Bupropion / Naltrexone: package leaflet

Mysimba contains 2 active substances: naltrexone hydrochloride and bupropion hydrochloride and is used in obese or overweight adults to manage weight together with a reduced calorie diet and physical exercise. This medicine works on areas on the brain involved in the control of food intake and energy expenditure.

Obesity in adults over 18 years of age is defined as a body mass index of greater than or equal to 30 and overweight in adults over 18 years of age is defined as a body mass index greater than or equal to 27 and less than 30. The body mass index is calculated as the measured body weight (kg) divided by the measured height squared (m2).

Mysimba is approved for use in patients with an initial body mass index of 30 or greater; it can also be given to those with a body mass index between 27 and 30 if they have additional weight-related conditions such as controlled high blood pressure (hypertension), type 2 diabetes or high levels of lipid (fat) in the blood.

Mysimba may be discontinued by your doctor after 16 weeks if you have not lost at least 5 percent of your initial body weight. Your doctor may also recommend stopping treatment if you have not maintained the loss of at least 5 percent of your initial body weight after 1 year of treatment or if there are concerns about increased blood pressure, or other concerns with the safety or tolerability of this medicine.

Do not take Mysimba:
- if you are allergic to naltrexone, to bupropion or to any of the other ingredients of this medicine (listed in section 6);

• if you have an abnormally high blood pressure (hypertension) that is not controlled using a medicinal product;
• if you have a condition that causes fits (seizures) or if you have a history of fits;
• if you have a brain tumour;
• if you are usually a heavy drinker and you have just stopped drinking alcohol, or are going to stop while you are taking Mysimba;
• if you have recently stopped taking sedatives or medicines to treat anxiety (especially benzodiazepines), or if you are going to stop them while you are taking Mysimba;
• if you have or have had a bipolar disorder (extreme mood swings);
• if you are using any other medicines which contain bupropion or naltrexone;
• if you have an eating disorder or had one in the past (for example, bulimia or anorexia nervosa);
• if you are currently dependent on opioids, or taking opioids for the treatment of dependence (for example methadone or buprenorphine), or you are going through acute withdrawal (cold turkey);
• if you are taking medicines for depression or Parkinson’s disease called monoamine oxidase inhibitors (MAOIs) or have taken them in the last 14 days;
• if you have severe liver disease;
• if you have endstage kidney disease.

Warnings and precautions
Talk to your doctor or pharmacist before taking Mysimba.
This is important because some conditions make it more likely that you could have side effects (see also section 4).

If you feel depressed, contemplate suicide, have a history of attempting suicide, panic attacks or any other mental health problems, you should inform your doctor before taking this medicine.

Fits (seizures)
Mysimba has been shown to cause fits (seizures) in up to 1 in 1,000 patients (see also section 4). You should inform your doctor before taking this medicine:
- if you have had a serious head injury or head trauma;
- if you regularly drink alcohol (see “Mysimba with alcohol”);
- if you regularly use medicines to help you to sleep (sedatives);
- if you are currently dependent on or addicted to cocaine or other stimulating products;
- if you have diabetes for which you use insulin or oral medicines that may cause low sugar levels in your blood (hypoglycaemia); or
- if you are taking medicines that may increase the risk of fits (see “Other medicines and Mysimba”).
If you have a fit (seizure), you should stop taking Mysimba and consult your doctor immediately.

Hypersensitivity reactions
You should stop taking Mysimba immediately and consult your doctor if you are experiencing any symptoms of an allergic reaction such as swelling of the throat, tongue, lips, or face, difficulty swallowing or breathing, dizziness, fever, rash, pain in the joints or in the muscles, itching or hives after taking this medicine (see also section 4).

Serious skin reactions, including Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN),acute generalised exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with bupropion-containing products, including Mysimba. Stop using Mysimba and seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions described in section 4.

Talk to your doctor, before taking Mysimba, if:
- you have ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after taking Mysimba or other medicines containing bupropion (e.g. for depression or to quit smoking).

- you have high blood pressure , because it can become worse. You will have your blood pressure and heart rate measured before you start taking Mysimba and while you are taking it.
If your blood pressure or heart rate increases significantly, you may need to stop taking Mysimba.
- you have uncontrolled coronary artery disease (a heart disease caused by poor blood flow in the blood vessels of the heart) with symptoms such as angina (characterised by chest pain) or a recent heart attack.
- you already have or have had a condition affecting the circulation of blood in the brain (cerebrovascular disease).
- you have any liver problems .
- you have any kidney problems .
- you have a history of mania (feeling elated or over-excited, which causes unusual behaviour). you are taking medicines for depression, the use of these medicines together with Mysimba can lead to serotonin syndrome, a potentially life-threatening condition (see “Other medicines and Mysimba” in this section and section 4.)

Brugada syndrome
- if you have a condition called Brugada syndrome (a rare hereditary syndrome that affects the heart rhythm) or if cardiac arrest or sudden death occurred in your family.

Older People
Use caution when taking Mysimba, if you are 65 years or older. Mysimba is not recommended if you are over 75 years.

Children and adolescents
No studies have been conducted in children and adolescents under the age of 18. Therefore Mysimba should not be used in children and adolescents below 18 years.

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

Do not take Mysimba with:
- Monoamine oxidase inhibitors (medicines to treat depression or Parkinson’s disease) such as phenelzine, selegiline, or rasagiline. You must stop taking these medicines for at least 14 days before starting Mysimba (see “Do not take Mysimba”).
- Opioid-containing medicines for example to treat cough and cold (such as mixtures containing dextromethorphan or codeine), opioid addiction (such as methadone or buprenorphine), pain (for example, tramadol, morphine or codeine), diarrhoea (for example, paregoric). You must have stopped taking any opioid medicines at least 7-10 days before starting Mysimba. Your doctor may carry out a test to ensure that your body has cleared these medicines before starting your treatment.
If you require treatment with opioids (for example during surgery) while taking Mysimba, you should stop taking Mysimba at least 3 days before starting the treatment with opioids or a surgical procedure. Naltrexone contained in Mysimba blocks the effects of opioids for several days after you stop taking Mysimba.
Taking Mysimba together with medicines for treating depression and opioids may cause serious life-threatening reactions, such as serotonin syndrome and seizure (see section 2. Tell your doctor if…), (see “Possible side effects”).
If you take higher doses of opioids to overcome these effects of naltrexone, you may suffer from an acute opioid intoxication which may be life threatening. After you stop treatment with Mysimba you may be more sensitive to low doses of opioids (see “Do not take Mysimba”).

Tell your doctor if you are taking any of the following medicines, as your doctor will closely monitor you for side effects:

- Medicines that may, when used alone or in combination with naltrexone/bupropion, increase the risk of fits such as:
o medicines for depression and other mental health problems;
o steroids (except drops, creams, or lotions for eye and skin conditions or inhalers for breathing disorders such as asthma);
o medicines used to prevent malaria;
o quinolones (antibiotics such as ciprofloxacine to treat infections);
o theophylline (used in the treatment of asthma);
o antihistamines (medicines to treat hayfever, itch, and other allergic reactions) that cause sleepiness (such as chlorphenamine);
o medicines to lower sugar levels in your blood (such as insulin, sulphonylureas such as glyburide or glibenclamide, and meglitinides such as nateglinide or repaglinide);
o medicines to help you to sleep (sedatives such as diazepam).
- Medicines to treat depression (such as amitriptyline, desipramine, imipramine, venlafaxine, paroxetine, fluoxetine, citalopram, escitalopram) or other mental health problems (such as risperidone, haloperidol, thioridazine). Mysimba may interact with some medicines used for treatment of depression and you may experience a so-called serotonin syndrome. Symptoms are mental status changes (e.g. agitation, hallucinations, coma), and other effects, such as body temperature above 38°C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, muscular rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea) (see section 4.)
- Some medicines used to treat high blood pressure (beta-blockers such as metoprolol, and clonidine, a centrally acting antihypertensive);
- Some medicines used to treat irregular heart rhythm (such as propafenone, flecainide);
- Some medicines used to treat cancer (such as cyclophospamide, ifosphamide, tamoxifen);
- Some medicines for Parkinson’s disease (such as levodopa, amantadine or orphenadrine);
- Ticlopidine or clopidogrel, mainly used in the treatment of heart disease or stroke;
- Medicines used in the treatment of HIV infection and AIDS, such as efavirenz and ritonavir;
- Medicines used to treat epilepsy such as valproate, carbamazepine, phenytoin or phenobarbital.

Your doctor will closely monitor you for side effects and/or may need to adjust the dose of the other medicines or Mysimba.
Mysimba may make other medicines less effective when taken at the same time:
- If you take digoxin for your heart
If this applies to you, tell your doctor. Your doctor may consider adjusting the dose of digoxin.

Mysimba with alcohol
Excessive use of alcohol while being treated with Mysimba might increase the risk for fits (seizures), mental disorder events or might reduce alcohol tolerance. Your doctor may suggest you do not drink alcohol while you are taking Mysimba, or try to drink as little as possible. If you do drink a lot now, do not just stop suddenly, because that may put you at risk of having a fit.

Pregnancy and breast-feeding
Mysimba should not be used during pregnancy, or in women currently planning to become pregnant, or while breast-feeding.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines
Ask your doctor for advice before you drive and operate machines since Mysimba might make you feel dizzy and sleepy which may weaken your ability to concentrate and react.

Do not drive, use any tools or machines, or perform dangerous activities until you know how this medicine affects you.

If you experience fainting, muscle weakness or fits during treatment, do not drive or use machines.

In case of doubt, check with your doctor, who might consider to interrupt the treatment depending on your situation.

Mysimba contains lactose (a type of sugar)
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The initial dose is usually one tablet (8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride) once a day in the morning. The dose will be gradually adapted as follows:
- Week 1: One tablet once a day in the morning
- Week 2: Two tablets every day, one in the morning and one in the evening
- Week 3: Three tablets every day, two in the morning and one in the evening
- Week 4 and onward: Four tablets every day, two in the morning and two in the evening The maximum recommended daily dose of Mysimba is two tablets taken twice a day.
After 16 weeks and each year after your treatment initiation, your doctor will evaluate whether you should continue to take Mysimba.

If you have problems with your liver or kidney, or if you are older than 65, and depending on the severity of your problems, your doctor may carefully consider whether this medicine is suitable for you or recommend that you take a different dose, and monitor you more closely for potential side effects. Your doctor may test your blood before initiating treatment with Mysimba if you have high blood sugar (diabetes) or if you are older than 65, so that your doctor can decide if you should take this medicine or if you need to take a different dose.

This medicine is for oral use. Swallow your tablets whole. Do not cut them, chew them or crush them. The tablets should preferably be taken with food.

If you take more Mysimba than you should
If you take too many tablets, you may be more likely to have a fit or other side effects similar to those described in section 4 below. Do not delay, contact your doctor or your nearest hospital emergency department immediately.

If you forget to take Mysimba
Skip the missed dose and take your next dose at the next usual time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Mysimba
You may need to take Mysimba for at least 16 weeks to have its full effect. Do not stop taking Mysimba without talking to your doctor first.

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

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

Serious side effects
Stop using Mysimba and seek medical attention immediately if you notice any of the following symptoms:

- Serious skin reactions
Not known- frequency cannot be estimated from the available data in people taking Mysimba
- reddish non-elevated, target-like or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These serious skin rashes can be preceded by fever and flu-like symptoms [Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN)]
- widespread rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).
- A red, scaly widespread rash with bumps under the skin and blisters accompanied by fever.
The symptoms usually appear at the initiation of treatment [acute generalised exanthematous pustulosis (AGEP)].

Tell your doctor straight away, if you notice any of the following serious side effects:
- Suicidal thoughts and feeling depressed
Frequency of the side effects suicide attempts, suicidal behavior, suicidal thoughts and feeling depressed are not known and cannot be estimated from the available data in people taking Mysimba.
There have been reports of depression, suicidal thoughts, and suicide attempts during treatment with Mysimba. If you have thoughts about harming yourself or other distressing thoughts, or if you are depressed and notice that you feel worse or develop new symptoms, contact your doctor or go to a hospital straight away.
- Fits (seizures):
Rare - may affect up to 1 in 1,000 people taking Mysimba with risk of having a fit.
Symptoms of a fit include convulsions and usually loss of consciousness. Someone who has had a fit may be confused afterwards and may not remember what has happened. Fits are more likely if you take too much, if you take some other medicines or if you are at a higher than usual risk of fits (see section 2).
- Erythema multiforme
Not known - frequency cannot be estimated from the available data in people taking Mysimba.
Erythema multiforme is a severe condition of the skin that may affect the mouth and other parts of the body, with red, often itchy spots starting on the limbs.
- Rhabdomyolysis
Not known - frequency cannot be estimated from the available data in people taking Mysimba.
Rhabdomyolysis is an abnormal breakdown of muscle tissue which can lead to kidney problems. Symptoms include severe muscle cramps, muscle pain or muscle weakness.
- Lupus skin rash or worsening of lupus symptoms
Not known - frequency cannot be estimated from the available data in people taking Mysimba.
Lupus is an immune system disorder affecting the skin and other organs. If you experience lupus flares, skin rash or lesions (particularly on sun-exposed areas) while taking Mysimba, contact your doctor straight away, as it might be necessary to stop the treatment.
- Serotonin syndrome, that can manifest as mental status changes (e.g. agitation, hallucinations, coma), and other effects, such as body temperature above 38°C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, muscular rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea), while taking Mysimba together with medicines used for treatment of depression (such as paroxetine, citalopram, escitalopram, fluoxetine and venlafaxine and opioids (see section 2.) Not known - frequency cannot be estimated from the available data in people taking Mysimba)

Other side effects include:

Very common side effects (may affect more than 1 in 10 people):
- Feeling sick (nausea), being sick (vomiting)
- Constipation
- Headache

Common side effects (may affect up to 1 in 10 people):
- Anxiety

• Dizziness, feeling of dizziness or “spinning” (vertigo)
• Feeling shaky (tremor)
• Difficulty in sleeping (make sure you do not take Mysimba near to bedtime)
• Changes in the taste of food (dysgeusia), dry mouth
• Difficulty concentrating
• Feeling of tiredness (fatigue) and sleepiness, drowsiness or lack of energy (lethargy)
• Ringing in the ears (tinnitus)
• Fast or irregular heartbeat
• Hot flush
• Increased blood pressure (sometimes severe)
• Pain in the upper part of the abdomen
• Pain in the abdomen
• Excessive sweating (hyperhidrosis)
• Rash, itching (pruritus)
• Hair loss (alopecia)
• Irritability
• Feeling jittery

Uncommon side effects (may affect up to 1 in 100 people):
- Hives (uticaria)
- Hypersensitivity
- Abnormal dreams
- Feeling nervous, feeling spacey, tension, agitation, mood swings, Tremor of the head or a limb which increases when trying to perform a particular function (intention tremor)
- Balance disorder
- Loss of memory (amnesia), Tingling or numbness of the hands or feet
- Motion sickness
- Burping
- Abdominal discomfort
- Indigestion
- Inflammation of the gallbladder (cholecystitis)
- Increased creatinine levels in the blood (indicating loss of kidney function)
- Increased liver enzymes and bilirubin levels, liver disorders
- Difficulty in getting or keeping an erection
- Feeling abnormal, weakness (asthenia)
- Thirst, feeling hot
- Chest pain
- Increased appetite, weight gain

Rare side effects (may affect up to 1 in 1,000 people):
- Low amount of certain white blood cells (Lymphocyte count decreased)
- Decreased haematocrit (indicating loss of red blood cell volume)
- Swelling of eyelids, face, lips, tongue or throat, which can cause great difficulty in breathing (angioedema)
- Excessive loss of body water (dehydration)
- Hallucinations
- Fainting, almost fainting (presyncope), loss of consciousness
- Fits
- Passage of fresh blood through the anus usually in or with stool (haematochezia)
- Projection of an organ or the tissue encompassing an organ through the wall of the cavity that normally contains it (hernia)
- Toothache
- Dental caries, cavities
- Pain in the lower part of the abdomen
- Injury to the liver due to drug toxicity
- Jaw pain
- A disorder characterised by a sudden compelling urge to urinate (micturition urgency)
- Irregular menstrual cycle, vaginal bleeding, dryness of the female vulva and vagina

• Coldness of extremities (hands, feet)

Not known side effects (frequency cannot be estimated from the available data):
- Swollen glands in the neck, armpit or groin (lymphadenopathy)
- Mood disorders
- Irrational ideas (delusions)
- Psychosis
- Feeling of acute and disabling anxiety (panic attack)
- Loss of sexual desire
- Feeling hostile
- Severe suspiciousness (paranoia)
- Aggression
- Attention disturbance
- Nightmares
- Confusion, disorientation
- Memory impairment
- Restlessness
- Muscle stiffness, uncontrolled movements, problems with walking or coordination
- Blurred vision, eye pain, eye irritation, eye swelling, watery eyes, increased sensitivity to light (photophobia)
- Ear pain, ear discomfort
- Difficulty in breathing
- Nasal discomfort, congestion, runny nose, sneezing, sinus disorder
- Sore throat, disorder of the voice, cough, yawning Haemorrhoids,
- ulcer
- Diarrhoea
- Passing wind (flatulence)
- Hepatitis
- Acne
- Groin pain
- Muscle pain
- Joint pain Abnormally frequent urination, painful urination
- Chills
- Increased energy

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 listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 and blister after “EXP”.
The expiry date refers to the last day of that month.

Do not store above 30°C.

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

What Mysimba contains

• The active substances are naltrexone hydrochloride and bupropion hydrochloride. Each tablet contains 8 milligrams of naltrexone hydrochloride, equivalent to 7.2 milligrams of naltrexone, and 90 milligrams of bupropion hydrochloride, equivalent to 78 milligrams of bupropion.
• The other ingredients (excipients) are:
• Tablet core: microcrystalline cellulose, hydroxypropyl cellulose, lactose anhydrous, lactose monohydrate (see section 2 “Mysimba contains lactose”), cysteine hydrochloride, crospovidone type A, magnesium stearate, hypromellose, edetate disodium, colloidal silicon dioxide, and indigo carmine aluminium lake (E132). Film-coating: poly(vinyl alcohol), titanium dioxide (E171), macrogol (3350), talc and indigo carmine aluminium lake (E132).

What Mysimba looks like and contents of the pack
Mysimba prolonged-release tablets are blue, biconvex, round tablets debossed with “NB-890” on one side. Mysimba is available in packs containing 28 or 112 tablets. Not all pack sizes may be marketed.

Patient Card: handling information
With the packaging of Mysimba you will find a Patient Card that includes important safety information for you and your doctors. Carry the patient card with you at all times.

Marketing Authorisation Holder and Manufacturer

Orexigen Therapeutics Ireland Limited
9-10 Fenian Street,
Dublin 2,
D02 RX24
Ireland

Siegfried Barberà S.L.
Ronda de Santa María, 158,
08210 Barberà del Vallès,
Barcelona, Spain

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgique/België/Belgien
GOODLIFE Pharma SA/NV
Tel: +32 800 79510

Lietuva
B-LINK PHARMA UAB
Tel: +370 880 033407
България
PharmaSwiss EOOD
Teл.: 008001100179

Luxembourg/Luxemburg
GOODLIFE Pharma SA/NV
Tel: +352 800 23603
Česká republika
PharmaSwiss Česká republika s.r.o.
Tel: +420 800 202135

Magyarország
Bausch Health Magyarország Kft.
Tel.: +36 800 14337
Danmark
Navamedic AB
Tlf.:+45 80 253432

Malta
Vivian Corporation Limited
Tel: +356 800 62176
Deutschland
Goodlife Endocrinologie B.V.
Tel: +49 0800 9020202

Nederland
Goodlife Endocrinologie B.V.
Tel: +31 800 0200800

Eesti
B-LINK PHARMA UAB
Tel: +372 800 0112023

Norge
Navamedic AB
Tlf: +47 800 31511
Ελλάδα
Win Medica Pharmaceutical S.A.
Τηλ: +30 800 3252735

Österreich
Orexigen Therapeutics Ireland Limited
Tel: +43 800 232905

España
Orexigen Therapeutics Ireland Limited
Tel: +34 900 808 093

Polska
Bausch Health Poland sp. z o.o.
Tel.: +48 800 999969
France
Orexigen Therapeutics Ireland Limited
Tél: +33 805 543871

Portugal
Laboratório Medinfar - Produtos Farmacêuticos, S.A.
Tel: +351 800 509600
Hrvatska
BioMedica EE, s.r.o.
Tel: +385 800 791 186

România
BioMedica EE, s.r.o.
Tel: +40 800 896562
Ireland
Consilient Health Limited
Tel: +353 1800 849099

Slovenija
BioMedica EE, s.r.o.
Tel: +386 800 83132
Ísland
Navamedic AB
Sími: +354 800 4383
Slovenská republika
Bausch Health Slovakia s.r.o.
Tel: +421 800 601203

Italia
Bruno Farmaceutici S.p.A.
Tel: +39 800 187271

Suomi/Finland
Navamedic AB
Puh: +358 800 416203

Κύπρος
Orexigen Therapeutics Ireland Limited
Τηλ: +357 800 80575

Sverige
Navamedic AB
Tel:+46 200 336733
Latvija
B-LINK PHARMA UAB
Tel: +371 800 05400

This leaflet was last revised in .

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

Annex IV
Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

Scientific conclusions
Taking into account the PRAC Assessment Report on the PSUR(s) for naltrexone / bupropion, the scientific conclusions of PRAC are as follows:
In view of available data on the risk of toxic epidermal necrolysis (TEN) that was assessed for the mono- component bupropion and the scientific rational to have this risk also with the other products containing bupropion including NB, the PRAC concluded that the product information of products containing bupropion should be amended accordingly.
In view of available data on the risk of drug reaction with eosinophilia and systemic symptoms (DRESS) that was assessed for the mono-component bupropion and the scientific rational to have this risk also with the other products containing bupropion including NB, the PRAC concluded that the product information of products containing bupropion should be amended accordingly.
Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall conclusions and grounds for recommendation.
Grounds for the variation to the terms of the marketing authorisation(s)
On the basis of the scientific conclusions for naltrexone / bupropion the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing naltrexone / bupropion is unchanged subject to the proposed changes to the product information The CHMP recommends that the terms of the marketing authorisation(s) should be varied.