ZYBAN - PACKAGE LEAFLET - LEAFLETS

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Zyban - Package Leaflet

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

Active ingredients: Bupropion (Bupropion hydrochloride)

Zyban 150 mg prolonged-release tablets

Why is Zyban used? What is it for?

Zyban is a medicine prescribed to help you quit smoking, when you will also have motivational support such as taking part in a "stop smoking" program.

Zyban will be much more effective if you are absolutely determined to quit smoking.

Ask your doctor or pharmacist for advice on treatments and other aids to help you stop smoking.

Contraindications When Zyban should not be used

Do not take Zyban:

If you are allergic to bupropion or any of the other ingredients of this medicine
If you are taking any other medicines containing bupropion (e.g. Wellbutrin to treat depression)
If you have a medical condition that can cause seizures, such as epilepsy or have a history of seizures
If you have, or have ever had, an eating disorder (eg bulimia or anorexia nervosa)
If you have severe liver disease such as cirrhosis
If you have a brain tumor
If you normally drink alcohol in large quantities and have just stopped drinking alcohol or intend to do so shortly while taking Zyban
If you have recently stopped taking sedatives or anxiety medications (especially benzodiazepines or similar medicines) or are planning to stop while taking Zyban
If you have bipolar disorder (excessive mood swings), since Zyban can trigger an episode of this disease
If you are currently taking, or have taken within the past 14 days, a medicine from the group called monoamine oxidase inhibitors (MAOIs), which are normally used to treat depression or Parkinson's disease. Your doctor will advise you that the time period may be shorter for some types of MAOIs.

If any of the above apply to you, talk to your doctor immediately, and do not take Zyban.

Precautions for use What you need to know before taking Zyban

Talk to your doctor or pharmacist before taking Zyban. This is because some conditions can increase the risk of side effects.

Children and adolescents

Zyban is not recommended for people under the age of 18.

Adults

Seizures (convulsions)

Zyban can cause seizures (convulsions) in about 1 in 1000 people. (For more information see "Other medicines and Zyban" later in this section and also section 4 "Possible side effects"). The likelihood of having seizures is higher if:

is used to drinking alcohol abundantly
have diabetes that requires treatment with insulin or other oral medicines
have suffered a severe head injury or have a history of head injury

If any of the above apply to you, do not take Zyban without checking with your doctor that there is a good reason to take this medicine.

If you have a seizure (convulsion) during treatment:

Stop taking Zyban and don't take it again. Talk to your doctor.

It may have an increased risk of side effects:

if you have kidney or liver problems
if you are over the age of 65.

You will need to take a lower dose and have regular checkups while you are taking Zyban.

If you have had any form of mental illness ...

Some people taking Zyban have had hallucinations or delusions (seeing, hearing or believing things that don't exist), confused thoughts or excessive mood swings. These effects are more common in those people who have previously had mental illness.

If you feel depressed or have suicidal thoughts

Some people become depressed when they try to quit smoking; very rarely, they may come to think that they are committing suicide, or even try to commit suicide. These symptoms have been seen in people taking Zyban, most often in the first few weeks of treatment.

If you feel depressed or are thinking about suicide:

Contact your doctor or go to a hospital immediately.

High blood pressure and Zyban

Some people taking Zyban have had a rise in blood pressure that requires treatment. If you already have high blood pressure, it can get worse. This may be more common if you are also using nicotine patches to help you quit smoking.

You will need to check your blood pressure before taking Zyban and while you are taking it, especially if you already have high blood pressure. If you are also using nicotine patches, your blood pressure needs to be checked every week. If your blood pressure rises, you may need to stop taking Zyban.

Interactions Which drugs or foods can change the effect of Zyban

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

You may be at a higher risk of seizures than normal if you are taking:

medicines for depression or medicines to treat other mental illnesses (see also "Do not take Zyban" at the beginning of section 2)

theophylline for asthma or lung disease

tramadol, which is a strong pain reliever

anti-malarial medicines

stimulants or other drugs to control weight or appetite

steroids (except ointments and lotions for eye and skin diseases)

antibiotics belonging to the quinolone group

some types of antihistamines used primarily to treat allergies, which can cause drowsiness

diabetes medications

If you take any of the medications on this list, talk to your doctor as soon as possible, before taking Zyban.

Some medications can interact with Zyban or make the risk of side effects more likely. These include:

medicines for depression (such as desipramine, imipramine, paroxetine) or medicines to treat other mental illnesses (such as risperidone, thioridazine)
medicines used to treat Parkinson's disease (for example levodopa, amantadine or orphenadrine)
carbamazepine, phenytoin or valproate used to treat epilepsy or certain mental illnesses
some medicines used to treat malignant tumors (such as cyclophosphamide, ifosfamide)
ticlopidine or clopidogrel, which are medicines mainly used to treat heart disease or stroke
some beta-blockers (such as metoprolol) used mainly to treat high blood pressure
medicines used to treat heart rhythm abnormalities (such as propafenone, flecainide)
ritonavir or efavirenz, to treat HIV infections

If you take any of the drugs on this list, consult your doctor. Your doctor will evaluate the benefit / risk for you of taking Zyban, or may decide to change the dose of the other medicines you are taking.

Zyban may make other medicines less effective:

If you are taking tamoxifen used to treat breast cancer

If this applies to you, tell your doctor. You may need to use another smoking cessation treatment.

If you are taking digoxin for the heart

If this applies to you, tell your doctor. Your doctor may consider changing your digoxin dose.

Warnings It is important to know that:

When you stop smoking, the dose of some medicines may need to be reduced

When you smoke, chemicals absorbed into your body can make some medicines less effective. When you stop smoking, the dose of these medicines may need to be reduced; otherwise, it could have side effects.

If you are taking other medications, consult your doctor if you notice any new symptoms that you think may be a side effect.

Zyban and alcohol

Some people find that they are more sensitive to the effects of alcohol when taking Zyban. Your doctor may advise you not to drink alcohol while taking Zyban, or to drink very little alcohol. If you are currently drinking a significant amount of alcohol, do not stop suddenly because this can put you at risk of having a seizure.

Interference with urinalysis

Zyban may interfere with some urine tests due to the presence of other medications. If you require a urinalysis, please tell your doctor or hospital that you are taking Zyban.

Pregnancy and breastfeeding

Zyban should not be used in pregnancy. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Some, but not all studies have reported an increased risk of birth defects, particularly heart defects, in babies whose mothers took Zyban. It is not known whether these are due to the use of Zyban.

The components of Zyban can pass into breast milk. Ask your doctor or pharmacist for advice before taking Zyban.

Driving cars and using machines

Some of the side effects of Zyban, such as dizziness and lightheadedness, can decrease concentration and judgment.

Affected patients should not drive or operate machinery.

Dose, Method and Time of Administration How to use Zyban: Posology

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

When to start therapy and the dose to take:

You start taking Zyban while you are still smoking
Define a "quit date" ideally during the second week of treatment

Week 1 You can ideally continue smoking while taking Zyban from 1st to 6th day Take one tablet (150 mg) once a day 7th day Increase the dose to one tablet twice a day, leaving at least 8 hours between each dose and not before bedtime 2nd week Continue to take one tablet twice a day. Stop smoking during this week, on your "smoking cessation date" From the 3rd to the 9th week Continue to take one tablet twice a day until the 9th week. Your doctor will ask you to stop taking Zyban if you are unable to stop smoking after 7 weeks of treatment. Your doctor may advise you to stop taking Zyban gradually, after 7-9 weeks.

Some people need to take a lower dose,

… Since they are more likely to experience undesirable effects.

if they are over the age of 65,
if you have liver or kidney disease,
if they are at increased risk for seizures

the maximum recommended dose for these patients is one 150 mg tablet once a day.

How to take the tablets

Take the Zyban tablets, leaving at least 8 hours between each dose. Do not take Zyban before bed - it can cause sleep disturbances.

Zyban can be taken with or without food.

Swallow each tablet whole. Do not chew, break, or break the tablets as the medicine can be released too quickly into the body. This will lead to a higher chance of side effects, including seizures.

Overdose What to do if you have taken too much Zyban

If you take more Zyban than you should

If you take too many Zyban tablets, you may be at an increased risk of getting seizures or other side effects.

Do not wait - Contact your doctor or the nearest emergency department immediately.

Side Effects What are the side effects of Zyban

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

Seizures (convulsions)

About 1 in every 1000 people who take Zyban are at risk for seizures.

A seizure includes seizures and, typically, loss of consciousness. People who have had a seizure may later feel confused and not remember what happened. Seizures are more likely if you take more than prescribed, are taking other medicines, or are already more prone to seizures.

If you have a seizure, tell your doctor as soon as you feel better. Do not take more Zyban tablets.

Allergic reactions

In rare cases (around 1 in 1000), potentially serious allergic reactions to Zyban may occur. These include:

skin rash (including itchy rashes and wheals). Some skin reactions may require hospital treatment, especially if you also experience "irritation in the mouth or eyes."
unusual wheezing or difficulty in breathing
swelling of the eyelids, lips or tongue
pain in the muscles or joints
collapse or loss of consciousness

If you notice any signs of an allergic reaction, contact your doctor immediately. Do not take more Zyban tablets.

Very common side effects

These may affect more than 1 in 10 people:

difficulty sleeping (avoid taking Zyban at bedtime)

Common side effects

These may affect up to 1 in every 10 people:

feeling depressed
feeling agitated or anxious
difficulty in concentrating
feeling of instability, tremor
headache
malaise (nausea and vomiting)
stomach pain or other complaints (such as constipation) changes in the taste of food, dry mouth
fever, dizziness, sweating, rash (sometimes due to an allergic reaction), itching

Uncommon side effects

These may affect up to 1 in 100 people:

ringing in the ears, visual disturbances
increased blood pressure (sometimes severe), flushing
loss of appetite (anorexia)
weakness
chest pain
feeling confused
increased heart rate

Rare side effects

These may affect up to 1 in every 1000 people:

convulsive forms (see the beginning of this paragraph)
muscle twitching, muscle stiffness, uncontrolled movements, problems with walking or coordination (ataxia)
palpitations
fainting, feeling faint on getting up suddenly, due to a drop in blood pressure
feeling of irritability / hostility, strange dreams (including nightmares)
memory loss
tingling or numbness
severe allergic reactions: rash associated with muscle or joint pain (as described at the beginning of this section)
urinating more or less than normal
severe skin rashes that can affect the mouth and other parts of the body and can be life-threatening
worsening of psoriasis (thickened plaques of red skin)
yellowing of the skin or eyes (jaundice), elevated liver enzymes, hepatitis
changes in blood sugar levels
feelings of unreality or weirdness (depersonalization), seeing or hearing things that are not real (hallucinations).

Very rare side effects

These may affect up to 1 in 10,000 people:

feeling of restlessness, aggression
feeling or feeling things that are not real (delusions); severe suspicious behavior (paranoia)

Other side effects

Other side effects have occurred in a limited number of people but their exact frequency is not known:

thoughts of harming or killing yourself while taking Zyban or shortly after stopping it. If you have these thoughts, contact your doctor or go to a hospital immediately
loss of contact with reality or inability to think or judge clearly (psychosis); other symptoms may include hallucinations and / or delusions.
reduction in the number of red blood cells in the blood (anemia), reduction in the number of white blood cells in the blood (leukopenia) and reduction in the number of platelets (thrombocytopenia).

Effects of smoking cessation

People who quit smoking often have nicotine withdrawal symptoms; similar effects have been experienced in patients treated with Zyban. Such symptoms can include:

sleep disorders
trembling or sweating
feelings of anxiety, agitation or depression (sometimes with suicidal thoughts).

If you are not sure how you feel, talk to your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, nurse 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 / responsible ". 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 package. The expiry date refers to the last day of that month.

Do not store this medicine above 25 ° C. Store in the original packaging.

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.

Other Information

If you forget to take Zyban

If you have forgotten to take a dose, wait and take the next one at the usual time.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Zyban

You may need to take Zyban for more than 7 weeks to be fully effective.

Do not stop taking Zyban without consulting your doctor first. The dose may need to be reduced gradually.

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

What Zyban contains

Each tablet contains 150 mg of the active ingredient, bupropion hydrochloride.

The other ingredients are: Tablet core: microcrystalline cellulose, hypromellose, cysteine hydrochloride monohydrate, magnesium stearate. Tablet coating: hypromellose, macrogol 400, titanium dioxide (E171), carnauba wax. Printing ink: hypromellose, black iron oxide (E172).

What Zyban looks like and contents of the pack

Zyban 150 mg tablets are white, biconvex and have "GX CH7" printed on one side. They are available in blister packs of 30, 40, 50, 60 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.

More information about Zyban 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 ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 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 HOLDER08 .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 RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ZYBAN 150 MG TABLETS COATED WITH PROLONGED RELEASE FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 150 mg of bupropion hydrochloride.

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Prolonged-release film-coated tablet.

Round, white, film-coated, biconvex tablet, debossed with GX CH7 on one side and plain on the other side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Zyban tablets are indicated as a smoking cessation aid in conjunction with motivational support in nicotine-dependent patients.

04.2 Posology and method of administration

Zyban should be used in accordance with the smoking cessation guidelines.

Prescribers should check the patient's motivation to quit smoking. Smoking cessation therapies are most likely to be successful in those patients who are motivated to quit and are supported by motivational support for smoking cessation.

Zyban tablets should be swallowed whole. The tablets should not be crushed or chewed, as this can lead to an increased risk of side effects including seizures.

Zyban can be taken with or without food (see sections 4.5 and 5.2).

Patients should be treated for 7-9 weeks.

Although no reactions to Zyban cessation are expected, a period of tapering off the drug may be considered.

If no effect occurs at the seventh week, the treatment should be discontinued.

Use in adults

It is recommended to start treatment while the patient is still a smoker and to set a 'smoking cessation date' within the first two weeks of treatment with Zyban, preferably during the second week.

The starting dose is 150 mg to be taken once a day for six days, increasing to 150 mg twice a day starting on the seventh day.

An interval of at least 8 hours should be left between two subsequent doses.

The maximum single dose should not exceed 150 mg and the maximum total daily dose should not exceed 300 mg.

Insomnia is a very common adverse event that can be reduced by avoiding taking the dose at bedtime (taking care in any case to put an interval of at least 8 hours between each dose).

Use in children and adolescents

Use in patients under 18 years of age is not recommended as the safety and efficacy of Zyban tablets have not been evaluated in these patients.

Use in elderly patients

Zyban should be administered with caution to elderly patients. In some elderly individuals, increased sensitivity cannot be ruled out. The recommended dose in the elderly is 150 mg once daily (see section 4.4).

Use in patients with hepatic insufficiency

Zyban should be administered with caution in patients with hepatic insufficiency. Due to the greater variability of pharmacokinetics in patients with mild to moderate hepatic impairment, the recommended dose in such patients is 150 mg once daily.

Use in patients with renal insufficiency

Zyban should be used with caution in patients with renal insufficiency. The recommended dose in such patients is 150 mg once daily (see section 4.4).

04.3 Contraindications

Zyban is contraindicated in patients with hypersensitivity to bupropion or to any of the excipients.

Zyban is contraindicated in patients with ongoing seizure disease or with any history of seizures.

Zyban is contraindicated in patients with known central nervous system (CNS) tumor disease.

Zyban is contraindicated in patients who abruptly stop drinking alcohol or any medicine known to be associated with a risk of withdrawal seizures at any time during treatment (particularly benzodiazepines or benzodiazepine-like drugs).

Zyban is contraindicated in patients with a current or previous diagnosis of bulimia or anorexia nervosa.

The use of Zyban is contraindicated in patients with severe liver cirrhosis.

Concomitant use of Zyban and monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 14 days should elapse between stopping treatment with irreversible monoamine oxidase inhibitors and starting treatment with Zyban. For reversible monoamine oxidase inhibitors, it is sufficient. a period of 24 hours.

Zyban is contraindicated in patients with a history of bipolar disorder as it can facilitate the onset of a manic episode during the depressive phase of their illness.

Zyban should not be given to patients being treated with other medicines that contain bupropion as the incidence of seizures is dose-dependent.

04.4 Special warnings and appropriate precautions for use

Convulsions

The recommended dose of Zyban should not be exceeded as the use of bupropion is associated with a dose-related risk of seizures. At doses up to the maximum recommended daily dose (300mg of Zyban per day), the incidence of seizures is approximately 0.1% (1/1000).

In the presence of predisposing risk factors that lower the seizure threshold, the use of Zyban increases the risk of seizures. Zyban should not be used in patients with predisposing risk factors, unless there is an inalienable clinical reason for whereby the potential clinical benefit expected from smoking cessation outweighs the potential increased risk of seizures A maximum dose of 150 mg per day should be considered for the duration of treatment in these patients.

All patients should undergo an assessment for predisposing risk factors, which include:

• concomitant administration of other medicines known to lower the threshold for the occurrence of seizures (eg antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones and antihistamine drugs with sedative properties). For patients prescribed such drugs during treatment with Zyban, a maximum dose of 150 mg per day of Zyban should be considered for the remaining treatment period.

• alcohol abuse (see also section 4.3)

• history of head injury

• diabetes treated with hypoglycaemics or insulin

• use of anorectic or stimulant drugs

Zyban therapy should be discontinued, and not subsequently resumed, in patients who have experienced seizures during treatment.

Interactions (see section 4.5)

Plasma levels of bupropion or its metabolites may be altered due to pharmacokinetic interactions, which may increase the risk of developing undesirable events (e.g. dry mouth, insomnia, convulsions). Therefore, caution should be used when bupropion is administered concomitantly with medicinal products that can induce or inhibit the metabolism of bupropion.

Bupropion inhibits cytochrome P4502D6-induced metabolism. Therefore, caution is advised in concomitant administration of medicinal products metabolised by this enzyme.

Neuropsychiatry

Zyban is a centrally acting norepinephrine / dopamine reuptake inhibitor. Neuropsychiatric reactions have been reported (see section 4.8). In particular, psychotic and manic symptoms were found in patients with a known history of psychiatric illness.

Depressed mood can be a symptom of nicotine withdrawal. Depression, rarely accompanied by suicidal thoughts and behaviors (including suicide attempt), has been reported in patients attempting to quit smoking. These symptoms have also been reported during treatment with Zyban and generally occurred in the early stages of treatment.

In some countries bupropion is indicated for the treatment of depression. A meta-analysis of placebo-controlled clinical trials conducted with antidepressant drugs in adults with major depressive and other psychiatric disorders showed an increased risk of suicidal thoughts and behaviors in patients under the age of 25 treated with antidepressants, compared to placebo.

Physicians should be aware of the possible onset of significant depressive symptoms in patients attempting to quit smoking and should inform patients accordingly.

Data collected in animal studies suggest the possibility of drug abuse. However, studies on the possibility of abuse in humans and the extensive clinical experience gathered show that bupropion has a low potential for abuse.

Hypersensitivity

The use of Zyban should be discontinued if the patient experiences hypersensitivity reactions during treatment. Physicians should be aware that symptoms may increase or recur following discontinuation of Zyban treatment and should ensure that a drug is administered. symptomatic treatment for an adequate period of time (at least one week). Symptoms typically include rash, itching, hives or chest pain, but more severe reactions such as angioedema, dyspnoea / bronchospasm, anaphylactic shock, erythema multiforme or Stevens-Johnson syndrome may also arise. Arthralgia, myalgia and fever associated with rash and other symptoms suggestive of delayed hypersensitivity have also been reported. These symptoms can be assimilated to so-called serum sickness (see section 4.8). Symptoms subside with discontinuation of bupropion and administration of antihistamines or corticosteroids in most patients, and resolve over time.

Hypertension

Hypertension, sometimes severe (see section 4.8) and requiring acute treatment, has been reported in clinical practice in patients treated with bupropion alone or in combination with nicotine replacement therapy. This phenomenon has been observed in patients with and without pre-existing hypertension. In particular, in patients with a history of hypertension, baseline blood pressure should be measured at the start of treatment with bupropion and subsequent monitoring should be carried out. The possibility of discontinuing therapy with Zyban should be considered if there is a clinically significant increase in blood pressure. blood pressure.

Limited data from clinical studies suggest that higher rates of smoking cessation can be achieved by combining the use of Zyban nicotine-based transdermal systems (STN). However, a higher incidence of hypertension arising during treatment was observed in the combination group. If combination therapy with nicotine-based transdermal systems is used, caution should be exercised and weekly blood pressure checks performed. Before initiating combination therapy, physicians should consult the summary of product characteristics of the relevant nicotine transdermal system.

Patients belonging to specific groups

Elderly - Clinical experience with bupropion has not identified any differences in tolerability between elderly patients and other adults. However, increased sensitivity in some elderly cannot be excluded; therefore the recommended dose in such patients is 150 mg once daily. day (see sections 4.2 and 5.2).

Patients with hepatic insufficiency - Bupropion is extensively metabolised in the liver to active metabolites which in turn are further metabolised. No statistically significant differences in the pharmacokinetics of bupropion were observed when administered to patients with mild to moderate liver cirrhosis compared to healthy volunteers, but plasma levels of bupropion showed greater variability between individual patients. Therefore Zyban should be used with caution in patients with mild to moderate hepatic impairment and 150 mg once daily is recommended in these patients.

All patients with hepatic insufficiency should be carefully monitored for the possible onset of undesirable effects (e.g., insomnia, dry mouth) which may indicate elevated levels of the drug or its metabolites.

Patients with renal insufficiency - Bupropion is mainly excreted in the urine as well as its metabolites. Therefore, a dose of 150 mg once daily is recommended in patients with renal insufficiency, as bupropion and its active metabolites may accumulate in greater than normal amounts (see sections 4.2 and 5.2). The patient should be carefully monitored for possible side effects which may indicate elevated levels of the drug or its metabolites.

04.5 Interactions with other medicinal products and other forms of interaction

In patients taking medicinal products known to lower the seizure threshold, Zyban should only be used if there is a compelling clinical reason that the potential medical benefit expected from smoking cessation exceeds the increased risk of seizures (see section 4.4).

The effect of bupropion on other medicines:

Although not metabolised by the CYP2D6 isoenzyme, bupropion and its major metabolite, hydroxybupropion, are inhibitors of the CYP2D6 isoenzyme-mediated metabolic pathway. Co-administration of bupropion hydrochloride and desipramine to healthy volunteers, known to be extensive metabolisers of the CYP2D6 isoenzyme, resulted in significant (2 to 5-fold) increases in desipramine Cmax and AUC. Inhibition of CYP2D6 isoenzyme occurred. maintained for at least 7 days after the last dose of bupropion hydrochloride.

Concomitant therapy with medicinal products with low therapeutic indices, mainly metabolised by the CYP2D6 isoenzyme, should be initiated at the lower end of the dose range of the concomitantly administered drug. Such medicinal products include some antidepressants (eg desipramine, imipramine, paroxetine), antipsychotics (e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), and Type 1C anti-arrhythmics (e.g. propafenone, flecainide). If Zyban is added to the treatment regimen of a patient already on therapy with one of these medicinal products, the need to decrease the dose of the parent medicinal product should be considered, in which case the expected benefit of treatment with Zyban should be carefully considered against the potential risks.

Although citalopram is not predominantly metabolised by the CYP2D6 isoenzyme, bupropion caused citalopram Cmax and AUC to increase by 30% and 40%, respectively, in one study.

The effect of other medicines on bupropion:

Bupropion is metabolised to its major active metabolite hydroxybupropion, mainly by cytochrome P450 CYP2B6 (see section 5.2). Co-administration of medicinal products that can affect the CYP2B6 isoenzyme-induced metabolism of bupropion (eg CYP2B6 substrates: cyclophosphamide, ifosfamide and CYP2B6 inhibitors: orphenadrine, ticlopidine, clopidogrel), may lead to increased plasma levels of bupropion and decreased levels of the active metabolite hydroxy-bupropion. The clinical consequences of inhibition of the metabolism of bupropion induced by the CYP2B6 enzyme and the consequent changes in the relationship between bupropion and hydroxybupropion are currently unknown.

As bupropion is extensively metabolised, caution is advised when administered concomitantly with medicinal products known to induce metabolism (e.g. carbamazepine, phenytoin, ritonavir, efavirenz) or to inhibit it (e.g. valproate) as these may affect its efficacy. clinic and its safety.

In a series of studies conducted in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg (Kaletra) twice daily reduced the exposure of bupropion and its major metabolites in a dose-dependent manner from about 20 to 80% (see section 5.2). Similarly, efavirenz 600 mg once daily for two weeks reduced bupropion exposure by approximately 55% in healthy volunteers. Patients receiving one of these drugs in combination with bupropion may require increased doses of bupropion, but the maximum recommended dose for bupropion should not be exceeded.

Nicotine, administered via transdermal patches, had no effect on the pharmacokinetics of bupropion and its metabolites.

Other interactions:

Smoking is associated with an increase in the activity of the CYP1A2 enzyme complex. Following cessation of smoking, there may be a reduction in the clearance of medicinal products metabolised by this enzyme, which may result in increased plasma levels of such medicinal products. This increase may be particularly important for those medicinal products with a limited therapeutic window (such as, for example, theophylline, tacrine and clozapine) that are primarily metabolised by the CYP1A2 enzyme system. The clinical consequences of cessation of the drug are not known. smoking on other medicinal products which are partially metabolised by the CYP1A2 enzyme complex (such as imipramine, olanzapine, clomipramine and fluvoxamine). Furthermore, limited data indicate that the metabolism of flecainide or pentazocine may also be induced by smoking.

Administration of Zyban to patients who are being treated with levodopa or amantadine should be undertaken with caution. Limited clinical data suggest an increased incidence of undesirable effects (e.g. nausea, vomiting and neuropsychiatric episodes - see section 4.8) in patients receiving bupropion concomitantly with levodopa or amantadine.

Although clinical data do not indicate a pharmacokinetic interaction between bupropion and alcohol, there have been rare reports of neuropsychiatric adverse events or impaired alcohol tolerance in patients who drank alcohol while taking Zyban. The consumption of alcohol during treatment with Zyban should be minimized or excluded.

Since monoamine oxidase inhibitors A and B also increase the catecholaminergic pathway, by a different mechanism than bupropion, the concomitant use of Zyban and monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.3) as there is an increased possibility of reactions adverse effects following their co-administration. At least 14 days must elapse between discontinuation of irreversible MAO inhibitors and initiation of treatment with Zyban. A period of 24 hours is sufficient for reversible MAO inhibitors.

Studies suggest that bupropion exposure may be increased when prolonged release bupropion tablets are taken with a high fat meal (see section 5.2).

04.6 Pregnancy and lactation

The safety of Zyban for use in pregnancy has not been established.

In a retrospective study, of over a thousand exposures to bupropion occurring in the first trimester of pregnancy, there was no higher proportion of congenital malformations or cardiovascular malformations than observed with the use of other antidepressants.

Evaluation of experimental animal studies did not indicate direct or indirect harmful effects on the development of the embryo or fetus, on the course of gestation and on peri- or postnatal development. systemic exposure achieved in humans at the maximum recommended dose. The potential risk in humans is unknown.

Pregnant women should be encouraged to stop smoking without the use of drug therapy. Zyban should not be used during pregnancy.

Bupropion and its metabolites are excreted in human milk. The decision whether to abstain from breastfeeding or to abstain from Zyban therapy must be made taking into account the benefit of breastfeeding for the infant / child and the benefit of Zyban therapy for the mother.

04.7 Effects on ability to drive and use machines

As with other drugs that affect the central nervous system (CNS), bupropion can affect the ability to perform tasks that require judgment or motor and cognitive skills. Zyban has also been reported to cause dizziness and light-headedness. Therefore, patients should take special care before driving or operating machines until they are reasonably certain that Zyban tablets will not adversely affect their performance.

04.8 Undesirable effects

The list below provides information on undesirable effects identified from clinical experience, divided by incidence and according to system organ class. It is important to bear in mind that smoking cessation is often associated with withdrawal symptoms. nicotine (e.g. agitation, insomnia, tremor, sweating), some of which are also found among the adverse events associated with Zyban.

Undesirable effects are listed according to the frequency of their occurrence, according to the following convention: very common (≥1 / 10); common (≥1 / 100,

Immune system disorders * Common Hypersensitivity reactions such as hives Rare More severe hypersensitivity reactions, including angioedema, dyspnoea / bronchospasm and anaphylactic shock. Arthralgia, myalgia and fever have also been reported in conjunction with skin reaction and other symptoms suggestive of delayed hypersensitivity. These symptoms may be similar to those of serum sickness. Metabolism and nutrition disorders Uncommon Anorexia Rare Alterations in blood sugar Psychiatric disorders Very common Insomnia (see section 4.2) common Depression (see section 4.4), agitation, anxiety Uncommon Confusion Rare Irritability, hostility, hallucinations, depersonalization, abnormal dreams including nightmares Very rare Delusions, paranoid ideation, restlessness, aggression Not known Suicidal ideation and behavior ***, psychosis Nervous system disorders common Tremor, disturbed concentration, headache, dizziness, altered taste Rare Convulsions (see note at the end of the table) **, dystonia, ataxia, parkinsonism, incoordination, memory impairment, paraesthesia, syncope Eye disorders Uncommon Visual disturbances Ear and labyrinth disorders Uncommon Tinnitus Cardiac pathologies Uncommon Tachycardia Rare Palpitations Vascular pathologies Uncommon Increased blood pressure (sometimes severe), flushing Rare Vasodilation, postural hypotension Gastrointestinal disorders common Dry mouth, gastrointestinal disturbances including nausea and vomiting, abdominal pain, constipation Hepatobiliary disorders Rare Elevation of liver enzymes, jaundice, hepatitis Skin and subcutaneous tissue disorders * common rash, itching, sweating Rare Erythema multiforme and Stevens-Johnson syndrome, exacerbation of psoriasis have also been reported Musculoskeletal and connective tissue disorders Rare Muscle spasms (tics) Renal and urinary disorders Rare Pollakiuria and / or urinary retention General disorders and administration site conditions common Fever Uncommon Chest pain, asthenia

*: "Hypersensitivity can manifest itself in the form of skin reactions. See" Immune system disorders "and" Skin and subcutaneous tissue disorders "

**: the incidence of seizures is about 0.1% (1/1000). The most common types of seizures are generalized tonic-clonic seizures, a type that can lead in some cases to confusion or subsequent memory deficits attack (see section 4.4).

***: Cases of suicidal ideation and behavior have been reported during bupropion therapy (see section 4.4).

04.9 Overdose

Ingestion of doses greater than 10 times the maximum therapeutic dose has been reported. In addition to the events reported in the Undesirable Effects section, the overdose resulted in symptoms such as drowsiness, loss of consciousness and / or ECG changes such as disturbances. conduction (including QRS lengthening), arrhythmias and tachycardia. QTc interval prolongation has also been reported but generally concomitant with QRS prolongation and an increase in heart rate. Although most patients recovered without sequelae, deaths associated with bupropion have rarely been reported in patients who had taken greatly in excess of the drug.

Treatment: In case of overdose, hospitalization of the patient is recommended. ECG and vital signs should be monitored.

Adequate airway patency, oxygenation and ventilation must be ensured. The use of activated charcoal is recommended. No specific antidote for bupropion is known. Further interventions will be performed as required by clinical practice.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antidepressants, ATC code: N06AX12

Bupropion is a selective inhibitor of the neuronal reuptake of catecholamines (noradrenaline and dopamine) with minimal effects on the reuptake of indolamines (serotonin) and does not inhibit monoamine oxidase. The mechanism by which bupropion promotes patients' ability to abstain from smoking is not known.

However, this action is assumed to be mediated by noradrenergic and / or dopaminergic mechanisms.

05.2 Pharmacokinetic properties

Absorption

Following oral administration of 150 mg prolonged-release bupropion hydrochloride tablets to healthy volunteers, peak plasma concentrations (Cmax) of approximately 100 nanograms per ml are observed over approximately 2.5 to 3 hours. The AUC and Cmax values of bupropion and its active metabolites hydroxybupropion and threohydrobupropion increase dose proportionally over a dose range of 50-200 mg following single administration and within a dose range of 300-450 mg / day to following chronic administration. The Cmax and AUC values of hydroxybupropion are approximately 3 and 14 times higher, respectively, than the Cmax and AUC values of bupropion. The Cmax of threohydrobupropion is comparable to the Cmax of bupropion, while the AUC of threohydrobupropion is approximately 5 times higher than that of bupropion. Peak plasma levels of hydroxybupropion and threohydrobupropion are reached approximately 6 hours after administration of a single dose of bupropion. Plasma levels of erythrohydrobupropion (an isomer of threohydrobupropion, which is also an active metabolite) are not quantifiable after a single administration of bupropion.

Following chronic administration of bupropion 150 mg twice daily, the Cmax of bupropion is similar to the values reported after single dose. For hydroxybupropion and threohydrobupropion, steady-state Cmax values are higher (approximately 4- and 7-fold, respectively) than after a single dose. Plasma levels of erythrohydrobupropion are comparable to steady-state plasma levels of bupropion. The steady state of bupropion and its metabolites is reached within 5-8 days. The absolute bioavailability of bupropion is unknown; urine excretion data, however, show that at least 87% of the bupropion dose is absorbed.

Two studies conducted in healthy volunteers with prolonged-release bupropion 150 mg tablets suggest that exposure to bupropion may be increased when Zyban prolonged-release tablets are taken with food. When taken after a high-fat meal, the peak plasma concentrations of bupropion (Cmax) increased by 11% and 35% in the two studies, while the overall bupropion exposure (AUC) increased by 16% and 19%.

Distribution

Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 liters.

Bupropion, hydroxybupropion and threohydrobupropion are moderately bound to plasma proteins (84%, 77% and 42%, respectively).

Bupropion and its active metabolites are excreted in human milk. Animal studies have shown that bupropion and its active metabolites cross the blood brain barrier and the placenta.

Metabolism

Bupropion is extensively metabolised in humans. Three pharmacologically active metabolites have been identified in plasma: hydroxybupropion and the amino alcohol isomers, threohydrobupropion and erythrohydrobupropion. They may be of clinical importance since their plasma concentrations are equal to or higher than those of bupropion Active metabolites are further metabolised to inactive metabolites (some of which have not been fully characterized but may include conjugates) and excreted in the urine.

Education in vitro indicate that bupropion is metabolised to its major active metabolite hydroxybupropion, mainly by CYP2B6, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. Conversely, threohydrobupropion formation involves carbonyl reduction but does not involve cytochrome P450 isoenzymes (see section 4.5).

The inhibition potential of threohydrobupropion and erythrohydrobupropion against cytochrome P450 has not been studied.

Bupropion and hydroxybupropion are both inhibitors of the CYP2D6 isoenzyme with Ki values of 21 and 13.3 μM, respectively (see section 4.5).

Following oral administration of a single 150 mg dose of bupropion, no difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its major metabolites was observed between smokers and nonsmokers.

Bupropion has been shown to induce its own metabolism in animals following subchronic administration. In humans, there is no evidence of enzyme induction of bupropion or hydroxybupropion in volunteers or patients treated with recommended doses of bupropion hydrochloride for 10-45 days.

Elimination

Following oral administration of 200 mg of 14C-bupropion to humans, 87% and 10% of the radioactive dose was recovered in the urine and faeces, respectively. The fraction of the bupropion dose excreted unchanged was only 0.5%, which is consistent with the extensive metabolism of bupropion. Less than 10% of this 14C-labeled dose was present in the urine as active metabolites.

The mean apparent clearance following oral administration of bupropion hydrochloride is approximately 200 L / h and the mean elimination half-life of bupropion is approximately 20 hours.

The elimination half-life of hydroxybupropion is approximately 20 hours. The elimination half-lives of threohydrobupropion and erythrohydrobupropion are longer (37 and 33 hours, respectively).

Special patient groups

Patients with renal impairment

The elimination of bupropion and its major active metabolites may be reduced in patients with impaired renal function. Limited data in patients with end-stage renal insufficiency or moderate to severe renal insufficiency indicate that exposure to bupropion and / or its metabolites is increased (see section 4.4).

Patients with hepatic impairment

The pharmacokinetics of bupropion and its active metabolites are not statistically significantly different in patients with mild to moderate cirrhosis than in healthy volunteers, although greater variability was observed in such patients (see paragraph 4.4). In patients with severe liver cirrhosis, the Cmax and AUC of bupropion were substantially increased (mean differences of approximately 70% and 3 times higher, respectively) and more variable when compared with the values found in healthy volunteers; the mean elimination half-life was also prolonged (by about 40%). For hydroxybupropion, the mean Cmax was lower (by about 70%), the mean AUC tended to be increased (by about 30%), the median T was delayed (approximately 20 hours) and the mean elimination half-lives were prolonged (approximately 4-fold), compared to healthy volunteers.For threohydrobupropion and erythrohydrobupropion, mean Cmax tended to be lower (by about 30%), mean AUC tended to be higher (by about 50%), median Tmax was delayed (by about 20 hours), and the mean elimination half-life was prolonged (approximately 2-fold) compared to healthy volunteers (see section 4.3).

Elderly patients

Pharmacokinetic studies in elderly patients have yielded variable results. A single-dose study demonstrated that the pharmacokinetics of bupropion and its metabolites in the elderly did not differ from that in younger patients. Another single-dose and repeat-dose pharmacokinetic study suggested that it may occur in the elderly. to a greater degree an accumulation of bupropion and its metabolites. Clinical experience has not identified differences in tolerability between elderly and younger patients, but greater drug sensitivity in older patients cannot be excluded (see section 4.4).

05.3 Preclinical safety data

In animal studies, doses of bupropion many times higher than therapeutic doses in humans caused, among others, the following dose-dependent symptoms: ataxia and convulsions in rats, general weakness, tremors and emesis in dogs and increased blood pressure. lethality in both species. Since there is enzyme induction in animals but not humans, systemic exposures in animals were similar to systemic exposures in humans at the maximum recommended dose.

Liver changes have been observed in animal studies, but these reflect the action of a hepatic enzyme inducer. At the recommended doses in humans, bupropion does not induce its own metabolism. This suggests that the hepatic effects observed in laboratory animal studies are of only limited importance in assessing and determining the risk associated with the use of bupropion.

Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mutagen for mammalian cells and therefore of no concern as a human genotoxic agent. Studies in mice and rats confirm the absence of carcinogenesis in these species.