Active ingredients: Bupropion (Bupropion hydrochloride)
ELONTRIL 150 mg modified release tablets
ELONTRIL 300 mg modified release tablets
Indications Why is Elontril used? What is it for?
Elontril is a medicine prescribed by your doctor to treat your depression. It is believed to interact with chemicals in the brain called norepinephrine and dopamine, which are linked to depression.
Contraindications When Elontril should not be used
Do not take Elontril
- If you are allergic to bupropion or any of the other ingredients of this medicine (listed in section 6)
- If you are taking any other medicines containing bupropion
- If you have been diagnosed with epilepsy or have had seizures in the past
- If you have, or have ever had, eating disorders (for example, bulimia or anorexia nervosa)
- If you have a brain tumor
- If you are a heavy drinker who has just quit or is about to stop drinking
- If you have severe liver problems
- If you have recently stopped taking sedatives, or are about to stop taking them while you are taking Elontril
- If you are taking or have taken other medicines for depression called monoamine oxidase inhibitors (MAOIs) in the past 14 days
If any of the above apply to you, talk to your doctor immediately, without taking Elontril.
Precautions for use What you need to know before taking Elontril
Talk to your doctor or pharmacist before taking Elontril
Children and adolescents
Elontril is not recommended for the treatment of patients under 18 years of age.
There is an increased risk of suicide-related thoughts and behaviors if patients under the age of 18 are treated with antidepressants.
Adults
Before you take Elontril, your doctor needs to know:
- If you regularly drink a large amount of alcohol
- If you have diabetes for which you use insulin or tablets
- If you have had a severe head injury or had a head injury in the past Elontril has been shown to cause seizures in about 1 in 1000 people. This side effect is more likely to occur in the individuals described above. If you have a fit during treatment you must stop taking Elontril. Stop taking it immediately and contact your doctor.
- If you have bipolar disorder (extreme mood changes), as Elontril may cause an episode of this disease
- If you have liver or kidney problems, you are more likely to experience side effects.
If any of the above apply to you, talk to your doctor again before taking Elontril. Your doctor may want to pay special attention to your therapy or recommend another treatment.
Interactions Which drugs or foods can change the effect of Elontril
If you are taking or have taken other antidepressants called monoamine oxidase inhibitors (MAOIs) in the past 14 days, please tell your doctor without taking Elontril (see also section 2 "Do not take Elontril").
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, herbal products or vitamins, even those obtained without a prescription. Your doctor may change the dose of Elontril, or advise you to change your other medicines.
Some medicines should not be taken together with Elontril. Some may increase the risk of seizures or fits. Other medicines may increase the risk of other side effects. Some examples are listed below, but the list is not complete.
There may be a higher than usual possibility of seizures ...
- If you take other medicines for depression or other mental illnesses
- If you are taking theophylline for asthma or lung disease
- If you take tramadol, a strong pain reliever
- If you have taken sedatives, or if you are about to stop them while you are taking Elontril (see also section 2 "Do not take Elontril")
- If you take medicines for malaria (such as mefloquine or chloroquine)
- If you are taking stimulants or other medicines to control your weight or appetite
- If you take steroids (by mouth or by injection)
- If you take antibiotics called quinolones
- If you take certain types of antihistamines which can make you sleepy
- If you take medicines for diabetes If any of the above apply to you, talk to your doctor immediately, before taking Elontril. Your doctor will evaluate the benefits and risks of taking Elontril.
There may be a higher than usual chance of other side effects ...
- If you take other medicines for depression (such as amitriptyline, fluoxetine, paroxetine, dosulepin, desipramine or imipramine) or for other mental illnesses (such as clozapine, risperidone, thioridazine or olanzapine)
- If you take medicines for Parkinson's disease (levodopa, amantadine or orphenadrine)
- If you take medicines that affect the body's ability to eliminate Elontril (carbamazepine, phenytoin, valproate)
- If you take certain medicines used to treat cancer (such as cyclophosphamide, ifosfamide)
- If you take ticlopidine or clopidogrel, used mainly to prevent stroke
- If you take certain beta blockers (such as metoprolol)
- If you take certain medicines for an irregular heart rhythm (propafenone or flecainide)
- If you use nicotine patches to help you quit smoking.
If any of the above apply to you, talk to your doctor immediately, before taking Elontril.
Elontril may be less effective
- If you take ritonavir or efavirenz, medicines to treat HIV infection.
If this applies to you, talk to your doctor. Your doctor will check how Elontril works on you. The dose may need to be increased or changed to another treatment for depression. Do not increase the dose of Elontril without your doctor's advice, as this may increase the risk of having side effects including seizures.
Elontril may make other medicines less effective
- If you are taking tamoxifen used to treat breast cancer
If this applies to you, tell your doctor. Another depression treatment may need to be used.
- If you are taking digoxin for the heart
If this applies to you, tell your doctor. Your doctor may consider changing your digoxin dose.
Elontril and alcohol
Alcohol can alter the way Elontril works and when used together it can rarely alter your nerves and mental state. Some people find that they are more sensitive to alcohol when they take Elontril. Your doctor may advise you not to drink alcohol (beer, wine or spirits) while you are taking Elontril or try to drink a small amount. But if you are currently drinking a lot, don't stop abruptly: it can put you at risk of having seizures.
Talk to your doctor about drinking alcohol before you start taking Elontril.
Warnings It is important to know that:
Thoughts related to suicide and worsening of depression
If you are depressed you can sometimes have thoughts of harming or killing yourself. These thoughts may be more frequent the first time you start taking antidepressants, as all these medicines take some time to work, usually about two weeks, but sometimes longer.
You may be more likely to have these thoughts:
- if you have previously had thoughts about killing yourself or harming yourself
- if you are a young adult. Data from clinical trials have shown an increased risk of suicidal behavior in adults under the age of 25 with psychiatric disorders who were treated with an antidepressant.
If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital immediately. You may find it helpful to tell a relative or friend that you have depression and ask them to read this leaflet. You can ask them if they think your depression is getting worse, or if they are worried about changes in your behavior.
Effects on urinalysis
Elontril can interfere with some urine tests used to detect other medications. If a urinalysis is required for you, please tell your doctor or hospital that you are taking Elontril.
Pregnancy and breastfeeding
Do not take Elontril if you are pregnant, suspect or are planning to become pregnant, unless your doctor recommends it. 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 Elontril. It is not known whether these are due to the use of Elontril.
The components of Elontril pass into breast milk. You should ask your doctor or pharmacist for advice before taking Elontril.
Driving and using machines
If Elontril causes you to feel dizzy or lightheaded, do not drive or use any tools or machinery.
Dose, Method and Time of Administration How to use Elontril: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. These are the usual doses, but your doctor's instructions are for you personally. If in doubt, consult your doctor or pharmacist.
It may take some time for you to feel better. It takes some time for the medicine to take full effect, sometimes weeks or months. When you start to feel better, your doctor may advise you to continue taking Elontril to prevent depression from coming back.
How much should you take
The usual recommended dose is one 150 mg tablet per day, for adults only.
Your doctor may increase your dose to 300 mg per day if your depression does not improve after several weeks.
Take your dose of Elontril tablets in the morning. Do not take Elontril more than once a day.
The tablet is covered with a coating that slowly releases the medicine into the body. You may notice something in your stool that looks like a tablet. This is the hollow lining that has gone through the body.
- Swallow the tablets whole. You should not chew, crush or divide them - if you do, there is a risk of overdose, as the medicine would be released into your body too quickly. This will make it more likely that you will experience side effects, including seizures.
Some people continue to take one 150 mg tablet per day throughout the entire treatment.
Your doctor may have prescribed this dosage for you if you have liver or kidney problems.
How long should it be taken
Only you and your doctor can decide how long to take Elontril. It can take weeks or months of treatment for you to see improvement. Talk to your doctor about your symptoms regularly to decide how long you should take it for. When you start to feel better your doctor may advise you to continue taking Elontril to prevent your depression from coming back.
If you forget to take Elontril
If you miss a dose, wait and take the next tablet at the usual time. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Elontril
Do not stop taking Elontril or reduce your dose without first talking to your doctor. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Elontril
If you take too many tablets, it may increase the risk of fits or fits. Don't waste time. Ask your doctor what to do or go to the emergency room of the nearest hospital straight away.
Side Effects What are the side effects of Elontril
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Convulsions or fits
About 1 in 1000 people who take Elontril are at risk of seizures (fits or fits). The chance of this happening is higher if you take too much of it, if you take certain medicines, or if you have a higher than usual risk of having seizures. If you are worried, talk to your doctor.
If you have a fit, tell your doctor as soon as you feel better. Do not take any other tablets.
Allergic reactions
Some people may have allergic reactions to Elontril. These include
- Red skin or rash (similar to hives), itchy blisters or blisters (hives) on the skin Some rashes may need hospital treatment, especially if you have pain in your mouth or eyes.
- Unusual wheezing and difficulty in breathing
- Swelling of the eyelids, lips or tongue
- Pain in the muscles or joints
- Collapse or loss of consciousness
If you have any signs of an allergic reaction, contact a doctor immediately. Do not take any other tablets.
Allergic reactions can last a long time. If your doctor prescribes something that relieves your allergy symptoms, be sure to finish the treatment.
Other side effects
Very common side effects: may affect more than one in 10 people
- Difficulty sleeping. Make sure you take Elontril in the morning
- Headache
- Dry mouth
- Nausea, vomiting
Common side effects: may affect up to one in 10 people
- Fever, dizziness, itching, sweating and rash (sometimes due to an allergic reaction)
- Shakes, tremors, weakness, fatigue, chest pain
- Feeling anxious or agitated
- Stomach pain or other complaints (constipation), changes in the taste of food, loss of appetite (anorexia)
- Sometimes severe increase in blood pressure, flushing (sudden redness)
- Ringing in the ear, disturbed vision
Uncommon side effects may affect up to one in 100 people
- Feeling depressed (see also Section 2 "Take special care with Elontril", in "Thoughts related to suicide and worsening of depression")
- Feeling confused
- Difficulty concentrating
- Increased heart rate
- Weight loss.
Rare side effects may affect up to one in 1,000 people
- Convulsions.
Very rare side effects may affect up to one in 10,000 people
- Palpitations, fainting
- Muscle twitching, muscle stiffness, uncontrolled movements, problems with walking or coordination
- Feeling agitated, irritated, hostile, aggressive, strange dreams, tingling or numbness, memory loss
- Yellow discoloration of the skin or whites of the eyes (jaundice) which may be caused by increased liver enzymes, hepatitis
- Severe allergic reactions; rash associated with pain in the joints and muscles
- Changes in blood sugar levels
- Urinating more or less than normal
- Severe skin rashes that can affect the mouth or other parts of the body and can be life-threatening
- Worsening of psoriasis (patches of red skin)
- Feeling of unreality or alienation (depersonalization); seeing or hearing things that are not there (hallucinations); feeling or believing in things that are not there (delusion); severe suspiciousness (paranoia).
Other side effects
Other side effects have occurred in a small number of people but their exact frequency is not known:
- thoughts of harming or killing yourself while taking Elontril or immediately after stopping treatment (see section 2, "What you need to know before you take Elontril"). If you have these thoughts, contact your doctor or go to a hospital straight away .
- loss of contact with reality and inability to think or judge clearly (psychosis); other symptoms may include hallucinations and / or delirium.
- Reduction in the number of red blood cells (anemia), reduction in the number of white blood cells (leukopenia) and reduction in the number of platelets (thrombocytopenia).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.
Store in the original package to protect from moisture and light. The bottle contains a small sealed container containing charcoal and silica gel to keep the tablets dry. Leave the container in the bottle. Do not swallow.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Elontril contains
The active ingredient is bupropion hydrochloride. Each tablet contains 150 mg or 300 mg of bupropion hydrochloride.
The other ingredients are: tablet core: polyvinyl alcohol, glyceryl dibeenate, tablet coating: ethylcellulose, povidone K-90, macrogol 1450, methacrylic acid copolymer dispersion ethyl acrylate, silicon dioxide, triethyl citrate.
Ink: shellac fixative, black iron oxide (E172) and ammonium hydroxide.
What Elontril looks like and contents of the pack
Elontril 150 mg tablets are creamy white to pale yellow round, imprinted with black ink on one side "GS5FV" and unprinted on the other side. They are available in white polyethylene bottles of 7, 30 or 90 ( 3x30) tablets.
Elontril 300 mg tablets are creamy white to pale yellow round, imprinted with black ink on one side "GS5YZ" and unprinted on the other side. They are available in white polyethylene bottles of 7, 30 or 90 ( 3x30) tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
ELONTRIL MODIFIED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each tablet contains 150 mg or 300 mg bupropion hydrochloride.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Modified-release tablets.
150 mg tablets: Creamy white to pale yellow round tablets imprinted in black ink on one side with "GS5FV" and without imprint on the other side.
300 mg tablets: creamy white to pale yellow round tablets imprinted in black ink on one side with "GS5YZ" and without imprint on the other side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
ELONTRIL is indicated for the treatment of major depressive episodes.
04.2 Posology and method of administration -
Use in adults
The recommended starting dose is 150 mg taken once a day. The optimal dose has not been established in clinical studies. If no improvement is seen after 4 weeks of treatment with 150 mg, the dose can be increased to 300 mg taken once daily. An interval of at least 24 hours is required between subsequent doses.
For bupropion, the onset of therapeutic action was observed 14 days after starting treatment. As with all other antidepressants, the full antidepressant effect of ELONTRIL may not be evident until after several weeks of treatment.
Patients with depression should be treated for a sufficient period of at least 6 months to ensure they are symptom-free.
Insomnia is a very common adverse event and is often transient. Insomnia can be reduced by avoiding taking the dose at bedtime (provided there are at least 24 hours between doses).
• Patients previously treated with WELLBUTRIN prolonged-release tablets:
When patients switch from prolonged-release bupropion tablets, twice a day
treatment with ELONTRIL modified-release tablets, administer the same total daily dose whenever possible.
Pediatric population
The use of ELONTRIL is not indicated in children and adolescents below 18 years of age (see section 4.4). The safety and efficacy of ELONTRIL in patients below 18 years of age have not been established.
Senior citizens
Efficacy in the elderly has not been clearly demonstrated. In a clinical study elderly patients followed the same dosage regimen as in adults (see Use in adults). Increased sensitivity in some elderly subjects cannot be excluded.
Patients with hepatic impairment
ELONTRIL should be used with caution in patients with hepatic insufficiency (see section 4.4). Due to an increased variability of pharmacokinetics in patients with mild to moderate impairment, the recommended dose in such patients is 150 mg once daily.
Patients with renal impairment
The recommended dose in these patients is 150 mg once daily, as bupropion and its active metabolites may accumulate to a greater extent than usual in such patients (see section 4.4).
Method of administration
ELONTRIL tablets should be swallowed whole. The tablets should not be cut, crushed or chewed, as this may lead to an increased risk of adverse effects including seizures.
ELONTRIL tablets can be taken with or without food.
Discontinuation of therapy
Although no withdrawal reactions (measured as spontaneous reports rather than rating scales) have been observed in clinical trials with ELONTRIL, a tapering period should be considered. Bupropion is a selective inhibitor of neuronal reuptake of catecholamines and an effect cannot be excluded rebound or withdrawal reactions.
04.3 Contraindications -
ELONTRIL is contraindicated in patients with hypersensitivity to bupropion or to any of the excipients listed in section 6.1.
ELONTRIL is contraindicated in patients taking any other medicinal product containing bupropion, as the incidence of seizures is dose dependent and to avoid overdose.
ELONTRIL is contraindicated in patients with seizure disorders or with a history of seizures.
ELONTRIL is contraindicated in patients with a tumor of the central nervous system.
ELONTRIL is contraindicated in patients who discontinue at any time during treatment
abruptly drinking alcohol or any medicine known to be associated with the risk of seizures when discontinued (particularly benzodiazepines and benzodiazepine-like agents).
ELONTRIL is contraindicated in patients with severe liver cirrhosis.
ELONTRIL is contraindicated in patients with a current or previous diagnosis of bulimia or anorexia nervosa.
The concomitant use of ELONTRIL and monoamine oxidase inhibitors (MAO inhibitors) is contraindicated. At least 14 days must elapse between discontinuation of irreversible MAO inhibitors and initiation of treatment with ELONTRIL. For reversible MAO inhibitors it is sufficient. a period of 24 hours.
04.4 Special warnings and appropriate precautions for use -
Convulsions
The recommended dose of modified-release bupropion tablets should not be exceeded, as bupropion is associated with a dose-related risk of seizures. The overall incidence of seizures with modified-release bupropion tablets in clinical trials with doses up to 450 mg per day was approximately 0.1%.
There is an increased risk of seizures occurring with the use of ELONTRIL in the presence of predisposing risk factors that lower the seizure threshold. Therefore, ELONTRIL should be administered with caution in patients with one or more conditions that predispose to lowering. of the seizure threshold.
All patients should be evaluated for predisposing risk factors, which include
§ Concomitant administration of other medicines known to lower the seizure threshold (e.g. antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones and sedative antihistamines)
§ Alcohol abuse (see also section 4.3)
§ History of head injury
§ Diabetes treated with hypoglycemic agents or insulin
§ Use of stimulant or anorectic products
ELONTRIL should be discontinued, and is not recommended, in patients who experience seizures during treatment.
Interactions (see section 4.5)
Due to pharmacokinetic interactions, plasma levels of bupropion or its metabolites may be altered, thus increasing the risk of occurrence of undesirable effects (e.g. xerostomia, insomnia, convulsions). Therefore, caution should be exercised when bupropion is administered concomitantly with medicinal products that may induce or inhibit its metabolism.
Bupropion inhibits the metabolism by cytochrome P450 2D6. Caution is advised if medicinal products metabolised by this enzyme are administered concomitantly.
It has been shown in the literature that drugs that inhibit CYP2D6 can lead to reduced concentrations of endoxifen, which is the active metabolite of tamoxifen. Therefore, the use of bupropion, which is a CYP2D6 inhibitor, should be avoided whenever possible during treatment with tamoxifen (see section 4.5).
Neuropsychiatry
Suicide / suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events).
This risk persists until significant remission occurs. As improvement may not occur during the first or immediate weeks of treatment, patients should be closely monitored until such improvement appears. It is common clinical experience that the risk of suicide may increase in the early stages of improvement.
Patients with a history of suicide-related events or who exhibit a significant degree of suicidal ideation prior to initiation of treatment are known to be at increased risk of suicidal thoughts or suicide attempts, and should be closely monitored during treatment.
A meta-analysis of clinical trials conducted with antidepressant drugs compared to placebo in adult patients with psychiatric disorders showed an increased risk of suicidal behavior in the age group below 25 years of patients treated with antidepressants compared to placebo.
Drug therapy should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (and caregivers) should be advised of the need to monitor for any clinical worsening, suicidal behaviors or thoughts, and unusual changes in behavior and should consult immediately if such symptoms occur. a doctor. It should be recognized that the onset of some neuropsychiatric symptoms may be related to either the underlying disease state or drug therapy (see below Neuropsychiatric symptoms including mania and bipolar disorder; see section 4.8).
Modification of the regimen, including possible discontinuation of treatment, should be considered in patients presenting with onset of suicidal ideation / behaviors, especially if such symptoms are severe, with sudden onset, or not included in the onset symptomatology.
Neuropsychiatric symptoms including mania and bipolar disorder
Neuropsychiatric symptoms have been reported (see section 4.8). In particular, psychotic and manic symptoms have been observed, mainly in patients with a history of psychiatric illness. Furthermore, major depressive episodes can be the premise of bipolar disorder. It is generally believed (although not established from controlled clinical trials) that treating this episode with an antidepressant alone may increase the likelihood of experiencing a mixed / manic episode in patients at risk for bipolar disorder. Limited clinical data on the use of bupropion in combination with mood stabilizers in patients with a history of bipolar disorder indicate a low rate of transition to mania. Before starting treatment with an antidepressant, patients should be properly screened to determine if they are at risk for bipolar disorder; this selection should include a detailed psychiatric history, including family history of suicide, bipolar disorder and depression.
Animal data indicate a potential for abuse. However, studies on the possibility of abuse in humans and extensive clinical experience show that bupropion has a low potential for abuse.
Clinical experience with bupropion in patients receiving electroconvulsive therapy (ECT) is limited. Caution should be exercised in patients receiving electroconvulsive therapy (ECT) concomitantly with bupropion treatment.
Hypersensitivity
ELONTRIL should be discontinued immediately if patients experience hypersensitivity reactions during treatment. Physicians should be advised that symptoms may progress or recur following discontinuation of ELONTRIL and ensure that symptomatic treatment is administered for an adequate period of time (at least one week). Symptoms typically include skin rash, itching, hives or chest pain, but more severe reactions may include angioedema, dyspnoea / bronchospasm, anaphylactic shock, erythema multiforme, or Stevens-Johnson syndrome.Arthralgia, myalgia and fever have also been reported in association with rash or other symptoms suggestive of delayed hypersensitivity (see section 4.8). Symptoms improved after discontinuation of bupropion and initiation of antihistamines and corticosteroids in most patients, and resolved over time.
Cardiovascular diseases
Clinical experience in the use of bupropion to treat depression in patients with cardiovascular disease is limited. Care should be taken if bupropion is used in such patients. However, bupropion was generally well tolerated in smoking cessation studies in patients with ischemic cardiovascular disease (see section 5.1).
Blood pressure
Bupropion has been shown not to induce significant increases in blood pressure in non-depressed patients with Stage I hypertension. However, in clinical practice, hypertension, which in some cases was severe, has been reported in patients taking bupropion (see section 4.8). and required acute treatment. This has been observed in patients with and without pre-existing hypertension.
Baseline blood pressure should be measured at the start of treatment, with follow-up checks particularly in patients with pre-existing hypertension. Care should be taken when discontinuing treatment with ELONTRIL if a clinically significant increase in blood pressure is observed.
The concomitant use of bupropion and transdermal nicotine delivery systems may result in increases in blood pressure.
Specific groups of patients
Pediatric population - Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behaviors in children and adolescents with major depressive disorder and other psychiatric disorders.
Patients with hepatic impairment - Bupropion is extensively metabolised by the liver to its active metabolites; these metabolites are further metabolised. No statistically significant differences in the pharmacokinetics of bupropion were observed in patients with mild to moderate hepatic cirrhosis compared to healthy volunteers, but plasma levels of bupropion showed greater variability between individual patients. Therefore ELONTRIL should be used with caution in patients with mild to moderate hepatic impairment (see section 4.2).
All patients with hepatic impairment should be carefully monitored for possible side effects (e.g. insomnia, xerostomia, seizures) which could indicate elevated drug or metabolite levels.
Patients with renal impairment - Bupropion is mainly excreted in the urine as its metabolites. Therefore, in patients with impaired renal function, bupropion and its active metabolites may accumulate more extensively than usual. Patients should be carefully monitored for possible undesirable effects (eg insomnia, xerostomia, seizures) which could indicate elevated drug or metabolite levels (see section 4.2).
Elderly - Efficacy has not been unambiguously demonstrated in the elderly. In a clinical trial, the elderly followed the same dosing regimen as adults (see sections 4.2 Use in adults and 5.2). Increased sensitivity in some non-elderly individuals. it can be excluded.
Interference with urinalysis
Bupropion, because it has an amphetamine-like chemical structure, interferes with the tests used in some rapid tests for the presence of drugs in the urine, resulting in false positives, particularly for amphetamines. A positive result must generally be confirmed with a more specific method.
Improper routes of administration
ELONTRIL is for oral use only. Inhalation of crushed tablets or injection of bupropion have been reported and may lead to rapid release, more rapid absorption and potential overdose. Convulsions and / or cases of death have been reported with intra-nasal administration or parenteral injection of bupropion.
04.5 Interactions with other medicinal products and other forms of interaction -
Since monoamine oxidase A and B inhibitors also increase the catecholaminergic pathway, by a different mechanism from bupropion, the concomitant use of ELONTRIL and monoamine oxidase inhibitors (MAO inhibitors) is contraindicated (see section 4.3) as there is an increase of the possibility of adverse reactions following their co-administration. At least 14 days must elapse between discontinuation of irreversible MAO inhibitors and initiation of treatment with ELONTRIL. For reversible MAO inhibitors a period of 24 hours is sufficient .
Effects of bupropion on other medicinal products
Although not metabolised by the CYP2D6 isoenzyme, bupropion and its major metabolite hydroxybupropion inhibit the CYP2D6 pathway. Co-administration of bupropion and desipramine to healthy volunteers known to be strong metabolisers of CYP2D6 resulted in a large increase ( 2-5 times) of the Cmax and AUC of desipramine. Inhibition of CYP2D6 was maintained for at least 7 days after the last dose of bupropion.
Concomitant therapy with medicinal products with a reduced therapeutic index, which are predominantly metabolised by CYP2D6, should be initiated at the lowest doses in the dose range of the concomitant medicinal product. Such medicinal products include some antidepressants (eg desipramine, imipramine), antipsychotics (for e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), selective serotonin reuptake inhibitors (SSRIs) and Type 1C antiarrhythmics (e.g. propafenone, flecainide). , the need to decrease the dose of the parent medicinal product should be considered. In such cases the expected benefit of ELONTRIL treatment should be carefully compared with the potential risks.
Drugs that require metabolic activation by CYP2D6 in order to be effective (eg tamoxifen) may have reduced efficacy when co-administered with CYP2D6 inhibitors, such as bupropion (see section 4.4).
Although citalopram (an SSRI) is not primarily metabolised by CYP2D6, in one study, bupropion increased the C and AUC of citalopram by 30% and 40%, respectively.
Effects of other medicinal products on bupropion
Bupropion is primarily metabolised to its major active metabolite, hydroxybupropion, by cytochrome P450 CYP2B6 (see section 5.2).
Concomitant administration of medicinal products that may affect the CYP2B6 isoenzyme-induced metabolism of bupropion (eg CYP2B6 substrates: cyclophosphamide, ifosfamide and CYP2B6 inhibitors: orphenadrine, ticlopidine, clopidogrel) may result in increased plasma levels of bupropion and decreased the levels of the active metabolite hydroxybupropion. The clinical consequences of inhibition of the metabolism of bupropion induced by the CYP2B6 enzyme and the consequent changes in the bupropion-hydroxybupropion ratio are currently unknown.
As bupropion is predominantly metabolised, caution is advised when bupropion is co-administered with medicinal products known to induce metabolism (e.g. carbamazepine, phenytoin, ritonavir, efavirenz) or to inhibit metabolism (e.g. valproate), as these they can influence clinical efficacy and tolerability.
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major metabolites by dose. dependent from 20% to about 80% (see section 5.2). Similarly, efavirenz 600 mg once daily for two weeks reduced bupropion exposure by approximately 55% in healthy volunteers. The clinical consequences of reduced exposure are unclear, but may include decreased efficacy in the treatment of major depression 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.
Learn more about interactions
Administration of ELONTRIL to patients concomitantly receiving either levodopa or amantadine should be done with caution. Limited clinical data indicate a higher incidence of undesirable effects (e.g. nausea, vomiting and neuropsychiatric events - see section 4.8) in patients treated with bupropion concomitantly with levodopa or amantadine.
Although clinical data do not point to 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 during bupropion treatment. Alcohol consumption while taking ELONTRIL should be minimized or avoided.
There are no pharmacokinetic studies with co-administered bupropion and benzodiazepines. Considering the metabolic pathways in vitro, there is no basis to justify this interaction. Following co-administration of bupropion with diazepam in healthy volunteers, there was less sedation than with diazepam alone.
There has been no systematic evaluation of the association of bupropion with antidepressants (other than desipramine and citalopram), benzodiazepines (other than diazepam), or neuroleptics. Clinical experience with St. John's wort is also limited.
Concomitant use of ELONTRIL and nicotine delivery transdermal systems may result in increases in blood pressure.
04.6 Pregnancy and breastfeeding -
Pregnancy
Some epidemiological studies on pregnancy outcomes following maternal exposure to bupropion in the first trimester have reported an "association with increased risk of certain congenital cardiovascular malformations, particularly ventricular septal defects and heart defects related to the left ventricular outflow tract. These findings are not consistent between studies. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). ELONTRIL should not be used in pregnancy. Pregnant women should be encouraged to stop smoking without the use of drug therapy.
Feeding time
Bupropion and its metabolites are excreted in human breast milk. A decision on whether to abstain from breastfeeding or to abstain from ELONTRIL therapy must be made taking into account the benefit of breastfeeding for the infant and the benefit of ELONTRIL therapy for the mother.
Fertility
There are no data on the effect of bupropion on human fertility. A reproduction study in rats showed no signs of impaired fertility (see section 5.3).
04.7 Effects on ability to drive and use machines -
Like other medicines that affect the central nervous system, bupropion can affect the ability to perform tasks that require attention or motor and cognitive skills. Patients should therefore exercise caution before driving or operating machinery until they are reasonably certain that ELONTRIL does not adversely affect their performance.
04.8 Undesirable effects -
The list below provides information on undesirable effects identified from clinical experience, broken down by incidence and system organ class.
Side effects are sorted by frequency using the following convention; very common (≥1 / 10), common (≥1 / 100,
* Hypersensitivity may manifest as skin reactions. See "Immune system disorders" and "Skin and subcutaneous tissue disorders".
** The incidence of seizures is approximately 0.1% (1 / 1,000). The most common type of seizures are generalized tonic-clonic seizures, a type of seizure that in some cases can result in post-ictal confusion o memory impairment (see section 4.4).
*** Cases of suicidal ideation and suicidal behavior have been reported during bupropion therapy or soon after treatment discontinuation (see section 4.4).
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after authorization of the medicinal product is
important, as it allows continuous monitoring of the benefit / risk ratio of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Acute ingestion of doses greater than 10 times the maximum therapeutic dose has been reported. In addition to the events reported in Undesirable Effects, overdose resulted in symptoms including drowsiness, loss of consciousness and / or ECG changes such as disturbances. conduction (including QRS prolongations), arrhythmias and tachycardia. QTc interval prolongation has also been reported, but this has generally been observed in association with QRS prolongation and an increase in heart rate. Although most patients recovered without consequences, deaths have rarely been reported. associated with bupropion in patients who had ingested large quantities of the drug in overdose.
Treatment: In the event of an overdose, hospitalization is recommended. ECG and vital signs should be monitored.
Adequate airway clearance, oxygenation and ventilation must be ensured. The use of activated charcoal is recommended. There is no known specific antidote for bupropion. Further treatments will be undertaken on the basis of the clinical picture.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Other antidepressants - ATC code N06AX12
Mechanism of action
Bupropion is a selective inhibitor of the neuronal reuptake of catecholamines (noradrenaline and dopamine), with a minimal effect on the reuptake of indolamines (serotonin) and does not inhibit monoamine oxidase.
The mechanism of action of bupropion as an antidepressant is not known. However, its action is assumed to be mediated by noradrenergic and / or dopaminergic mechanisms.
Clinical efficacy
The antidepressant activity of bupropion was studied in a clinical program performed in patients with Major Depressive Disorder (MDD) which included a total of 1155 patients treated with ELONTRIL and 1868 patients treated with WELLBUTRIN prolonged-release tablets. Seven studies examined the " efficacy of ELONTRIL: 3 were conducted in the European Union at doses up to 300 mg per day and 4 were conducted in the USA as part of a range flexible doses up to 450 mg per day. In addition, 9 studies with WELLBUTRIN prolonged-release tablets in Major Depressive Disorder were considered supportive, based on the bioequivalence of ELONTRIL (once daily) and WELLBUTRIN prolonged-release (twice daily) tablets.
ELONTRIL was shown to be statistically superior to placebo based on the evaluation of the improvement in the total score of the Montgomery-Asberg Depression Rating Scale (MADRS) in one of two identical studies using doses ranging from range of 150-300 mg.Response and remission rates were also statistically significantly higher with ELONTRIL than with placebo. In a third study in elderly patients, statistical superiority over placebo was not achieved in the primary parameter, mean reduction of baseline values in MADRS (within the "analysis" Last Observational Carried Forward), although statistically significant effects were observed in a "secondary analysis (analysis on observed cases, Observed Cases).
A significant benefit was observed in the "endpoint primary in 2 of 4 studies conducted in the USA with ELONTRIL (300-450 mg). Of the 2 positive studies, one was a placebo controlled study in patients with Major Depressive Disorder and the other was an active comparator controlled study in patients with Major Depressive Disorder.
In a relapse prevention study, patients who responded to 8 weeks of acute treatment with open-label WELLBUTRIN prolonged-release tablets (300 mg daily) were randomized to either WELLBUTRIN prolonged-release tablets or placebo for an additional 44 weeks. . WELLBUTRIN prolonged-release tablets demonstrated statistically significant superiority compared to placebo (primary outcome. The incidence of maintenance of the effect during the follow up in the 44-week double-blind study was 64% and 48% for WELLBUTRIN prolonged-release tablets and placebo, respectively.
Clinical safety
The proportion of congenital cardiac defects in pregnancies observed prospectively with prenatal exposure to bupropion in the first trimester was 9/675 (1.3%) in the International Pregnancy Registry. In a retrospective study there was no greater proportion of congenital malformations or cardiovascular malformations between more than a thousand first trimesters of exposure to bupropion compared to the use of other antidepressants.
In a retrospective analysis using data from the National Birth Defects Prevention Study, a statistically significant association was observed between the occurrence of a heart defect in a left outflow tract in the neonate and self-reported maternal use of bupropion in infants. Early stages of pregnancy: No association was observed between maternal use of bupropion and any other type of heart defect or with all categories of heart defects combined.
Further analysis of data from the Slone Epidemiology Center Birth Defects Study found no statistically significant increase in left ventricular outflow tract heart defects with maternal use of bupropion. However, a statistically significant association was observed for ventricular septal defects following use of bupropion alone during the first trimester.
In a study in healthy volunteers, no clinically significant effect of modified-release bupropion tablets (450 mg / day) on the QTcF interval was observed compared to placebo after 14 days of steady-state dosing.
05.2 "Pharmacokinetic properties -
Absorption
Following once-daily oral administration of 300 mg bupropion hydrochloride modified-release tablets to healthy volunteers, maximum plasma concentrations (Cmax) of approximately 160 ng / mL are observed after approximately 5 hours. At the steady state the Cmax and AUC values of hydroxybupropion are approximately 3 and 14 times those of bupropion, respectively. The Cmax of threohydrobupropion at steady state is similar to that of bupropion and the AUC is approximately 5 times higher, while plasma concentrations of erythrohydrobupropion are comparable to those of bupropion. Peak plasma levels of hydroxybupropion are reached after 7 hours, while those of threohydrobupropion and erythrohydrobupropion are reached after 8 hours. The AUC and Cmax of bupropion and its active metabolites hydroxybupropion and threohydrobupropion increase dose proportionally over a range dosage of 50-200 mg following single doses and in the context of a range dosage of 300-450 mg per day after chronic administration.
The absolute bioavailability of bupropion is unknown; however, the data relating to urinary excretion show that at least 87% of the dose of bupropion is absorbed.
The absorption of bupropion modified release tablets is not significantly affected when they are taken with food.
Distribution
Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 liters.
Bupropion, hydroxybupropion and threohydrobupropion bind moderately to plasma proteins (84%, 77% and 42%, respectively).
Bupropion and its active metabolites are excreted in human milk. Animal studies show that bupropion and its active metabolites cross the blood-brain barrier and the placenta.
Positron Emission Tomography (PET) studies performed in healthy volunteers show that bupropion penetrates the central nervous system and binds to the striatal transporter for dopamine reuptake (approximately 25% with the dose of 150 mg twice daily ).
Biotransformation
Bupropion is extensively metabolised in humans. Three pharmacologically active metabolites have been identified in plasma: hydroxybupropion and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion. These may be of clinical significance, as their plasma concentrations are as high as those of bupropion or higher. 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 predominantly by CYP2B6, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. In contrast, threohydrobupropion formation involves carbonyl reduction but does not involve cytochrome P450 isoenzymes (see section 4.5).
The inhibition potential of threohydrobupropion and erythrohydrobupropion towards cytochrome P450 has not been studied.
Bupropion and hydroxybupropion are both inhibitors of the CYP2D6 isoenzyme with Ki values of 21 and 13.3 microM, respectively (see section 4.5).
In animals, bupropion has been shown to induce its metabolism following sub-chronic administration. In humans, there is no evidence of enzyme induction of bupropion or hydroxybupropion in volunteers or patients receiving 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 were recovered in 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 dose was measured in urine as active metabolites.
There clearance apparent mean following oral administration of bupropion hydrochloride is approximately 200 liters / hour 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) and the AUC values at steady state they are 8 and 1.6 times higher than those of bupropion, respectively. The steady state for bupropion and its metabolites it is reached within 8 days.
The insoluble coating of the modified release tablet may remain intact during gastrointestinal transit and be eliminated in the faeces.
Special patient populations:
Patients with renal impairment
The elimination of bupropion and its major active metabolites may be reduced in patients with renal impairment. Limited data in patients with end stage renal failure or moderate to severe renal impairment 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 did not differ statistically significantly in patients with mild to moderate cirrhosis compared to healthy volunteers, although greater inter-patient variability was observed (see section 4.4). For patients with severe liver cirrhosis, the Cmax and AUC of bupropion were substantially increased (mean difference approximately 70% and 3-fold, respectively) and more variable when compared with the values of healthy volunteers; the mean half-life was also longer (by about 40%). For hydroxybupropion, the mean Cmax was lower (by about 70%), the mean AUC tended to be higher (by about 30%) , the mean Tmax was delayed (by about 20 hours), and the mean half-lives were longer (by about 4 times) than in healthy volunteers. For threohydrobupropion and erythrohydrobupropion, mean Cmax tended to be lower (by about 30%), mean AUC tended to be higher (by about 50%), mean Tmax was delayed (by about 20 hours), and "mean half-life was longer (approximately 2 times) than in healthy volunteers (see section 4.3).
Senior citizens
Pharmacokinetic studies in the elderly have shown variable results. A single dose study showed that the pharmacokinetics of bupropion and its metabolites in the elderly did not differ from that in young adults. Another single and multiple dose pharmacokinetic study indicated that accumulation of bupropion and its metabolites may occur more extensively in the elderly. Clinical experience has not identified any differences in tolerability between elderly and younger patients. , but increased sensitivity in older patients cannot be excluded (see section 4.4).
Release in-vitro of bupropion with alcohol
Test in-vitro show that at high alcohol concentrations (up to 40%), bupropion is released more rapidly from the modified release formulation (up to 20% dissolved at 2 hours) (see section 4.5).
05.3 Preclinical safety data -
Reproductive toxicity studies conducted in rats at exposure levels similar to those obtained with the maximum recommended human dose (based on systemic exposure data) did not reveal any adverse effects on fertility, pregnancy and fetal development.
Reproductive toxicity studies conducted in rabbits treated with doses up to 7 times the maximum recommended human dose on a mg / m² basis (no systemic exposure data available) revealed only a slight increase in skeletal variations (increased incidence of common anatomical variations of an accessory thoracic rib and delayed ossification of the phalanges). In addition, a decrease in fetal weight of rabbits was observed at maternally toxic doses.
In animal studies, much higher doses of bupropion than the therapeutic doses used in humans caused, among others, the following dose-related symptoms: ataxia and convulsions in rats, general weakness, tremors and emesis in dogs and increased blood pressure. lethality in both species. Due to enzyme induction in animals but not humans, systemic exposures in animals were similar to the systemic exposures observed 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 liver findings in laboratory animals have only limited relevance in assessing and defining the risk associated with bupropion.
Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mutagen in mammals, and therefore is not of interest as a genotoxic agent in humans. Studies in mice and rats confirm the absence of carcinogenicity in these species.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Tablet core:
Polyvinyl alcohol
Glyceryl dibeenate
Tablet coating:
Ink:
Black printing ink (Opacode S-1-17823).
Opacode S-1-17823 containing ≈45% shellac fixative (20% esterified), black iron oxide (E172) and 28% ammonium hydroxide.
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
18 months.
06.4 Special precautions for storage -
Store in the original package to protect from moisture and light.
06.5 Nature of the immediate packaging and contents of the package -
Opaque white high-density polyethylene (HDPE) bottle containing a metal-wrapped desiccant with a carbon / silica gel combination and fitted with a heat-sealed membrane child-resistant closure.
150 mg: 7, 30 and 90 (3x30) tablets.
300 mg: 7, 30 and 90 (3x30) tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions for disposal.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - Verona
Dealership for sale:
Sigma Tau Industrie Farmaceutiche Riunite S.p.A. - Viale Shakespeare, 47 - Rome
08.0 MARKETING AUTHORIZATION NUMBER -
150 mg modified release tablets - 7 A.I.C. n .: 037697012
150 mg modified release tablets - 30 A.I.C. n .: 037697024
150 mg modified release tablets - 90 A.I.C. n .: 037697036
300 mg modified release tablets - 7 A.I.C. n .: 037697048
300 mg modified release tablets - 30 A.I.C. n .: 037697051
300 mg modified release tablets - 90 tablets A.I.C. n .: 037697063
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
January 22, 2008
10.0 DATE OF REVISION OF THE TEXT -
02/2015
