will decide how to increase the dose and this will normally be done as follows:

  • 1.25 mg bisoprolol once daily for 1 week,
  • 2.5 mg bisoprolol once daily for 1 week,
  • 3.75 mg bisoprolol once daily for 1 week,
  • 5 mg bisoprolol once daily for 4 weeks,
  • 7.5 mg bisoprolol once daily for 4 weeks,
  • 10 mg bisoprolol once daily for maintenance therapy.

The maximum recommended dose is 10 mg bisoprolol per day.

Depending on how well you tolerate the medicine, your doctor may decide to lengthen the time between dose increases. If your condition gets worse or you can no longer tolerate the medicine, it may be necessary to reduce the dose or stop treatment. A maintenance dose of less than 10 mg bisoprolol may be sufficient in some patients.

Your doctor will tell you what to do.

Children

The use of Bisoprolol Mylan is not recommended because there is insufficient experience with the use of this medicine in children.

Elderly patients

A dose adjustment is generally not necessary. It is recommended to start with the lowest possible dose.

If you notice that your dose of Bisoprolol Mylan is too strong or does not work well enough, consult your doctor or pharmacist.

Overdose What to do if you have taken an overdose of Bisoprolol - Generic Drug

If you take more Bisoprolol Mylan than you should

If you take more Bisoprolol Mylan than you should contact your doctor or emergency department immediately. Take the container and any remaining tablets with you.

If you forget to take Bisoprolol Mylan

If you have forgotten to take a dose of Bisoprolol Mylan do not take a double dose to make up for a forgotten one. Take your next dose at the scheduled time. If you have missed several doses, contact your doctor.

If you stop taking Bisoprolol Mylan

If you suddenly stop taking Bisoprolol Mylan it is possible that you will suffer from side effects. Your doctor will slowly reduce your dose over 2 weeks.

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

Side Effects What are the side effects of Bisoprolol - Generic Drug

Like all medicines, Bisoprolol Mylan can cause side effects, although not everybody gets them.

The following side effects are important and require immediate action if they appear. You should stop taking Bisoprolol Mylan tablets and contact a doctor immediately if the following symptoms appear:

Common side effects (affects less than 1 in 10 patients):

  • worsening of heart failure causing shortness of breath and / or fluid retention.

Frequency not established:

  • worsening of symptoms of obstruction of the main blood vessels in the legs, particularly at the start of treatment.

The following side effects have also been reported:

Very common side effects (affects more than 1 in 10 patients):

  • slow heart rate.

Common side effects (affects less than 1 in 10 patients):

  • cold hands and / or feet
  • numbness of the hands and / or feet
  • lowering of blood pressure
  • nausea, vomiting, diarrhea, constipation
  • tiredness*
  • feeling of weakness
  • dizziness *
  • headache*

Uncommon side effects (affects less than 1 in 100 patients):

  • worsening of irregular heartbeat
  • sleep disorders
  • depression
  • breathing problems in patients with asthma or with chronic lung disease
  • muscle weakness, muscle cramps.

Rare side effects (affects less than 1 in 1000 patients):

  • changes in blood test results
  • reduced lacrimation (can be a problem if you use contact lenses)
  • hearing disorders
  • stuffy or runny nose
  • inflammation of the liver (hepatitis) which causes abdominal pain, loss of appetite and sometimes jaundice with yellowing of the whites of the eyes and skin and dark urine
  • hypersensitivity reactions, such as itching, redness and rash
  • reduced sexual activity
  • nightmares
  • hallucinations (seeing imaginary things)
  • fainting.

Very rare side effects (affects less than 1 user in 10,000):

  • eye inflammation (conjunctivitis)
  • worsening of psoriasis or appearance of a "rash-like" rash with dry, flaky skin
  • hair loss

* during treatment for hypertension or angina, these symptoms appear especially at the start of treatment or when the dose is changed. They are usually mild and often disappear within 1 to 2 weeks.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Keep out of the reach and sight of children.

Do not use Bisoprolol Mylan after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of that month.

Blisters: 1.25 mg, 2.5 mg: do not store above 25 ° C; 3.75 mg, 5 mg, 7.5 mg, 10 mg: Do not store above 30 ° C. Store in the original package in order to protect from moisture.

Bottle: 1.25 mg, 2.5 mg: do not store above 25 ° C; 3.75 mg, 5 mg, 7.5 mg, 10 mg: Do not store above 30 ° C. Store in the original package to protect from moisture. Use within 30 days of opening. Once opened, keep the bottle tightly closed.

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.

What Bisoprolol Mylan contains

Each film-coated tablet contains 1.25mg, 2.5mg, 3.75mg, 5mg, 7.5mg, 10mg of the active substance bisoprolol fumarate.

The other excipients are:

Tablet: microcrystalline cellulose, anhydrous lactose, anhydrous colloidal silica, magnesium stearate, sodium laurilsulfate, croscarmellose sodium, yellow iron oxide (E172) (only in 2.5 mg, 3.75 mg, 5 mg, 7.5 mg tablets ), red iron oxide (E172) (only in 2.5 mg and 10 mg tablets).

Film-coating: titanium dioxide (E171), polydextrose (E1200), hypromellose (E464), macrogol, black iron oxide (E172) (only in 2.5 mg tablets), yellow iron oxide (E172) (only in 3.75 mg and 10 mg tablets), tartrazine (E102) (5 mg and 7.5 mg tablets only), indigo carmine (E132) (5 mg tablets only), Sunset Yellow dye (only in tablets) 10 mg).

What Bisoprolol Mylan looks like and contents of the pack

Film-coated tablets

1.25 mg tablet: White, oval, biconvex film-coated tablets, "BL & 1" debossed on one side of the tablet and "M" debossed on the other side. 2.5 mg tablet: Film-coated tablets, gray, oval, biconvex, with scalloped edge; "BL & 2" engraved on one side of the score line on one side of the tablet and "M" engraved on the other side.

3.75 mg tablet: Cream colored, oval, biconvex, film-coated tablets with serrated edge; "BL & 3" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

5 mg tablet: Pale yellow, oval, biconvex, film-coated tablets with serrated edge; "BL & 4" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

7.5 mg tablet: Pale yellow, oval, biconvex, film-coated tablets with serrated edge; "BL & 5" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

10 mg tablet: Pale orange to light orange film-coated tablets, oval, biconvex, with serrated edge; "BL & 6" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

Bisoprolol Mylan tablets are packaged in blisters containing 28, 30, 84 and 90 film-coated tablets.

Bisoprolol Mylan tablets are packaged in bottles containing 100 and 500 film-coated 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.

More information on Bisoprolol - Generic Drug 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 interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 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 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

BISOPROLOL MYLAN TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

1.25 mg tablet

Each tablet contains 1.25 mg bisoprolol fumarate.

2.5 mg tablet

Each tablet contains 2.5 mg of bisoprolol fumarate.

3.75 mg tablet

Each tablet contains 3.75 mg of bisoprolol fumarate.

5 mg tablet

Each tablet contains 5 mg of bisoprolol fumarate.

7.5 mg tablet

Each tablet contains 7.5 mg of bisoprolol fumarate.

10 mg tablet

Each tablet contains 10 mg of bisoprolol fumarate.

Excipients with known effect:

1.25 mg tablet

Each tablet contains: 30 mg of lactose (anhydrous)

2.5 mg tablet

Each tablet contains: 30 mg of lactose (anhydrous)

3.75 mg tablet

Each tablet contains: 30 mg of lactose (anhydrous)

5 mg tablet

Each tablet contains: 0.069 mg of tartrazine (E102)

30 mg of lactose (anhydrous)

7.5 mg tablet

Each tablet contains: 0.018 mg of tartrazine (E102)

30 mg of lactose (anhydrous)

10 mg tablet

Each tablet contains: 0.042 mg of yellow dye (E110)

30 mg of lactose (anhydrous)

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

1.25 mg tablet:

White, oval, biconvex film-coated tablets, "BL & 1" debossed on one side of the tablet and "M" debossed on the other side.

2.5 mg tablet:

Gray, oval, biconvex, film-coated tablets with scalloped edge; "BL & 2" scored on one side of the score line on one side of the tablet and "M" scored on the other side.

3.7 mg tablet:

Cream colored, oval, biconvex, film-coated tablets with serrated edge; "BL & 3" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

5 mg tablet:

Pale yellow, oval, biconvex, film-coated tablets with serrated edge; "BL & 4" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

7.5 mg tablet:

Yellow, oval, biconvex, film-coated tablets with serrated edge; "BL & 5" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

10 mg tablet:

Pale orange to light orange, oval, biconvex, film-coated tablets with serrated edge; "BL & 6" engraved on the side of the score on one side of the tablet and "M" engraved on the other side.

2.5mg, 3.75mg, 5mg, 7.5mg, 10mg tablet:

The tablet can be divided into equal halves.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of hypertension.

Treatment of chronic stable angina pectoris.

Treatment of chronic, stable heart failure with reduced systolic ventricular function in addition to therapy with ACE inhibitors and diuretics and possibly cardiac glycosides (for further information see section 5.1).


04.2 Posology and method of administration

Dosage

Treatment of hypertension and chronic stable angina pectoris

Adults

The dose must be individually adjusted. It is recommended to start with 5 mg / day. The usual dose is 10 mg once daily with a recommended maximum of 20 mg / day.

Patients with renal or hepatic impairment

In patients with severe renal impairment (creatinine clearance

Senior citizens

Dosage adjustment is not normally required. It is recommended to start with the lowest possible dose.

Children

There is no experience regarding the use of bisoprolol in children, therefore its use cannot be recommended in children.

Suspension of treatment

Treatment should not be stopped suddenly (see section 4.4). Dosage should be tapered slowly, with weekly dose halving.

Treatment of stable chronic heart failure

Adults

Standard treatment of chronic heart failure includes an ACE inhibitor (or angiotensin receptor antagonist, in case of intolerance to ACE inhibitors), a beta blocker, diuretics and, when appropriate, cardiac glycosides. When starting treatment with bisoprolol, the patient must be stable (without acute failure).

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

Titration phase

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

Treatment with bisoprolol should begin with a gradual titration according to the following scheme:

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

• 2.5 mg once daily for another week, if well tolerated increase to

• 3.75 mg once daily for another week, if well tolerated increase to

• 5 mg once daily 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.

Transient worsening of heart failure, hypotension or bradycardia, may appear during the titration period and thereafter.

During the titration phase, careful monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended. Symptoms may appear during the first day after initiation of therapy.

Modification of treatment

If the maximum recommended dose is not well tolerated, a dose reduction may be considered.

In case of temporary worsening of heart failure, hypotension or bradycardia, dosage review of concomitant medications is recommended. It may also be necessary to temporarily reduce the dose of bisoprolol or consider discontinuing it.

When the patient becomes stable again, re-initiation of bisoprolol and / or titration should always be considered.

If discontinuation is considered, a gradual decrease in dose is recommended, as abrupt withdrawal may lead to deterioration of the patient's condition.

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

Special populations

Renal or hepatic impairment

There is no information regarding the pharmacokinetics of bisoprolol in patients with chronic heart failure and impaired hepatic or renal function. Increasing the dosage in these patients should be done with greater caution.

Senior citizens

Dose adjustments are not normally required.

Children

There is no experience regarding the use of bisoprolol in children, therefore its use cannot be recommended in children.

Method of administration

For oral use.

Bisoprolol Mylan tablets should be taken in the morning and can be taken with food. The tablet should be swallowed with liquid and should not be chewed.


04.3 Contraindications

Bisoprolol is contraindicated in patients with:

- hypersensitivity to the active substance or to one of the excipients listed in section 6.1,

- acute heart failure or during episodes of decompensated heart failure requiring intravenous inotropic therapy,

- cardiogenic shock,

- second or third degree atrioventricular block,

- sick sinus syndrome,

- sino-atrial block,

- symptomatic bradycardia,

- symptomatic hypotension,

- severe bronchial asthma or severe chronic obstructive pulmonary disease,

- severe forms of peripheral arterial occlusion or severe forms of Raynaud's syndrome,

- untreated pheochromocytoma (see section 4.4),

- metabolic acidosis.


04.4 Special warnings and appropriate precautions for use

Special warnings

They only concern chronic heart failure

Treatment of stable chronic heart failure with bisoprolol should begin with a particular titration phase (see section 4.2).

They concern all indications

Particularly in patients with ischemic heart disease, discontinuation of bisoprolol treatment should not be done suddenly unless clearly necessary, as it may lead to temporary worsening of the heart condition (see section 4.2).

The tablet contains lactose (anhydrous). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

5 mg and 7.5 mg tablet:

The tablet contains tartrazine (E102) - may cause allergic reactions.

10 mg tablet:

The tablet contains the dye Sunset yellow (E110) - may cause allergic reactions.

Precautions

They only concern hypertension or angina pectoris

Bisoprolol should be used with caution in patients with hypertension or angina pectoris associated with heart failure.

They only concern chronic heart failure

The initiation and termination of bisoprolol treatment requires regular monitoring. For the posology and method of administration see section 4.2.

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

• insulin-dependent diabetes mellitus (type I),

• severely impaired kidney function,

• severely impaired liver function,

• restrictive cardiomyopathy,

• congenital heart disease,

• hemodynamically significant organic valve disease,

• myocardial infarction within the previous 3 months.

They concern all indications

Bisoprolol should be used with caution in:

• bronchospasm (bronchial asthma, obstructive pulmonary disease),

• diabetes mellitus with large fluctuations in blood glucose values. Symptoms of hypoglycaemia (eg tachycardia, palpitations or sweating) can be masked,

• strict fasting,

• undergoing desensitization therapy. As with other beta-blockers, bisoprolol can increase both sensitivity to allergens and the severity of anaphylactic reactions. Treatment with adrenaline may not always lead to the expected therapeutic effect,

• 1st degree AV block,

• Prinzmetal's angina,

• peripheral occlusive arterial disease. Aggravation of symptoms may appear especially at the beginning of therapy.

Patients with psoriasis or a history of psoriasis should only be treated with beta-blockers (eg bisoprolol) after a "careful evaluation of the risks and benefits.

Symptoms of thyrotoxicosis may be masked during treatment with bisoprolol.

In patients with pheochromocytoma, bisoprolol should not be administered until alpha-receptor blockade.

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 normally recommended that maintenance beta-blocker treatment be continued during the period. peri-operative. The anesthetist should be advised of the use of the beta-blocker due to the potential interactions with other drugs that can cause bradyarrhythmias, alleviation of reflex tachycardia and decreased ability to reflexively compensate for blood loss. deems it necessary to discontinue beta-blocker therapy prior to surgery, discontinuation should be done gradually and completed approximately 48 hours prior to anesthesia.

In bronchial asthma or other chronic obstructive pulmonary diseases, which 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 airway resistance may be required. increased dose of beta-2 stimulants.


04.5 Interactions with other medicinal products and other forms of interaction

Combinations not recommended

They only concern chronic heart failure:

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

It covers all indications:

- Calcium antagonists 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.

- Centrally acting antihypertensive drugs such as clonidine and others (eg, methyldopa, moxonidine, rilmenidine): concomitant use of centrally acting antihypertensive drugs can worsen heart failure by a decrease in central sympathetic tone (reduction in frequency and cardiac output, 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:

They only concern hypertension or angina pectoris

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

They concern all indications

- Dihydropyridine calcium antagonists (eg amlodipine and felodipine): concomitant use may increase the risk of hypotension and an increase in the risk of further worsening 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 atrioventricular 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 the atrio-ventricular conduction time and the risk of bradycardia.

- Insulin and oral antidiabetics: increased hypoglycaemic effect. Blockade of beta-adrenergic receptors may mask the onset of hypoglycaemic symptoms.

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

- Sympathomimetics that activate both beta- and alpha-adrenergic receptors (such as noradrenaline, adrenaline): the combination with bisoprolol may unmask the vasoconstrictive effects of these agents mediated by alpha-adrenergic receptors, leading to an increase in blood pressure and worsening of intermittent claudication. 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 keep in mind

- Mefloquine: increased risk of bradycardia.

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

- Rifampicin: slight reduction in the half-life of bisoprolol, probably due to the induction of hepatic drug metabolising enzymes. Dosage adjustment is not normally necessary.

- Derivatives of ergotamine: exacerbation of peripheral circulatory disorders.

Pediatric population

Interaction studies have only been performed in adults.

For those who carry out sporting activities, the use of medicines containing bisoprolol can determine positive anti-doping tests.


04.6 Pregnancy and lactation

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 necessary, selective beta-1 blockers are preferred.

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. Monitor the neonate closely, as symptoms of hypoglycemia and bradycardia usually appear within the first three days.

Feeding time

There are no data on the excretion of bisoprolol in breast milk or on the safety of exposure to bisoprolol in infants. Therefore it is not recommended to take bisoprolol while breastfeeding.


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 treatment, in the event of a change in therapy and in the case of simultaneous alcohol intake.


04.8 Undesirable effects

The following definitions apply to the frequency terminology used below:

Very common (≥1 / 10),

Common (≥1 / 100 e

Uncommon (≥1 / 1000 and

Rare (≥1 / 10,000 e

Frequency unknown (cannot be determined from the available data).

Psychiatric disorders

Uncommon: sleep disturbances, depression.

Rare: nightmares, hallucinations.

Nervous system disorders

Common: dizziness *, headache *.

Rare: syncope.

Eye disorders

Rare: reduced lacrimation (to be considered in patients using lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders

Rare: hearing disorders.

Cardiac pathologies

Very common: bradycardia (in patients with chronic heart failure).

Common: worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon: AV conduction disturbances, worsening of pre-existing heart failure (in patients with hypertension or angina pectoris), bradycardia (in patients with hypertension or angina pectoris).

Vascular pathologies

Common: feeling of cold or numbness in the extremities, hypotension, particularly in patients with heart failure.

Respiratory, thoracic and mediastinal disorders

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

Rare: allergic rhinitis.

Gastrointestinal disorders

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

Hepatobiliary disorders

Rare: hepatitis.

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions, such as itching, flushing, rash.

Very rare: Beta-blockers can cause or worsen psoriasis or induce psoriasiform rash, alopecia.

Musculoskeletal and connective tissue disorders

Uncommon: muscle weakness, muscle cramps.

Diseases of the reproductive system and breast

Rare: erectile disorders

General disorders and administration site conditions

Common: asthenia (in patients with chronic heart failure), fatigue *.

Uncommon: asthenia (in patients with hypertension or angina pectoris).

Diagnostic tests

Rare: increased triglycerides and liver enzymes (ALT, AST).

Pediatric population

No data are available.

They only concern hypertension or angina pectoris

* These symptoms appear especially at the beginning of therapy. They are generally mild and often disappear within 1 to 2 weeks.


04.9 Overdose

Symptoms

The most common symptoms expected in the event of an overdose of a beta-blocker are: bradycardia, hypotension, bronchospasm, acute heart failure and hypoglycaemia. Experience with bisoprolol overdose is limited, only a few cases of bisoprolol overdose have been reported, manifesting bradycardia and / or hypotension. All patients recovered. There is a "large individual variability in sensitivity to a single dose. bisoprolol and patients with heart failure are likely to be very sensitive.

Treatment

In general, in the event of an overdose, bisoprolol treatment should be discontinued and supportive and symptomatic therapy instituted.

Based on the expected pharmacological actions and recommendations of other beta-blockers, the following general measures should be considered when clinically justified:

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 vasopressors should be administered. Intravenous administration of glucagon may be helpful.

Atrioventricular block (2nd or 3rd degree): Patients should be monitored closely and treated with isoprenaline infusion or a temporary pacemaker may need to be introduced.

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

Bronchospasm: administration of borncodilators, such as isoprenaline, beta-2 agonists and / or aminophylline.

Hypoglycemia: give glucose by i.v.

Limited data suggest that bisoprolol is difficult to dialyzable.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta-blocking agents, selective.

ATC code: C07AB07.

Chronic heart failure:

Mechanism of action

Bisoprolol is a potent beta-blocker highly selective for beta-1 receptors, devoid of intrinsic sympathomimetic activity and related membrane stabilizing activity. It has only 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 extends beyond the therapeutic dose range.

Clinical efficacy

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. Patients had stable, symptomatic heart failure (ejection fraction ≤ 35 %, detected on echocardiography). Total mortality decreased from 17.3% to 11.8% (relative reduction of 34%). A reduction in sudden death was observed (3.6% vs. 6.3%, with a relative reduction in 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 demonstrated in patients (NYHA class). 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 fatal and disabling strokes was 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III study evaluated 1010 patients ≥ 65 years of age with mild to moderate heart failure (NYHA class II or III) and left ventricular ejection fraction ≤ 35% who had not previously been treated with ACE inhibitors, beta- angiotensin receptor blockers or inhibitors. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months, following an initial 6 month treatment with bisoprolol or enalapril.

There was a trend towards a higher rate of worsening of chronic heart failure when bisoprolol was used as initial treatment in the first 6 months. In the "protocol" analysis, non-inferiority of bisoprolol was not proven as first treatment vs. enalapril as first treatment, although the two treatment initiation strategies for chronic heart failure showed a similar frequency of the combined "death" and hospitalization endpoint at the end of the study (32.4% in the group initiating with bisoprolol vs. 33.15 in the enalapril starting group in the per-protocol population). The study shows that bisoprolol can also be used in elderly patients with mild to moderate chronic heart failure.

Hypertension or angina pectoris

Mechanism of action

Antianginal mechanism: By inhibiting cardiac beta receptors, bisoprolol inhibits the response given to sympathomimetic activation. This leads to a decrease in heart rate and contractility, thus decreasing the oxygen demand of the heart muscle.

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.

Pharmacodynamic effects

Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other beta1-blockers, the mechanism of action in hypertension is unclear. However, bisoprolol is known to markedly reduce plasma renin activity.


05.2 "Pharmacokinetic properties

Absorption

Bisoprolol is absorbed almost completely through the gastrointestinal tract. Together with the very small first pass effect in the liver, this leads to a very high bioavailability of approximately 90%.

Distribution

The plasma protein binding of bisoprolol is approximately 30%. The volume of distribution is 3.5 l / kg. Total clearance is approximately 15 l / h.

The plasma half-life (10 - 12 hours) allows 24 hours of therapeutic efficacy after once daily administration.

Biotransformation

50% is transformed into inactive metabolites in the liver, which are then eliminated by the kidney.

Excretion

Bisoprolol is excreted via two routes: approximately 50% is transformed into inactive metabolites in the liver, which are then eliminated by the kidney. The remaining 50% is excreted unchanged via the kidney. Since elimination occurs equally in the kidney and liver, no dose adjustment is normally required in patients with hepatic impairment or renal insufficiency.

Other special populations

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 steady 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 show no particular risk for humans based on conventional studies on pharmacological safety, repeated dose toxicity, genotoxicity or carcinogenic potential, toxicity to reproduction and development.

Like other beta-blockers bisoprolol caused pregnancy toxicity (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

1.25 mg tablets

Tablet

Microcrystalline cellulose

Anhydrous lactose

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Croscarmellose sodium.

Coating film

Titanium dioxide (E171)

Polydextrose FCC (E1200)

Hypromellose (E464)

Macrogol.

2.5 mg tablets

Tablet

Microcrystalline cellulose

Anhydrous lactose

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Yellow iron oxide (E172)

Red iron oxide (E172)

Croscarmellose sodium.

Coating film

Titanium dioxide (E171)

Polydextrose FCC (E1200)

Hypromellose (E464)

Macrogol

Black iron oxide (E172).

3.75 mg tablets

Tablet

Microcrystalline cellulose

Anhydrous lactose

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Yellow iron oxide (E172)

Croscarmellose sodium.

Coating film

Titanium dioxide (E171)

Polydextrose FCC (E1200)

Hypromellose (E464)

Macrogol

Yellow iron oxide (E172).

5 mg tablets

Tablet

Microcrystalline cellulose

Anhydrous lactose

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Yellow iron oxide (E172)

Croscarmellose sodium.

Coating film

Titanium dioxide (E171)

Polydextrose FCC (E1200)

Hypromellose (E464)

Macrogol

Tartrazine (E102)

Indigo carmine (E132)

7.5 mg tablets

Tablet

Microcrystalline cellulose

Anhydrous lactose

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Yellow iron oxide (E172)

Croscarmellose sodium.

Coating film

Titanium dioxide (E171)

Polydextrose FCC (E1200)

Hypromellose (E464)

Macrogol

Tartrazine (E102)

10 mg tablets

Tablet

Microcrystalline cellulose

Anhydrous lactose

Anhydrous colloidal silica

Magnesium stearate

Sodium lauryl sulfate

Red iron oxide (E172)

Croscarmellose sodium.

Coating film

Titanium dioxide (E171)

Polydextrose FCC (E1200)

Hypromellose (E464)

Macrogol

Yellow iron oxide (E172)

Sunset yellow (E110).


06.2 Incompatibility

Not applicable.


06.3 Period of validity

For 1.25 mg and 2.5 mg strengths only:

Blister: 18 months.

Bottle: 18 months.

For 3.75mg, 5mg, 7.5mg, 10mg strengths only:

Blister: 21 months.

Bottle: 24 months.


06.4 Special precautions for storage

For 1.25 mg and 2.5 mg strengths only:

Blisters: Store at a temperature not exceeding 25 ° C. Store in the original package in order to protect from moisture.

Bottle: Store at a temperature not exceeding 25 ° C. Store in the original package to protect from moisture. Use within 100 days of opening. Once opened, keep the bottle tightly closed.

For 3.75mg, 5mg, 7.5mg, 10mg strengths only:

Blisters: Store at a temperature not exceeding 30 ° C. Store in the original package in order to protect from moisture.

Bottle: Store at a temperature not exceeding 30 ° C. Store in the original package to protect from moisture. Use within 100 days of opening. Once opened, keep the bottle tightly closed.


06.5 Nature of the immediate packaging and contents of the package

PVC / Al blisters. The blister consists of clear and transparent PVC film with aluminum foil coated with heat seal lacquer containing 28, 30, 84 and 90 film-coated tablets.

White HDPE bottles, with white opaque polypropylene cap, containing 100 and 500 film-coated tablets.

The bottle contains a perforated HDPE filter with silica gel and desiccant activated carbon.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

Mylan S.p.A.

Via Vittor Pisani, 20

20124 Milan

08.0 MARKETING AUTHORIZATION NUMBER

Packaging

"1.25 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486019 / M (base 10) 16MK43 (base 32)

Packaging

"1.25 mg film-coated tablets" 30 tablets in PVC / AL blister

AIC n. 040486021 / M (base 10) 16MK45 (base 32)

Packaging

"1.25 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486033 / M (base 10) 16MK4K (base 32)

Packaging

"1.25 mg film-coated tablets" 90 tablets in PVC / AL blister

AIC n. 040486045 / M (base 10) 16MK4X (base 32)

Packaging

"2.5 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486058 / M (base 10) 16MK5B (base 32)

Packaging

"2.5 mg film-coated tablets" 30 tablets in PVC / AL blister

AIC n. 040486060 / M (base 10) 16MK5D (base 32)

Packaging

"2.5 mg film-coated tablets" 84 tablets in PVC / AL blister

AIC n. 040486072 / M (base 10) 16MK5S (base 32)

Packaging

"2.5 mg film-coated tablets" 90 tablets in PVC / AL blister

AIC n. 040486084 / M (base 10) 16MK64 (base 32)

Packaging

"3.75 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486096 / M (base 10) 16MK6J (base 32)

Packaging

"3.75 mg film-coated tablets" 30 tablets in PVC / AL blister

AIC n. 040486108 / M (in base 10) 16MK6W (in base 32)

Packaging

"3.75 mg film-coated tablets" 84 tablets in PVC / AL blister

AIC n. 040486110 / M (base 10) 16MK6Y (base 32)

Packaging

"3.75 mg film-coated tablets" 90 tablets in PVC / AL blister

AIC n. 040486122 / M (base 10) 16MK7B (base 32)

Packaging

"5 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486134 / M (base 10) 16MK7Q (base 32)

Packaging

"5 mg film-coated tablets" 30 tablets in PVC / AL blister

AIC n. 040486146 / M (base 10) 16MK82 (base 32)

Packaging

"5 mg film-coated tablets" 84 tablets in PVC / AL blister

AIC n. 040486159 / M (base 10) 16MK8H (base 32)

Packaging

"5 mg film-coated tablets" 90 tablets in PVC / AL blister

AIC n. 040486161 / M (base 10) 16MK8K (base 32)

Packaging

"7.5 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486173 / M (base 10) 16MK8X (base 32)

Packaging

"7.5 mg film-coated tablets" 30 tablets in PVC / AL blister

AIC n. 040486185 / M (in base 10) 16MK99 (in base 32)

Packaging

"7.5 mg film-coated tablets" 84 tablets in PVC / AL blister

AIC n. 040486197 / M (base 10) 16MK9P (base 32)

Packaging

"7.5 mg film-coated tablets" 90 tablets in PVC / AL blister

AIC n. 040486209 / M (base 10) 16MKB1 (base 32)

Packaging

"10 mg film-coated tablets" 28 tablets in PVC / AL blister

AIC n. 040486211 / M (base 10) 16MKB3 (base 32)

Packaging

"10 mg film-coated tablets" 30 tablets in PVC / AL blister

AIC n. 040486223 / M (in base 10) 16MKBH (in base 32)

Packaging

"10 mg film-coated tablets" 84 tablets in PVC / AL blister

AIC n. 040486235 / M (base 10) 16MKBV (base 32)

Packaging

"10 mg film-coated tablets" 90 tablets in PVC / AL blister

AIC n. 040486247 / M (base 10) 16MKC7 (base 32)

"1.25 mg film-coated tablets" 100 tablets in HDPE bottles

AIC n. 040486250 / M (base 10) 16MKCB (base 32)

Packaging

"1.25 mg film-coated tablets" 500 tablets in HDPE bottles

AIC n. 040486262 / M (base 10) 16MKCQ (base 32)

Packaging

"2.5 mg film-coated tablets" 100 tablets in HDPE bottles

AIC n. 040486274 / M (base 10) 16MKD2 (base 32)

Packaging

"2.5 mg film-coated tablets" 500 tablets in HDPE bottles

AIC n. 040486286 / M (base 10) 16MKDG (base 32)

Packaging

"3.75 mg film-coated tablets" 100 tablets in HDPE bottles

AIC n. 040486298 / M (base 10) 16MKDU (base 32)

Packaging

"3.75 mg film-coated tablets" 500 tablets in HDPE bottles

AIC n. 040486300 / M (base 10) 16MKDW (base 32)

Packaging

"5 mg film-coated tablets" 100 tablets in HDPE bottles

AIC n. 040486312 / M (base 10) 16MKF8 (base 32)

Packaging

"5 mg film-coated tablets" 500 tablets in HDPE bottles

AIC n. 040486324 / M (base 10) 16MKFN (base 32)

Packaging

"7.5 mg film-coated tablets" 100 tablets in HDPE bottles

AIC n. 040486336 / M (base 10) 16MKG0 (base 32)

Packaging

"7.5 mg film-coated tablets" 500 tablets in HDPE bottles

AIC n. 040486348 / M (base 10) 16MKGD (base 32)

Packaging

"10 mg film-coated tablets" 100 tablets in HDPE bottles

AIC n. 040486351 / M (base 10) 16MKGH (base 32)

Packaging

"10 mg film-coated tablets" 500 tablets in HDPE bottles

AIC n. 040486363 / M (base 10) 16MKGV (base 32)

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

May 30, 2011

10.0 DATE OF REVISION OF THE TEXT

December 2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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