Mysimba
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Mysimba 8 mg/90 mg prolonged-release tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 8 mg naltrexone hydrochloride, equivalent to 7.2 mg of naltrexone, and 90 mg 
bupropion hydrochloride, equivalent to 78 mg of bupropion. 
 
Excipient with known effect: 
Each prolonged-release tablet contains 73.2 mg of lactose (see section 4.4). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release tablet. 
 
Blue, biconvex, round tablet of 12-12.2 mm diameter debossed with “NB-890” on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Mysimba is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the 
management of weight in adult patients (≥18 years) with an initial Body Mass Index (BMI) of 
 ≥ 30 kg/m2 (obese), or 
 ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of one or more weight-related 

co-morbidities (e.g., type 2 diabetes, dyslipidaemia, or controlled hypertension) 
 
Treatment with Mysimba should be discontinued after 16 weeks if patients have not lost at least 5% 
of their initial body weight (see section 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
Upon initiating treatment, the dose should be escalated over a 4-week period as follows: 
 
 Week 1: One tablet in the morning 
 Week 2: One tablet in the morning and one tablet in the evening 
 Week 3: Two tablets in the morning and one tablet in the evening 
 Week 4 and onwards: Two tablets in the morning and two tablets in the evening 
 
The maximum recommended daily dose of Mysimba is two tablets taken twice daily for a total dose 
of 32 mg naltrexone hydrochloride and 360 mg bupropion hydrochloride.  
The need for continued treatment should be evaluated after 16 weeks (see section 4.1) and re-
evaluated annually. 
 



 

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Missed dose  
If a dose is missed, patients should not take an additional dose, but take the prescribed next dose at 
the usual time.  
 
Special populations 
 
Elderly patients (over 65 years) 
Naltrexone/bupropion should be used with caution in patients over 65 years of age and is not 
recommended in patients over 75 years of age (see sections 4.4, 4.8 and 5.2). 
 
Patients with renal impairment 
Naltrexone/bupropion is contraindicated in patients with end-stage renal failure (see section 4.3). In 
patients with moderate or severe renal impairment, the maximum recommended daily dose for 
naltrexone/bupropion is two tablets (one tablet in the morning and one tablet in the evening) (see 
sections 4.4, 4.8 and 5.2). It is recommended that patients with moderate or severe renal impairment 
initiate treatment with one tablet in the morning for the first week of treatment, and escalate to one 
tablet in the morning and one tablet in the evening from week 2 onwards. Dose reduction is not 
necessary in patients with mild renal impairment. For individuals who are at elevated risk for renal 
impairment, in particular patients with diabetes or elderly individuals, estimated glomerular filtration 
rate (eGFR) should be assessed prior to initiating therapy with naltrexone/bupropion. 
 
Patients with hepatic impairment 
Naltrexone/bupropion is contraindicated in patients with severe hepatic impairment (see section 4.3). 
Naltrexone/bupropion is not recommended in patients with  moderate hepatic impairment (see 
sections 4.4 and 5.2). In patients with mild hepatic impairment, the maximum recommended daily 
dose for naltrexone/bupropion is two tablets (one tablet in the morning and one tablet in the evening) 
(see sections 4.4 and 5.2). It is recommended that patients with mild hepatic impairment initiate 
treatment with one tablet in the morning for the first week of treatment, and escalate to one tablet in 
the morning and one tablet in the evening from week 2 onwards. Degree of hepatic impairment 
should be assessed using the Child-Pugh score. 
 
Paediatric population 
The safety and efficacy of naltrexone/bupropion in children and adolescents below 18 have not yet 
been established. Therefore, naltrexone/bupropion should not be used in children and adolescents 
below 18. 
 
Method of administration  
 
Oral use. The tablets should be swallowed whole with some water. The tablets should preferably be 
taken with food (see section 5.2). The tablets should not be cut, chewed, or crushed. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 
 Patients with uncontrolled hypertension (see section 4.4) 
 Patients with a current seizure disorder or a history of seizures (see section 4.4) 
 Patients with a known central nervous system tumour 
 Patients undergoing acute alcohol or benzodiazepine withdrawal 
 Patients with a history of bipolar disorder 
 Patients receiving any concomitant treatment containing bupropion or naltrexone 
 Patients with a current or previous diagnosis of bulimia or anorexia nervosa 
 Patients currently dependent on chronic opioids (see sections 4.4 and 4.5) or opiate agonists 

(e.g., methadone), or patients in acute opiate withdrawal  
 Patients receiving concomitant administration of monoamine oxidase inhibitors (MAOI). At 

least 14 days should elapse between discontinuation of MAOI and initiation of treatment with 
naltrexone/bupropion (see section 4.5) 



 

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 Patients with severe hepatic impairment (see sections 4.2 and 5.2) 
 Patients with end-stage renal failure (see sections 4.2 and 5.2) 
 
4.4 Special warnings and precautions for use 
 
The safety and tolerability of naltrexone/bupropion should be assessed at regular intervals.  
 
The treatment should be discontinued if there are concerns with the safety or tolerability of ongoing 
treatment, including concerns about increased blood pressure (see section 4.8). 
 
Suicide and suicidal behaviour 
 
Naltrexone/bupropion contains bupropion. Bupropion is indicated for the treatment of depression in 
some countries. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult 
subjects with psychiatric disorders showed an increased risk of suicidal behaviour with 
antidepressants compared to placebo in subjects less than 25 years old.  
 
Although in placebo-controlled clinical trials with naltrexone/bupropion for the treatment of obesity 
in adult subjects, no suicides or suicide attempts were reported in studies up to 56 weeks duration 
with naltrexone/bupropion, suicidality events (including suicidal ideation) have been reported in 
subjects of all ages treated with naltrexone/bupropion post-marketing.  
 
Close supervision of patients, particularly those at high risk, should accompany therapy with 
naltrexone/bupropion especially in early treatment and following dose changes. Patients (and 
caregivers of patients) should be alerted about the need to monitor for any clinical worsening, 
suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice 
immediately if these symptoms present. 
 
Seizures 
 
Bupropion is associated with a dose-related risk of seizures, with bupropion sustained release (SR) 
300 mg yielding an estimated seizure incidence of 0.1%. Plasma concentrations of bupropion and 
metabolites of bupropion following single-dose administration of 180 mg of bupropion as 
naltrexone/bupropion tablets are comparable to concentrations observed after single-dose 
administration of bupropion SR 150 mg; however, no study has been conducted that determined the 
concentrations of bupropion and metabolites of bupropion after repeated dosing of 
naltrexone/bupropion tablets compared to bupropion SR tablets. As it is unknown whether the risk 
for seizure with bupropion is related to bupropion or a metabolite of bupropion, and there are no data 
demonstrating comparability of plasma concentrations with repeated dosing, there is uncertainty 
whether repeated-dose administration naltrexone/bupropion may be associated with a similar rate of 
seizures as bupropion SR 300 mg. The incidence of seizure in subjects receiving 
naltrexone/bupropion in clinical trials was approximately 0.06% (2/3,239 subjects) vs. 0.0% 
(0/1,515 subjects) on placebo. This incidence of seizure, along with incidence of seizure in subjects 
who received naltrexone/bupropion in a large cardiovascular outcomes trial (CVOT), was no higher 
than the seizure rate with bupropion as a single agent at approved doses. 
 
The risk of seizures is also related to patient factors, clinical situations, and concomitant medicinal 
products, which must be considered in the selection of patients treated with naltrexone/bupropion. 
Naltrexone/bupropion should be discontinued and not restarted in patients who experience a seizure 
while being treated with the medicinal product. Caution should be used when prescribing 
naltrexone/bupropion to patients with predisposing factors that may increase the risk of seizure 
including: 
 history of head trauma 
 excessive use of alcohol or addiction to cocaine or stimulants 
 as treatment with naltrexone/bupropion may result in lowered glucose in patients with 

diabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed to 
minimise the risk of hypoglycaemia, which could predispose patients to seizure 



 

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 concomitant administration of medicinal products that may lower the seizure threshold, 
including antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic 
steroids, quinolones and sedating antihistamines  

 
The consumption of alcohol during naltrexone/bupropion treatment should be minimised or avoided. 
 
Patients receiving opioid analgesics 
 
Naltrexone/bupropion must not be administered to patients receiving chronic opiate therapy (see 
section 4.3). If chronic opiate therapy is required, naltrexone/bupropion treatment must be stopped. 
In patients requiring intermittent opiate treatment, naltrexone/bupropion therapy should be 
temporarily discontinued and opiate dose should not be increased above the standard dose. During 
naltrexone/bupropion clinical studies, the use of concomitant opioid or opioid-like medicinal 
products, including analgesics or antitussives were excluded.  However, approximately 12% of 
subjects took a concomitant opioid or opioid-like medicinal product while enrolled in the 
naltrexone/bupropion clinical studies, the majority of whom continued study treatment without 
interruption of naltrexone/bupropion dose, without untoward consequences. 
 
Attempt to overcome blockade 
 
The attempt to overcome any naltrexone opioid blockade by administering large amounts of 
exogenous opioids is very dangerous and may lead to a fatal overdose or life endangering opioid 
intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be aware that they may be 
more sensitive to lower doses of opioids after naltrexone/bupropion treatment is discontinued.  
 
Allergic reactions 
 
Anaphylactoid/anaphylactic reactions characterised by symptoms such as pruritus, urticaria, 
angioedema, and dyspnoea requiring medical treatment have been reported in clinical trials with 
bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema 
multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient 
should stop taking naltrexone/bupropion and consult a doctor if experiencing allergic or 
anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, oedema, and 
shortness of breath) during treatment. 
 
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity 
have been reported in association with bupropion. These symptoms may resemble serum sickness. 
Patients should be advised to notify their prescribing physician if they experience these symptoms. If 
serum sickness is suspected, naltrexone/bupropion should be discontinued.  
 
Elevation of blood pressure 
 
Early, transient mean increases from baseline in systolic and diastolic blood pressure of up to 
1 mmHg were observed in naltrexone/bupropion Phase 3 clinical trials. In a cardiovascular outcomes 
trial (CVOT) of patients at increased risk of a cardiovascular event, mean increases from baseline in 
systolic and diastolic blood pressure of approximately 1 mmHg compared to placebo were also 
observed. In clinical practice with other bupropion containing products, hypertension, in some cases 
severe and requiring acute treatment, has been reported.   
 
Blood pressure and pulse should be measured prior to initiation of therapy with naltrexone/bupropion 
and should be assessed at regular intervals consistent with usual clinical practice. If patients 
experience clinically relevant and sustained increases in blood pressure or pulse rate as a result of 
naltrexone/bupropion treatment, it should be discontinued. 
 
Naltrexone/bupropion should be given with caution to those patients with controlled hypertension 
and must not be given to patients with uncontrolled hypertension (see section 4.3). 
 



 

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Cardiovascular disease 
 
There is no clinical experience establishing the safety of naltrexone/bupropion in patients with a 
recent history of myocardial infarction, unstable heart disease or NYHA class III or IV congestive 
heart failure. Naltrexone/bupropion should be used with caution in patients with active coronary 
artery disease (e.g., ongoing angina or recent history of myocardial infarction) or history of 
cerebrovascular disease. 
 
Hepatotoxicity 
 
In naltrexone/bupropion completed clinical studies, where naltrexone hydrochloride daily doses 
ranged from 16 mg to 48 mg, drug-induced liver injury (DILI) was reported. There have also been 
cases of elevated liver enzymes from post-marketing reporting. A patient with suspected DILI should 
stop taking naltrexone/bupropion. 
 
Elderly patients 
 
Clinical studies of naltrexone/bupropion did not include sufficient numbers of subjects aged 65 and 
over to determine whether they respond differently than younger subjects. Elderly patients may be 
more sensitive to the central nervous system adverse reactions of naltrexone/bupropion. Naltrexone 
and bupropion are known to be substantially excreted by the kidney, and the risk of adverse reactions 
to naltrexone/bupropion may be greater in patients with impaired renal function, a condition that is 
more common in elderly individuals. Due to these reasons, naltrexone/bupropion should be used with 
caution in patients over 65 years of age and is not recommended in patients over 75 years of age. 
 
Renal impairment 
 
Naltrexone/bupropion has not been extensively evaluated in subjects with renal insufficiency. 
Naltrexone/bupropion is contraindicated in patients with end-stage renal failure. In patients with 
moderate or severe renal impairment, the maximum recommended daily dose for 
naltrexone/bupropion should be reduced, as these patients may have higher drug concentrations 
which could result in an increase in adverse drug reactions (see sections 4.2, 4.8, and 5.2). For 
individuals who are at elevated risk for renal impairment, in particular, individuals with diabetes or 
elderly individuals, estimated glomerular filtration rate (eGFR) should be assessed prior to initiating 
therapy with naltrexone/bupropion. 
 
Hepatic impairment 
 
Naltrexone/bupropion has not been extensively evaluated in subjects with hepatic impairment. 
Naltrexone/bupropion is contraindicated in patients with severe hepatic impairment, and not 
recommended in patients with moderate hepatic impairment (see sections 4.2, 4.3, and 5.2). In 
patients with mild hepatic impairment, the maximum recommended daily dose for 
naltrexone/bupropion should be reduced, as these patients may have higher drug concentrations 
which could result in an increase in adverse drug reactions. (see sections 4.2 and 5.2). 
 
Neuropsychiatric symptoms and activation of mania 
 
Activation of mania and hypomania have been reported in patients with mood disorders who were 
treated with other similar medicinal products for major depressive disorder. No activation of mania 
or hypomania was reported in the clinical trials evaluating effects of naltrexone/bupropion in obese 
subjects, which excluded subjects receiving antidepressants. Naltrexone/bupropion should be used 
cautiously in patients with a history of mania. 
 
Data in animals suggest a potential for abuse of bupropion. However, studies on abuse liability in 
humans and extensive clinical experience show that bupropion has low abuse potential. 
 



 

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Influence on the ability to drive and use machines 
 
The use of naltrexone/bupropion has been associated with somnolence and episodes of loss of 
consciousness, sometimes caused by seizure. Patients must be advised to exercise caution while 
driving or operating machines during treatment with naltrexone/bupropion, especially at the 
beginning of the treatment or during the titration phase. Patients who experience dizziness, 
somnolence, loss of consciousness or seizure should be advised to avoid driving or operating 
machines until these adverse effects have resolved. Alternatively, treatment cessation might be 
considered (see sections 4.7 and 4.8). 
 
Lactose 
 
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Monoamine oxidase inhibitors (MAOI) 
 
Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by a 
different mechanism from bupropion, naltrexone/bupropion must not be used with MAOI (see 
section 4.3). 
 
Opioid analgesics 
 
Naltrexone/bupropion is contraindicated in patients currently dependent on chronic opioid or opiate 
agonist therapy (e.g., methadone), or patients in acute opiate withdrawal (see section 4.3). Due to the 
antagonistic effect of naltrexone at the opioid receptor, patients taking naltrexone/bupropion may not 
fully benefit from treatment with opioid-containing medicinal products, such as cough and cold 
remedies, antidiarrhoeal preparations and opioid analgesics. In patients requiring intermittent opiate 
treatment, naltrexone/bupropion therapy should be temporarily discontinued and opiate dose should 
not be increased above the standard dose (see section 4.4). If chronic opiate therapy is required, 
naltrexone/bupropion treatment must be stopped. Naltrexone/bupropion may be used with caution 
after chronic opioid use has been stopped for 7 to 10 days in order to prevent precipitation of 
withdrawal. 
 
Drugs metabolised by cytochrome P450 (CYP) enzymes 
 
Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the 
cytochrome P450 CYP2B6; thus, the potential exists for interaction when administered with 
medicinal products that induce or inhibit CYP2B6. Although not metabolised by the CYP2D6 
isoenzyme, bupropion and its main metabolite, hydroxybupropion, inhibit the CYP2D6 pathway and 
the potential exists to affect medicinal products metabolised by CYP2D6. 
 
CYP2D6 substrates 
In a clinical study, naltrexone/bupropion (32 mg naltrexone hydrochloride /360 mg bupropion 
hydrochloride daily) was co-administered with a 50 mg dose of metoprolol (a CYP2D6 substrate). 
Naltrexone/bupropion increased metoprolol AUC and Cmax by approximately 4- and 2-fold, 
respectively, relative to metoprolol alone. Similar clinical drug interactions resulting in increased 
pharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a single 
medicinal product with desipramine and venlafaxine. 
 
Co-administration of bupropion with drugs that are metabolised by CYP2D6 isozyme including 
certain antidepressants (SSRIs and many tricyclic antidepressants, e.g. desipramine, imipramine, 
paroxetine), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., 
metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide), should be approached 
with caution and should be initiated at the lower end of the dose range of the concomitant medicinal 



 

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product. Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion 
increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Drugs which require 
metabolic activation by CYP2D6 in order to be effective (e.g., tamoxifen), may have reduced 
efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. If 
naltrexone/bupropion is added to the treatment regimen of a patient already receiving a drug 
metabolised by CYP2D6, the need to decrease the dose of the original medicinal product should be 
considered, particularly for those concomitant medicinal products with a narrow therapeutic index. 
When feasible, the option of therapeutic drug monitoring should be considered for medicinal 
products with a narrow therapeutic index, such as tricyclic antidepressants. 
 
CYP2B6 inducers, inhibitors and substrates  
Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the CYP2B6 
isozyme. The potential exists for a drug interaction between naltrexone/bupropion and drugs that 
induce or are substrates of the CYP2B6 isozyme.  
 
Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion is 
co-administered with medicinal products known to induce CYP2B6 (e.g., carbamazepine, phenytoin, 
ritonavir, efavirenz) as these may affect the clinical efficacy of naltrexone/bupropion. In a series of 
studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 
100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major 
metabolites in a dose dependent manner by 20 to 80%. Similarly, efavirenz 600 mg once daily for 
two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers. 
 
Co-administration of medicinal products that may inhibit the metabolism of bupropion via CYP2B6 
isoenzyme (e.g., CYP2B6 substrates: cyclophosphamide, ifosfamide, and CYP2B6 inhibitors: 
orphenadrine, ticlopidine, clopidogrel), may result in increased bupropion plasma levels and lower 
levels of active metabolite hydroxybupropion. The clinical consequences of the inhibition of the 
metabolism of bupropion via CYP2B6 enzyme and the consequent changes in the 
bupropion-hydroxybupropion ratio are currently unknown, but could potentially lead to reduced 
efficacy of naltrexone/bupropion. 
 
OCT2 substrates 
 
Bupropion and its metabolites competitively inhibit the OCT2 in the basolateral membrane of the 
renal tubule responsible for creatinine secretion, in a manner similar to the OCT2 substrate 
cimetidine. Therefore, mild increases in creatinine observed after long-term treatment with 
naltrexone/bupropion are likely due to inhibition of OCT2 and not indicative of changes in creatinine 
clearance. Use of naltrexone/bupropion with other OCT2 substrates (e.g., metformin) in clinical trials 
did not indicate the need for dose adjustment or other precautions. 
 
Other interactions 
 
Although clinical data do not identify a pharmacokinetic interaction between bupropion and alcohol, 
there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in 
patients drinking alcohol during bupropion treatment. There are no known pharmacokinetic 
interactions between naltrexone and alcohol.  The consumption of alcohol during 
naltrexone/bupropion treatment should be minimised or avoided.  
 
Caution should be used when prescribing naltrexone/bupropion to patients with predisposing factors 
that may increase the risk of seizure including: 
 as treatment with naltrexone/bupropion may result in lowered glucose in patients with 

diabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed to 
minimise the risk of hypoglycaemia, which could predispose patients to seizure 

 concomitant administration of medicinal products that may lower the seizure threshold, 
including antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic 
steroids, quinolones and sedating antihistamines  

 



 

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Naltrexone/bupropion is contraindicated in patients receiving concomitant treatment with 
monoamine oxidase inhibitors, bupropion or naltrexone, patients undergoing  acute alcohol or 
benzodiazepine withdrawal, patients currently dependent on chronic opioids, or opiate agonists (see 
section 4.3). 
 
Administration of naltrexone/bupropion to patients receiving either levodopa or amantadine 
concurrently should be undertaken with caution. Limited clinical data suggest a higher incidence of 
adverse reactions (e.g., nausea, vomiting, and neuropsychiatric adverse reactions – see section 4.8) in 
patients receiving bupropion concurrently with either levodopa or amantadine. 
 
Administration of naltrexone/bupropion with inhibitors or inducers of UGT 1A2 and 2B7 should be 
undertaken with caution as these may alter the exposure of naltrexone. 
 
Naltrexone/bupropion has not been studied in conjunction with alpha-adrenergic blockers or 
clonidine. 
 
Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion is 
co-administered with medicinal products known to inhibit metabolism (e.g. valproate), as these may 
affect its clinical efficacy and safety. 
 
Naltrexone/bupropion should preferably be taken with food, as it is known that both naltrexone and 
bupropion plasma concentrations are increased with food and the safety and efficacy data from 
clinical trials is based on dosing with food. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amounts of data from the use of naltrexone/bupropion in pregnant women. 
The combination has not been tested in reproductive toxicity studies. Studies with naltrexone in 
animals have shown reproductive toxicity (see section 5.3); animal studies with bupropion show no 
clear evidence of reproductive harm. The potential risk for humans is unknown.  
 
Naltrexone/bupropion should not be used during pregnancy or in women currently attempting to 
become pregnant. 
 
Breast-feeding 
 
Naltrexone and bupropion and their metabolites are excreted in human milk.   
 
Since there is limited information on the systemic exposure to naltrexone and bupropion in 
infants/newborns being breast-fed, a risk to the newborns/infants cannot be excluded. 
Naltrexone/bupropion should not be used during breast-feeding.  
 
Fertility 
 
There are no data on fertility from the combined use of naltrexone and bupropion. No effect on 
fertility in reproductive toxicity studies have been observed with bupropion. Naltrexone administered 
orally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates at 
approximately 30 times the naltrexone dose provided by naltrexone/bupropion. The relevance of 
these observations to human fertility is not known (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Naltrexone/bupropion has influence on the ability to drive and use machines. When driving vehicles 
or using machines, it should be taken into account that dizziness, somnolence, loss of consciousness 
and seizure may occur during treatment. 



 

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Patients should be cautioned about driving or operating hazardous machinery in case 
naltrexone/bupropion may affect their ability to engage in such activities (see sections 4.4 and 4.8) 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
In clinical studies, 23.8% of subjects receiving naltrexone/bupropion and 11.9% of subjects receiving 
placebo discontinued treatment due to an adverse reaction. The most frequent adverse reactions for 
naltrexone/bupropion are nausea (very common), constipation (very common), vomiting (very 
common), dizziness (common), and dry mouth (common). The most frequent adverse reactions 
leading to discontinuation with naltrexone/bupropion were nausea (very common), headache (very 
common), dizziness (common) and vomiting (very common). 
 
Tabulated list of adverse reactions 
 
The safety profile of naltrexone/bupropion (NB) summarised in Table 1 below is based on clinical 
studies performed with the fixed-dose combination (adverse reactions at an incidence of at least 0.1% 
and twice that of placebo). The list of terms in Table 2 provides information on the adverse reactions 
of the individual components naltrexone (N) and bupropion (B) identified in their respective 
approved SmPCs for different indications.   
 
The frequencies of adverse reactions are ranked according to the following: very common (≥1/10), 
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100); rare (≥1/10,000, <1/1,000); very rare 
(<1/10,000); not known (cannot be estimated from the available data). 
 
Table 1. Adverse reactions reported in subjects who received naltrexone/bupropion as a fixed-
dose combination  

System Organ Class Frequency Adverse reaction  
Blood and lymphatic system disorders Rare Decreased haematocrit  

Lymphocyte count decreased  
Not known Lymphadenopathy 

Immune system disorders Uncommon Hypersensitivity  
Urticaria  

 Rare Angioedema 
Metabolism and nutrition disorders Rare  Dehydration  
Psychiatric disorders Common Anxiety 

Insomnia 
Uncommon  Abnormal dreams  

Agitation  
Mood swings  
Nervousness  
Tension  
Dissociation (feeling spacey) 

Rare Hallucination 
 Not known Affective disorders  

Aggression  
Confusional state  
Delusions  
Depression  
Disorientation  
Disturbance in attention  
Hostility  
Loss of libido  
Nightmares  



 

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System Organ Class Frequency Adverse reaction  
Paranoia  
Psychotic disorder  
Suicidal ideation*  
Suicide attempt  
Suicidal behaviour 

Nervous system disorders  
  

Very common Headache  
Common  Dizziness  

Tremor  
Dysgeusia  
Lethargy  
Somnolence  

Uncommon  Intention tremor  
Balance disorder  
Amnesia  

Rare Loss of consciousness  
Paraesthesia  
Presyncope  
Seizure**  
Syncope 

Not known Dystonia  
Memory impairment  
Parkinsonism  
Restlessness 

Eye disorders Not known Eye irritation  
Eye pain or asthenopia  
Eye swelling  
Lacrimation increased  
Photophobia  
Vision blurred 

Ear and labyrinth disorders  Common Tinnitus  
Vertigo 

Uncommon  Motion sickness 
Not known Ear discomfort  

Ear pain 
Cardiac disorders Common Palpitations  

Heart rate increased 
Uncommon Tachycardia 

Vascular disorders  Common  Hot flush  
Hypertension  
Blood pressure increased 

Not known Blood pressure fluctuation 
Respiratory, thoracic and mediastinal 
disorders 

Not known Cough  
Dysphonia  
Dyspnoea  
Nasal congestion  
Nasal discomfort  
Oropharyngeal pain  
Rhinorrhea  
Sinus disorder  
Sneezing  
Yawning 

Gastrointestinal disorders  Very common  Nausea  
Constipation  
Vomiting 



 

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System Organ Class Frequency Adverse reaction  
Common  Dry mouth  

Abdominal pain upper  
Abdominal pain 

Uncommon  Abdominal discomfort  
Dyspepsia  
Eructation  

Rare Haematochezia  
Hernia  
Lip swelling  
Lower abdominal pain  
Dental caries***  
Toothache*** 

Not known Diarrhoea  
Flatulence  
Haemorrhoids   
Ulcer 

Hepatobiliary disorders Uncommon  Cholecystitis  
ALT increased  
AST increased  
Hepatic enzyme increased 

Rare Drug induced liver injury  
Not known Hepatitis 

Skin and subcutaneous tissue disorders Common Hyperhidrosis  
Pruritus  
Alopecia  
Rash 

Not known Acne  
Erythema multiforme and Stevens 
Johnson syndrome 

Musculoskeletal and connective tissue 
disorders 

Rare Jaw pain  
Not known Arthralgia  

Groin pain  
Myalgia  
Rhabdomyolysis 

Renal and urinary disorders 
 

Uncommon  Blood creatinine increased 
Rare Micturition urgency 
Not known Dysuria,  

Pollakiuria  
Urinary frequency and/or retention 

Reproductive system and breast 
disorders 

Uncommon 
 

Erectile Dysfunction 

Rare 
 

Irregular menstruation  
Vaginal haemorrhage  
Vulvovaginal dryness  

General disorders and administration 
site conditions 

Common Fatigue  
Feeling jittery  
Irritability 

Uncommon  Asthenia  
Feeling abnormal 
Feeling hot  
Increased appetite  
Thirst 



 

13 

System Organ Class Frequency Adverse reaction  
Rare Chest pain   

Peripheral coldness  
Pyrexia 

Not known Chills  
Energy increased 

* Cases of suicidal ideation and suicidal behaviour have been reported during NB therapy (see section 4.4). 
** The incidence of seizures is approximately 0.1% (1/1,000). The most common type of seizures is 

generalised tonic-clonic seizures, a seizure type which can result in some cases in post-ictal confusion or 
memory impairment (see section 4.4). 

*** Toothache and dental caries, while not meeting the criteria for inclusion in this table, are listed based on 
the subset of patients with dry mouth, in which a higher incidence of toothache and dental caries was 
observed in subjects treated with NB versus placebo. 

 
As NB is a fixed combination of two active ingredients, in addition to the terms listed in Table 1, 
additional adverse reactions seen with one of the active substances may potentially occur. The 
additional undesirable effects occurring with either of the individual components (bupropion or 
naltrexone) when used for non-obesity indications are summarized in Table 2. 
 
Table 2. Adverse reactions of the individual components naltrexone and bupropion identified 
in the respective approved SmPCs. 

System Organ Class Frequency Adverse Reaction 
Infections and infestations Uncommon Oral herpes (N)  

Tinea pedis (N) 
Blood and lymphatic system 
disorders 

Uncommon Idiopathic thrombocytopenic purpura (N)  

Immune system disorders Very rare More severe hypersensitivity reactions 
including angioedema, dyspnoea/ 
bronchospasm and anaphylactic shock. 
Arthralgia, myalgia and fever have also 
been reported in association with rash and 
other symptoms suggestive of delayed 
hypersensitivity. These symptoms may 
resemble serum sickness. (B) 

Metabolism and nutrition disorders Common Decreased appetite (N) 
Uncommon Anorexia (B)  

Blood glucose disturbances (B) 
Psychiatric disorders Common Concentration disturbance (B) 

Uncommon Delusions (B)  
Depersonalisation (B)  
Libido disorder (N)  
Paranoid ideation (B)  

Nervous system disorders Uncommon Ataxia (B) 
Incoordination (B) 

Eye disorders Uncommon Visual disturbance (B) 
Cardiac disorders Common Electrocardiogram change (N) 
Vascular disorders Uncommon Postural hypotension (B)  

Vasodilatation (B) 
Respiratory, thoracic and 
mediastinal disorders 

Uncommon Sputum increased (N) 

Gastrointestinal disorders Common Taste disorders (B) 
Hepatobiliary disorders Uncommon Blood bilirubin increased (N)  

Jaundice (B) 
Skin and subcutaneous tissue 
disorders 

Uncommon Exacerbation of psoriasis (B)  
Seborrhea (N) 



 

14 

System Organ Class Frequency Adverse Reaction 
Musculoskeletal and connective 
tissue disorders 

Uncommon Twitching (B) 

Reproductive system and breast 
disorders 

Common Ejaculation delayed (N) 

General disorders and administration 
site conditions 

Uncommon Weight gain (N) 

 
Description of selected adverse reactions 
 
Seizures  
The incidence of seizure in naltrexone/bupropion over the course of the clinical program was 0.06% 
(2/3,239 subjects). Among the group of subjects treated with naltrexone/bupropion, both cases of 
seizures were considered as serious and led to treatment discontinuation (see section 4.4). There were 
no cases of seizures in the placebo group. 
 
Gastrointestinal adverse reactions  
The vast majority of subjects treated with naltrexone/bupropion who experienced nausea reported the 
event within 4 weeks of starting treatment. Events were generally self-limited; the majority of events 
resolved within 4 weeks and almost all resolved by week 24. Similarly, the majority of events of 
constipation in subjects treated with naltrexone/bupropion were reported during the dose escalation 
phase. The time to resolution of constipation was similar between subjects treated with 
naltrexone/bupropion and subjects treated with placebo. Approximately half of the subjects treated 
with naltrexone/bupropion who experienced vomiting first reported the event during the dose 
escalation phase. Time to resolution for vomiting was typically rapid (within one week) and almost 
all events resolved within 4 weeks. The incidence of these common gastrointestinal adverse reactions 
in naltrexone/bupropion versus placebo was as follows: nausea (31.8% vs. 6.7%), constipation 
(18.1% vs. 7.2%), and vomiting (9.9% vs. 2.9%). The incidence of severe nausea, severe 
constipation, and severe vomiting was low, but was higher in subjects treated with 
naltrexone/bupropion compared to subjects treated with placebo (severe nausea: 
naltrexone/bupropion (1.9%), placebo (<0.1%); severe constipation: naltrexone/bupropion (0.6%), 
placebo (0.1%); severe vomiting: naltrexone/bupropion (0.7%), placebo (0.3%)). No events of 
nausea, constipation, or vomiting were considered serious. 
 
Other frequent adverse reactions  
The majority of subjects treated with naltrexone/bupropion who reported dizziness, headache, 
insomnia, or dry mouth, first reported these events during the dose escalation phase. Dry mouth may 
be associated with toothache and dental caries; in the subset of patients with dry mouth, a higher 
incidence of toothache and dental caries were observed in subjects treated with naltrexone/bupropion 
compared to subjects treated with placebo. The incidence of severe headache, severe dizziness, and 
severe insomnia was low, but was higher in subjects treated with naltrexone/bupropion compared to 
subjects treated with placebo (severe headache: naltrexone/bupropion (1.1%), placebo (0.3%); severe 
dizziness: naltrexone/bupropion (0.6%), placebo (0.2%); severe insomnia: naltrexone/bupropion 
(0.4%), placebo (<0.1%)). No events of dizziness, dry mouth, headache, or insomnia in subjects 
treated with naltrexone/bupropion were considered serious. 
 
Elderly patients 
Elderly patients may be more sensitive to some of the central nervous system-related adverse 
reactions of naltrexone/bupropion (primarily dizziness and tremor). There is an increased incidence 
of gastrointestinal disorders with higher age categories. Common events leading to withdrawal 
among elderly were nausea, vomiting, dizziness, constipation. 
 
Type 2 diabetes 
Patients with type 2 diabetes treated with naltrexone/bupropion demonstrated a higher incidence of 
gastrointestinal adverse reactions, primarily nausea, vomiting, and diarrhoea, than subjects without 



 

15 

diabetes. Patients with type 2 diabetes may be more prone to these events due to concomitant 
medicinal product use (e.g., metformin) or may be more likely to have underlying gastrointestinal 
disorders (e.g., gastroparesis) predisposing to gastrointestinal symptoms. 
 
Renal impairment 
Patients with moderate renal impairment had a higher incidence of gastrointestinal and central 
nervous system-related adverse reactions, thus these patients generally had lower tolerability of 
naltrexone/bupropion at a total daily dose of 32 mg naltrexone hydrochloride/360 mg bupropion 
hydrochloride, which is thought to be due to higher plasma concentrations of active metabolites. The 
types of tolerability events were similar to the events observed in patients with normal renal function 
(see sections 4.2, 4.4, and 5.2).  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Human overdose experience 
 
There is no clinical experience with overdose with combined use of bupropion and naltrexone. The 
maximum daily dose of combined use of bupropion and naltrexone administered in clinical trials 
contained 50 mg naltrexone hydrochloride and 400 mg bupropion hydrochloride. The most serious 
clinical implications of combined use of bupropion and naltrexone overdose are likely related to 
bupropion.   
 
Bupropion 
Acute ingestion of doses in excess of 10 times the maximum therapeutic dose of bupropion 
(equivalent to approximately in excess of 8 times the recommended daily dose of 
naltrexone/bupropion) has been reported. Seizure was reported in approximately one third of these 
overdose cases. Other serious reactions reported with overdoses of bupropion alone included 
hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction 
disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, 
hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was 
part of multiple drug overdoses. 
 
Although most subjects recovered without sequelae, deaths associated with overdoses of bupropion 
alone have been reported in subjects ingesting large doses of the drug.  
 
Naltrexone 
There is limited experience with overdose of naltrexone monotherapy in humans. In one study, 
subjects received 800 mg naltrexone hydrochloride daily (equivalent to 25 times the recommended 
daily dose of naltrexone/bupropion) for up to one week showing no evidence of toxicity. 
 
Overdose management 
 
An adequate airway, oxygenation, and ventilation should be ensured. Cardiac rhythm and vital signs 
should be monitored.  EEG monitoring is also recommended for the first 48 hours post-ingestion. 
General supportive and symptomatic measures are also recommended. Induction of emesis is not 
recommended.   
 
Activated charcoal should be administered. There is no experience with the use of forced diuresis, 
dialysis, hemoperfusion, or exchange transfusion in the management of combined use of bupropion 



 

16 

and naltrexone overdoses. No specific antidotes for combined use of bupropion and naltrexone are 
known. 
 
Due to the dose-related risk of seizures with bupropion, hospitalisation following suspected overdose 
with naltrexone/bupropion should be considered. Based on studies in animals, it is recommended that 
seizures be treated with intravenous benzodiazepine administration and other supportive measures, as 
appropriate. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antiobesity preparations excluding diet products, centrally acting 
antiobesity products, ATC code: A08AA62. 
 
Mechanism of action and pharmacodynamic effects 
 
The exact neurochemical appetite suppressant effects of naltrexone/bupropion are not fully 
understood. The medicinal product has two components: naltrexone, a mu-opioid antagonist, and 
bupropion, a weak inhibitor of neuronal dopamine and norepinephrine reuptake. These components 
affect two principal areas of the brain, specifically the arcuate nucleus of the hypothalamus and the 
mesolimbic dopaminergic reward system. 
 
In the arcuate nucleus of the hypothalamus, bupropion stimulates pro-opiomelanocortin (POMC) 
neurons that release alpha-melanocyte stimulating hormone (α-MSH), which in turn binds to and 
stimulates melanocortin 4 receptors (MC4-R). When α-MSH is released, POMC neurons 
simultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptors. Binding of 
β-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMC 
neurons leading to a decrease in the release of α-MSH. Blocking this inhibitory feedback loop with 
naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, 
thereby amplifying the effects of bupropion on energy balance. Preclinical data suggests that 
naltrexone and bupropion may have greater than additive effects in this region to reduce food intake 
when administered together. 
 
Clinical efficacy and safety  
 
The effects of naltrexone/bupropion on weight loss, weight maintenance, waist circumference, body 
composition, obesity-related markers for cardiovascular and metabolic parameters and patient 
reported assessments were examined in double-blind, placebo-controlled obesity Phase 2 and Phase 3 
trials (BMI range 27-45 kg/m2) with study durations of 16 to 56 weeks randomised to naltrexone 
hydrochloride (16 to 50 mg/day) and/or bupropion hydrochloride (300 to 400 mg/day) or placebo.  
 
Effect on weight loss and weight maintenance  
Four multicentre, double-blind, placebo-controlled obesity Phase 3 studies (NB-301, NB-302, 
NB-303 and NB-304) were conducted to evaluate the effect of naltrexone/bupropion in conjunction 
with lifestyle modification in 4,536 subjects randomised to naltrexone/bupropion or placebo. 
Treatment was initiated with a dose escalation period. Three of these studies (NB-301, NB-302 and 
NB-304) designated the primary endpoint at 56 weeks, and 1 study (NB-303) designated the primary 
endpoint at week 28, but continued for 56 weeks. Studies NB-301, NB-303, and NB-304 included 
periodic instruction from the study sites to reduce caloric intake and increase physical activity, while 
NB-302 included an intensive behavioral modification program consisting of 28 group counseling 
sessions over 56 weeks, as well as a prescribed rigorous diet and exercise regimen. NB-304 evaluated 
subjects with type 2 diabetes not achieving glycaemic goal of HbA1c <7% (53 mmol/mol) with oral 
anti-diabetes agents or on diet and exercise alone. NB-303 included a re-randomisation in a blinded 
manner and the addition of a higher dose of naltrexone (naltrexone hydrochloride 48 mg/bupropion 
hydrochloride 360 mg) at week 28 to half of the cohort of subjects in the active treatment arm who 



 

17 

did not adequately respond to treatment, and as such the primary endpoint comparing weight change 
with 32 mg naltrexone hydrochloride /360 mg bupropion hydrochloride vs. placebo was evaluated at 
week 28. 
 
Of the overall population of 4,536 subjects in the naltrexone/bupropion Phase 3 studies, 25% had 
hypertension, 33% had fasting glucose levels ≥100 mg/dL (5.6 mmol/L) at baseline, 54% had 
dyslipidaemia at study entry, and 11% had type 2 diabetes. 
 
In the combined Phase 3 studies, the mean age was 46 years, 83% were female, and 77% were White, 
18% were Black and 5% were other races. Baseline mean BMI was 36 kg/m2 and mean waist 
circumference was 110 cm. The two co-primary endpoints were percent change from baseline body 
weight and the proportion of subjects achieving ≥5% total decreased body weight. Data summaries 
for mean change in body weight reflect the Intent-to-Treat (ITT) population, defined as subjects who 
were randomised, had a baseline body weight measurement, and had at least one post-baseline body 
weight measurement during the defined treatment phase, using a last observation carried forward 
(LOCF) analysis, as well as a completers analysis. Summaries of the proportion of subjects achieving 
≥5% or ≥10% reduction in body weight utilise a baseline observation carried forward (BOCF) 
analysis of all randomised subjects. Overall adherence was similar between trials, and similar 
between treatment groups. Treatment adherence rates for the integrated Phase 3 studies were: 67% 
NB vs. 74% placebo at 16 weeks, 63% NB vs. 65% Placebo at 26 weeks, 55% NB vs. 55% placebo 
at 52weeks. 
 
As seen in Table 2, in the NB-301 study subjects had a mean percent body weight loss of -5.4% 
while receiving naltrexone/bupropion compared to -1.3% in placebo-treated subjects. Weight loss of 
at least 5% baseline body weight was observed more frequently for subjects treated with 
naltrexone/bupropion (31%) compared to placebo (12%) (Table 3). More pronounced weight loss 
was observed in the cohort of subjects who completed 56 weeks of treatment with 
naltrexone/bupropion (-8.1%) compared to placebo (-1.8%). Comparable results were seen in the 
NB-303 study, which was of similar design, with significant weight loss observed in 
naltrexone/bupropion -treated subjects compared to placebo at the week 28 primary endpoint, and 
sustained through 56 weeks from baseline (Table 3). 
 
Naltrexone/bupropion was also evaluated in combination with intensive behavioural modification 
counseling in the NB-302 study. Correspondingly, there was greater mean weight loss from baseline 
for naltrexone/bupropion treatment (-8.1%) compared to study NB-301 (-5.4%) at week 56, and for 
placebo (-4.9%) compared to study NB-301 (-1.3%). 
 
The treatment effects observed in obese and overweight subjects with type 2 diabetes mellitus 
(Study NB-304) were somewhat less pronounced than those observed in the other Phase 3 studies. 
Naltrexone/bupropion (-3.7%) was significantly (p<0.001) more efficacious than placebo (-1.7%) 
treatment in this population. 
 



 

18 

Table 3. Mean weight loss (% Change) from baseline to week 56 in naltrexone / bupropion 
(NB) phase 3 Studies NB-301, NB-302, and NB-304 and from baseline to week 28 in phase 3 
study NB-303   
 56-Week Data 28-Week Data 

 
NB-301 NB-302 NB-304 NB-303 

NB PBO NB PBO NB PBO NB PBO 
Intent-to-treat analysis set+ 

  N 538 536 565 196 321 166 943 474 
Baseline 
(kg) 99.8 99.5 100.3 101.8 104.2 105.3 100.4 99.4 

 LS 
Mean 
(95% CI) 
% 
Change 
From 
Baseline 

-5.4* 
(-6.0, -4.8) 

-1.3 
(-1.9, -0.7) 

-8.1* 
(-8.8, -7.4) 

-4.9 
(-6.1, -3.7) 

-3.7* 
(-4.3, -3.1) 

-1.7 
(-2.5, -0.9) 

-5.7* 
(-6.1, -5.3) 

-1.9 
(-2.4, -

1.4) 

Completers analysis set++ 
  N 296 290 301 106 175 100 619 319 
Baseline 
(kg) 99.8 99.2 101.2 100.4 107.0 105.1 101.2 99.0 

  LS 
Mean 
(95% CI) 
% 
Change 
From 
Baseline 

-8.1 
(-9.0, -7.2) 

-1.8 
(-2.7, -0.9) 

-11.5 
(-12.6, -

10.4) 

-7.3 
(-9.0, -5.6) 

-5.9 
(-6.8, -5.0) 

-2.2 
(-3.4, -1.0) 

-7.8 
(-8.3, -7.3) 

-2.4 
(-3.0, -

1.8) 

CI, Confidence Interval; LS, Least Squares. 
95% confidence intervals calculated as LS Mean 1.96 Standard Error. 
+ Subjects who were randomised, had a baseline body weight measurement, and had at least one post-
baseline body weight measurement during the defined treatment phase. Results are based on last-observation-
carried-forward (LOCF). 
++ Subjects who have a baseline and a post-baseline body weight measurement and completed 56 weeks 
(Studies NB-301, NB-302, and NB-304) or 28 weeks (NB-303) of treatment.   
* Difference from placebo, p<0.001. 
Studies NB-301, NB-302, and NB-303 were conducted in subjects who were obese, or overweight or obese 
with comorbidities.  Study NB-302 had a more intensive behavioural modification program, while the 
primary endpoint of Study NB-303 was at week 28 to allow for re-randomization to different doses in the 
latter portion of the study.  Study NB-304 was conducted in subjects who were overweight or obese and had 
type 2 diabetes mellitus. 

 
The percentages of subjects with ≥ 5% or ≥ 10% body weight loss from baseline were greater with 
naltrexone/bupropion compared to placebo in all four Phase 3 obesity trials (Table 3). 
 



 

19 

Table 4. Percentage (%) of subjects losing ≥5% and ≥10% of body weight from baseline to 
week 56 in phase 3 studies NB-301, NB-302, and NB-304 and from baseline to week 28 in phase 
3 study NB-303 

 56-week data 28-week data 

 
NB-301 NB-302 NB-304 NB-303 

NB PBO NB PBO NB PBO NB PBO 
Randomised Population+  
  N 583 581 591 202 335 170 1001 495 
≥5% Weight 
Loss 31* 12 46** 34 28* 14 42* 14 

≥10% Weight 
Loss 17* 5 30* 17 13** 5 22* 6 

Completers++ 
  N 296 290 301 106 175 100 619 319 
≥5% Weight 
Loss 62 23 80 60 53 24 69 22 

≥10% Weight 
Loss 34 11 55 30 26 8 36 9 

+ With baseline observation carried forward (BOCF) 
++ Subjects who have a baseline and a post-baseline body weight measurement and completed 56 weeks 
(Studies NB-301, NB-302, and NB-304) or 28 weeks (NB-303) of treatment. 
* Difference from placebo, p<0.001 
** Difference from placebo, p<0.01 
Studies NB-301, NB-302, and NB-303 were conducted in subjects who were obese, or overweight or obese with 
comorbidities.  Study NB-302 had a more intensive behavioural modification program, while the primary 
endpoint of Study NB-303 was at week 28 to allow for re-randomisation to different doses in the latter portion of 
the study.  Study NB-304 was conducted in subjects who were overweight or obese and had type 2 diabetes 
mellitus. 
 
Of the subjects with observed data at week 16 in the four Phase 3 clinical trials, 50.8% of those 
randomised to receive naltrexone/bupropion had lost ≥5% of their baseline body weight, compared to 
19.3% of placebo-treated subjects (week 16 Responders). At one year, the average weight loss (using 
LOCF methodology) among these week 16 Responders who received naltrexone/bupropion was 
11.3%, with 55% losing ≥10% bodyweight. Additionally, week 16 Responders who received 
naltrexone/bupropion had a high retention rate with 87% completing 1 year of treatment. The ≥5% 
weight loss threshold at week 16 had 86.4% positive predictive value and 84.8% negative predictive 
value for determining whether a subject treated with naltrexone/bupropion would achieve at least 5% 
weight loss at week 56.  Patients who did not meet the early response criterion were not found to 
have increased tolerability or safety issues relative to patients who did have a favourable early 
response. 
 
Effect on cardiovascular and metabolic parameters   
Improvements were observed for waist circumference (including subjects with type 2 diabetes), 
triglycerides, HDL-C and LDL-C/HDL-C ratio for subjects treated with naltrexone/bupropion vs. 
placebo in all Phase 3 studies (Table 4). Improvements in triglycerides, HDL-C and LDL-C/HDL-C 
ratio were seen in naltrexone/bupropion-treated subjects diagnosed with baseline dyslipidaemia 
irrespective of dyslipidaemia treatment. Changes in mean blood pressure are described in section 4.4. 
In addition, in subjects who did not have type 2 diabetes, there were reductions in fasting insulin and 
HOMA-IR, a measure of insulin resistance, in naltrexone/bupropion-treated subjects. 
 
Effects on glycaemic control in obese subjects with type 2 diabetes 
After 56 weeks of treatment in subjects with type 2 diabetes (NB-304), naltrexone/bupropion 
exhibited improvements in glycaemic control parameters compared to placebo (Table 4). Greater 
HbA1c improvement compared to placebo was observed at the first post-baseline measurement 
(week 16, p<0.001). Mean HbA1c change from baseline at week 56 was -0.63% for subjects treated 
with naltrexone/bupropion compared to subjects on placebo -0.14% (p<0.001). In subjects with 



 

20 

baseline HbA1c >8% (64 mmol/mol), HbA1c changes at endpoint were -1.1% and -0.5% for 
naltrexone/bupropion compared to placebo, respectively. Improvements were observed for fasting 
glucose, fasting insulin, HOMA-IR and percent of subjects requiring rescue diabetes medicinal 
products for subjects treated with naltrexone/bupropion vs. placebo. 
 
Table 5. Change in cardiovascular and metabolic parameters from baseline to week 56 in phase 
3 studies NB-301, NB-302, and NB-304 and from baseline to week 28 in phase 3 study NB-303 

 56-Week Data 28-Week Data 

 
NB-301 NB-302 NB-304 NB-303 
NB  PBO NB PBO NB PBO NB PBO 

Full analysis set+ 

N 471 511 482 193 265 159 825 456 

Waist 
circumference, 
cm 

-6.2* -2.5 -10.0* -6.8 -5.0* -2.9 -6.2*  -2.7 

Triglycerides, 
% change -12.7* -3.1 -16.6* -8.5 -11.2* -0.8 -7.3* -1.4 

HDL-C,  
mg/dL 3.4* -0.1 4.1* 0.9 3.0* -0.3 1.2* -1.4 

LDL-C/HDL-C 
ratio -0.21* -0.05 -0.05* 0.12 -0.15* 0.04 -0.15* 0.07 

HbA1c, % Not applicable -0.6* -0.1 Not applicable 

Fasting glucose, 
mg/dL -3.2* -1.3  -2.4 -1.1 -11.9 -4.0 -2.1 -1.7 

Fasting insulin, 
% change -17.1* -4.6 -28.0* -15.5 -13.5 -10.4 -14.1* -0.5 

HOMA-IR,  
% change -20.2* -5.9 -29.9* -16.6 -20.6 -14.7 -16.4* -4.2 

+ Based on LOCF with the last on-drug observation carried forward. 
* P-value <0.05 (nominal values) compared to placebo group. 
Studies NB-301, NB-302, and NB-303 were conducted in subjects who were obese, or overweight or obese with 
comorbidities.  Study NB-302 had a more intensive behavioural modification program, while the primary 
endpoint of Study NB-303 was at week 28 to allow for re-randomisation to different doses in the latter portion of 
the study.  Study NB-304 was conducted in subjects who were overweight or obese and had type 2 diabetes 
mellitus. 
 
Effect on body composition  
In a subset of subjects, body composition was measured using dual energy X-ray absorptiometry 
(DEXA) (naltrexone/bupropion = 79 subjects and placebo = 45 subjects) and multislice computed 
tomography (CT) scan (naltrexone/bupropion = 34 subjects and placebo = 24 subjects). The DEXA 
assessment showed that treatment with naltrexone/bupropion was associated with greater reductions 
from baseline in total body fat and in visceral adipose tissue than placebo. As expected, 
naltrexone/bupropion -treated subjects had a greater mean increase from baseline compared with 
placebo-treated subjects in percent of total body lean mass. These results suggest that most of the 
total weight loss was attributable to a reduction in adipose tissue, including visceral adipose. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Mysimba in one or more subsets of the paediatric population in obesity (see section 4.2 for 
information on paediatric use). Naltrexone/bupropion should not be used in children and adolescents. 
 



 

21 

5.2 Pharmacokinetic properties 
 
The results of a single dose relative bioavailability study in healthy subjects demonstrated that 
naltrexone/bupropion tablets, when dose adjusted, are bioequivalent based on AUC0-∞ mean ratio and 
90% confidence intervals to naltrexone immediate release (IR) or bupropion prolonged release (PR) 
administered as single agents. 
 
Absorption 
  
Following single oral administration of naltrexone/bupropion tablets to healthy subjects, peak 
concentrations of naltrexone and bupropion occurred approximately 2 and 3 hours post 
administration of naltrexone/bupropion, respectively. There were no differences in bioavailability, as 
measured by AUC, of naltrexone or bupropion when administered in combination compared to each 
administered alone. However, given the prolonged nature of the drug release for 
naltrexone/bupropion, Cmax for naltrexone was markedly reduced compared to the 50 mg naltrexone 
hydrochloride IR administered alone (about 2-fold difference after dose adjustment). The bupropion 
Cmax from naltrexone/bupropion (180 mg bupropion hydrochloride) was equivalent to the Cmax of 
bupropion PR (150 mg bupropion hydrochloride), indicating that the bupropion Cmax achieved with 
naltrexone/bupropion (360 mg bupropion hydrochloride /day) is comparable to that achieved with 
commercially available bupropion PR (300 mg bupropion hydrochloride /day) administered alone. 
 
Naltrexone and bupropion are well absorbed from the gastrointestinal tract (>90% absorbed), 
however, naltrexone has a significant first pass effect thereby limiting systemic bioavailablity, with 
only 5-6% reaching the systemic circulation intact. 
 
Food effect 
 
When naltrexone/bupropion was given with a high-fat meal the AUC and Cmax for naltrexone 
increased 2.1-fold and 3.7-fold and the AUC and Cmax for bupropion increased 1.4-fold and 1.8-fold, 
respectively. At steady state, the food effect resulted in AUC and Cmax increases of 1.7- and 1.9-fold 
for naltrexone, and 1.1- and 1.3-fold for bupropion, respectively. Clinical experience included 
varying prandial conditions and supports the use of naltrexone/bupropion tablets with food. 
 
Distribution 
 
The mean volume of distribution at steady state of oral naltrexone and bupropion given as 
naltrexgone / bupropion, Vss/F, was 5697 liters and 880 liters, respectively.  
Plasma protein binding is not extensive for naltrexone (21%) or bupropion (84%) indicating low 
potential for drug interactions by displacement.  
 
Biotransformation and elimination 
 
Following single oral administration of naltrexone/bupropion tablets to healthy subjects, mean T½ 
elimination half-life was approximately 5 hours for naltrexone and 21 hours for bupropion.  
 
Naltrexone 
The major metabolite of naltrexone is 6-beta-naltrexol. Though less potent than naltrexone, 
6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than 
naltrexone. Naltrexone and 6-beta-naltrexol are not metabolised by cytochrome P450 enzymes and in 
vitro studies indicate that there is no potential for inhibition or induction of important isozymes. 
Naltrexone is primarily metabolised to 6-beta-naltrexol by the dihydrodiol dehydrogenases 
(DD1, DD2 and DD4). Other major metabolic routes are the formation of the metabolites 
2-hydroxy-3-O-methyl naltrexone and 2-hydroxy-3-O-methyl-6-beta-naltrexol, believed to be 
mediated by catechol-O-methyl transferases (COMT), and glucuronidation, thought to be mediated 
by UGT1A1 and UGT2B7. 
 



 

22 

Naltrexone and its metabolites are excreted primarily by the kidney (37 to 60% of the dose). The 
derived value for renal excretion of naltrexone after oral administration, adjusting for plasma protein 
binding, is 89 mL/min. The enzyme responsible for the main elimination pathway is not known.  
Faecal excretion is a minor elimination pathway. 
 
Bupropion 
Bupropion is extensively metabolised with three active metabolites: hydroxybupropion, 
threohydrobupropion and erythrohydrobupropion. The metabolites have longer elimination half-lives 
than bupropion and accumulate to a greater extent. In vitro findings suggest that CYP2B6 is the 
principal isozyme involved in the formation of hydroxybupropion, while CYP1A2, 2A6, 2C9, 3A4 
and 2E1 are less involved. In contrast, formation of threohydrobupropion has been reported in the 
literature to be mediated by 11-beta-hydroxysteroid dehydrogenase 1.  The metabolic pathway 
responsible for the formation of erythrohydrobupropion is unknown. 
 
Bupropion and its metabolites inhibit CYP2D6. Plasma protein binding of hydroxybupropion is 
similar to that of bupropion (84%) whereas the other two metabolites have approximately half the 
binding. 
 
Following oral administration of 200 mg of 14C-bupropion hydrochloride in humans, 87% and 10% 
of the radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral 
dose of bupropion excreted unchanged was 0.5%, a finding consistent with the extensive metabolism 
of bupropion. 
 
Accumulation  
 
Following twice daily administration of naltrexone/bupropion, naltrexone does not accumulate, while 
6-beta-naltrexol accumulates over time.  Based on its half-life, 6-beta-naltrexol is estimated to reach 
steady state concentrations in approximately 3 days. Metabolites of bupropion (and to a lesser extent 
unmetabolised bupropion) accumulate and reach steady state concentrations in approximately one 
week. No study has been performed comparing AUC or Cmax of naltrexone/bupropion 
prolonged-release tablets with bupropion PR or naltrexone IR administered as single agents in the 
multiple dose setting (i.e., under steady state conditions). 
 
Special populations  
 
Gender and race 
Pooled analysis of naltrexone/bupropion data revealed no meaningful gender or race-related 
differences in the pharmacokinetic parameters of bupropion or naltrexone. However, only Caucasian 
and Black subjects were investigated to a significant extent. No dosage adjustment is necessary based 
on gender or race. 
 
Elderly people 
The pharmacokinetics of naltrexone/bupropion have not been evaluated in the elderly population. 
Because naltrexone and bupropion metabolic products are excreted in the urine and elderly people 
are more likely to have decreased renal function, care should be taken in dose selection, and it may 
be useful to monitor renal function. Naltrexone/bupropion is not recommended in patients over 75 
years of age. 
 
Smokers 
Pooled analysis of naltrexone/bupropion data revealed no meaningful differences in the plasma 
concentrations of bupropion or naltrexone in smokers compared to nonsmokers. The effects of 
cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female 
volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral 
administration of a single 150 mg dose of bupropion hydrochloride, there was no statistically 
significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites 
between smokers and nonsmokers. 
 



 

23 

Hepatic impairment  
A single-dose pharmacokinetic study has been conducted with naltrexone/bupropion in patients with 
hepatic impairment. The results from this study demonstrated that in patients with mild hepatic 
impairment (Child-Pugh scores of 5-6 [Class A]), there was a modest increase in naltrexone 
concentrations, but concentrations of bupropion and most other metabolites were mostly comparable 
and no more than doubled to those in patients with normal hepatic function. In patients with 
moderate (Child-Pugh scores of 7-9 [Class B]) and severe (Child-Pugh scores of 10 or higher [Class 
C]) hepatic impairment, increases in the maximum concentration of naltrexone of ~6- and ~30-fold 
were observed for the moderate and severe patients respectively, while increases in bupropion were 
~2-fold for both groups. Increases of ~2- and ~4-fold for the area under the curve for bupropion were 
observed for patients with moderate and severe impairment respectively. There were no consistent 
changes in naltrexone or bupropion metabolites related to varying degrees of hepatic impairment. 
Naltrexone/bupropion is contraindicated in patients with severe hepatic impairment (see section 4.3) 
and is not recommended in patients with moderate hepatic impairment (see section 4.4). In patients 
with mild hepatic impairment, the maximum recommended daily dose for naltrexone/bupropion 
should be reduced (see section 4.2). 
 
Renal impairment  
A single-dosepharmacokinetic study has been conducted for naltrexone/bupropion in subjects with 
mild, moderate, and severe renal impairment, compared with subjects with normal renal function. 
The results from this study demonstrated that the area under the curve for plasma naltrexone and 
metabolites and for plasma bupropion and metabolites was increased by less than two-fold in patients 
with moderate and severe renal impairment, and smaller increases were observed for patients with 
mild renal impairment. Based on these results, there are no dose adjustments recommended for 
patients with mild renal impairment. For patients with moderate or severe renal impairment, the 
maximum recommended daily dose for naltrexone/bupropion should be reduced (see section 4.2). 
Naltrexone/bupropion is contraindicated in end-stage renal failure (see section 4.3). 
 
5.3 Preclinical safety data 
 
The effects of combined bupropion and naltrexone use have not been studied in animals. 
 
Non-clinical data on individual components reveal no special hazard for humans based on 
conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic 
potential. Any effects in non-clinical studies were observed only at exposures considered sufficiently 
in excess of the maximum human exposure indicating little relevance to clinical use. However, there 
is some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymes 
have been found in humans with therapeutic and higher doses (see section 4.4 and 4.8). Liver 
changes are seen in animal studies with bupropion but these reflect the action of a hepatic enzyme 
inducer. At recommended doses in humans, bupropion does not induce its own metabolism. This 
suggests that the hepatic findings in laboratory animals have only limited importance in the 
evaluation and risk assessment of bupropion. 
 
Reproduction toxicity 
 
Naltrexone (100 mg/kg/day, approximately 30 times the dose of naltrexone in naltrexone/bupropion 
on a mg/m2 basis) caused a significant increase in pseudo-pregnancy in the rat. A decrease in the 
pregnancy rate of mated female rats also occurred. There was no effect on male fertility at this dose 
level. The relevance of these observations to human fertility is not known. 
 
Naltrexone has been shown to have an embryocidal effect in rats dosed with 100 mg/kg/day of 
naltrexone (30 times the naltrexone/bupropion dose) prior to and throughout gestation, and in rabbits 
treated with 60 mg/kg/day of naltrexone (36 times the naltrexone/bupropion dose) during the period 
of organogenesis. 
 
A fertility study of bupropion in rats at doses up to 300 mg/kg/day, or 8 times the bupropion dose 
provided by naltrexone/bupropion revealed no evidence of impaired fertility. 



 

24 

 
Genotoxicity 
 
Naltrexone was negative in the following in vitro genotoxicity studies: bacterial reverse mutation 
assay (Ames test), the heritable translocation assay, CHO cell sister chromatid exchange assay, and 
the mouse lymphoma gene mutation assay. Naltrexone was also negative in an in vivo mouse 
micronucleus assay. In contrast, naltrexone tested positive in the following assays: Drosophila 
recessive lethal frequency assay, non-specific DNA damage in repair tests with E. coli and WI-38 
cells, and urinalysis for methylated histidine residues. The clinical relevance of these equivocal 
findings is unknown. 
 
Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mammalian 
mutagen, and therefore is of no concern as a human genotoxic agent. Mouse and rat studies confirm 
the absence of carcinogenicity in these species. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
 
Cysteine hydrochloride  
Microcrystalline cellulose  
Hydroxypropyl cellulose  
Magnesium stearate  
Lactose anhydrous 
Lactose monohydrate  
Crospovidone type A 
Indigo carmine aluminium lake (E132) 
Hypromellose 
Edetate disodium  
Colloidal silicon dioxide  
 
Film-coating: 
 
Polyvinyl alcohol 
Titanium dioxide (E171) 
Macrogol (3350) 
Talc 
Indigo carmine aluminium lake (E132) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
30 months 
 
6.4 Special precautions for storage 
 
Do not store above 30C. 
 
6.5 Nature and contents of container 

 
PVC/PCTFE/PVC/Aluminium blisters. 



 

25 

Pack sizes: 28, 112 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Orexigen Therapeutics Ireland Limited 
2nd Floor 
Palmerston House, Fenian Street 
Dublin 2 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/988/001-002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 March 2015 
Date of latest renewal: 17 January 2020 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



 

26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
  



 

27 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
MIAS Pharma Ltd 
Suite 2 Stafford House, Strand Road, Portmarnock, Co. Dublin, 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Additional risk minimisation measures  

 
The MAH shall ensure that in each Member State where Mysimba is marketed, all healthcare 
professionals who are expected to prescribe Mysimba are provided with a prescriber guide. 
Prior to launch of Mysimba in each Member State the Marketing Authorisation Holder (MAH) 
must agree the content and format of the prescriber guide with the National Competent 
Authority.  
 
The prescriber guide shall contain the following key elements: 
 a reminder of the indication and the need to discontinue treatment if there are concerns with the 

safety or tolerability of ongoing treatment, or if after 16 weeks patients have lost less than 5% 
of their initial body weight;  

 a reminder of the contraindications, warnings and precautions as well as patient characteristics 
that place patients at higher risk of adverse reactions to Mysimba, to help ensure appropriate 
patient selection.  

 



 

28 

 Obligation to conduct post-authorisation measures  
 

The MAH shall complete, within the stated timeframe, the below measures: 
 

Description Due date 
Post Authorisation Safety Study : 
 
The MAH should conduct and submit results of a multicentre, randomised, 
double-blind, placebo-controlled, phase 4 study to assess the effect of naltrexone 
extended release (ER) /bupropion ER on the occurrence of major adverse 
cardiovascular events (MACE) in overweight and obese subjects. The study is to 
be monitored regularly by a Data Monitoring Committee (DMC). The study 
protocol, including key aspects of the DMC charter, has to be agreed before 
initiation of the study. 

Submission 
of final study 
report by 31 
March 2022 
 
Submission 
of the 
protocol by 
31 March 
2015 

 
  



 

29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 

30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



 

31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Mysimba 8 mg/90 mg prolonged-release tablets  
naltrexone hydrochloride/bupropion hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 8  mg naltrexone hydrochloride, equivalent to 7.2 mg of naltrexone, and 90 mg 
bupropion hydrochloride, equivalent to 78 mg of bupropion. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 prolonged-release tablets 
112 prolonged-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Do not cut, chew or crush.  

 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
  
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 



 

32 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Orexigen Therapeutics Ireland Limited 
2nd Floor 
Palmerston House, Fenian Street 
Dublin 2 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/988/001 112 tablets 
EU/1/14/988/002  28 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
mysimba  
8 mg/90 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



 

33 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Mysimba 8 mg/90  mg prolonged-release tablets 
naltrexone hydrochloride/bupropion hydrochloride 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Orexigen 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 

 
 
 
  



 

34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

35 

Package leaflet: Information for the patient 
 

Mysimba 8 mg/90 mg prolonged-release tablets 
naltrexone hydrochloride/bupropion hydrochloride 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Mysimba is and what it is used for  
2. What you need to know before you take Mysimba  
3. How to take Mysimba  
4. Possible side effects  
5. How to store Mysimba  
6. Contents of the pack and other information 
 
 
1. What Mysimba is and what it is used for 
 
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 there are concerns 
about increased blood pressure, or other concerns with the safety or tolerability of this medicine. 
 
 
2. What you need to know before you take Mysimba 
 
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; 



 

36 

- 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 chronic opiates or opiate agonists (for example methadone), 

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 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. 
 
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).  
 
You should talk to your doctor, especially if: 
 you have high blood pressure before taking Mysimba, 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 before you start Mysimba.  
 you have any kidney problems before you start Mysimba. 
 you have a history of mania (feeling elated or over-excited, which causes unusual behaviour).  



 

37 

 
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”). 

 Opiates and opiate-containing medicines for example to treat cough and cold (such as 
mixtures containing dextromethorphan or codeine), opiate addiction (such as methadone), pain 
(for example, morphine and codeine), diarrhoea (for example, paregoric). You must have 
stopped taking any opiate medicines at least 7-10 days before starting Mysimba. Your doctor 
may carry out a blood test to ensure that your body has cleared these medicines before starting 
your treatment. Naltrexone blocks the effects of opiates; if you take higher doses of opiates to 
overcome these effects of naltrexone, you may suffer from an acute opiate intoxication which 
may be life threatening. After you stop treatment with Mysimba you may be more sensitive to 
low doses of opiates (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 tramadol (a painkiller belonging to the class of opiates); 
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 desipramine, venlafaxine, imipramine, paroxetine, 
citalopram) or other mental health problems (such as risperidone, haloperidol, thioridazine);  

 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. 



 

38 

 
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. 
 
 
3. How to take Mysimba 
 
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. 
 



 

39 

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. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
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 and Stevens Johnson Syndrome  
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. Stevens Johnson Syndrome is a 
rare skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals. 

- 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.  

 
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  



 

40 

- 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 



 

41 

- 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 
- 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 
- Fluctuating blood pressure 
- 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. 
 
 
5. How to store Mysimba 
 
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. 
 



 

42 

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. 
 
 
6. Contents of the pack and other information 
 
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. 
 
Marketing Authorisation Holder  
 
Orexigen Therapeutics Ireland Limited 
2nd Floor 
Palmerston House, Fenian Street 
Dublin 2 
Ireland 
 
Manufacturer 
 
MIAS Pharma Ltd 
Suite 2 Stafford House, Strand Road, Portmarnock, Co. Dublin, 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
GOODLIFE Pharma SA/NV 
Tel. 0800-795-10 
 

Lietuva 
UAB „PharmaSwiss“ 
Tel. 880 033 407 

България 
PharmaSwiss EOOD 
Teл.: 00 800 21 00 173  

Luxembourg/Luxemburg 
GOODLIFE Pharma SA/NV 
Tel. 800-2-3603 
 

Česká republika 
PharmaSwiss Česká republika s.r.o.  
Tel: 800 090 424 

Magyarország 
Valeant Pharma Magyarország Kft. 
Tel: 06 8 010 9471 
 

Danmark 
Navamedic AB 
Tel. 8025-3432  

Malta 
Orexigen Therapeutics Ireland Limited 
Tel. +44 1223771222 



 

43 

Deutschland 
Orexigen Therapeutics Ireland Limited 
Tel. +44 1223771222 

Nederland 
Goodlife Pharma B.V 
Tel. 0-800-022-8673 
 

Eesti 
PharmaSwiss Eesti OÜ 
Tel: 800 0100703  

Norge 
Navamedic AB 
Tel. 800-69-888 
 

Ελλάδα 
Bausch Health Hellas  
Τηλ: 008001 612 2030 465 
 

Österreich 
Kwizda Pharma GmbH 
Tel. 0800-298-403 

España 
Orexigen Therapeutics Ireland Limited 
Tel. +44 1223771222 

Polska 
Valeant Pharma Poland sp. z o.o. 
Tel.: 00 800 112 47 68 
 

France 
Orexigen Therapeutics Ireland Limited 
Tel. 0800-917765 

Portugal 
Laboratório Medinfar - Produtos Farmacêuticos, S.A. 
Tel. 800-819-976 
 

Hrvatska 
Orexigen Therapeutics Ireland Limited 
Tel. +44 1223771222 

România 
Orexigen Therapeutics Ireland Limited 
Tel. +44 1223771222 

Ireland 
Consilient Health Limited 
Tel. 1-800-902-210 

Slovenija 
Orexigen Therapeutics Ireland Limited 
Tel. +44 1223771222 

Ísland 
Navamedic AB 
Tel. +45 89871665 

Slovenská republika 
Bausch Health Slovakia s.r.o.  
Tel: 0800 606 097 
 

Italia 
Bruno Farmaceutici S.p.A. 
Tel. 800-781-623 

Suomi/Finland 
Navamedic AB 
Puh. 0800-912-717 
 

Κύπρος 
M.S. Jacovides & Co Ltd 
Tel: 800 90 819 
 

Sverige 
Navamedic AB 
Tel. 0200-336-733  

Latvija 
UAB „PharmaSwiss“ 
Tel: 800 05400 

United Kingdom 
Orexigen Therapeutics Ireland Limited 
Tel. 0800-051-6402 

 
Liechtenstein 
Orexigen Therapeutics Ireland Limited 
Tel. +49 89121409178 

 

 
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. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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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 there are concerns about increased blood pressure, or other concerns with the safety or tolerability of this medicine.', 'Entity_Recognition': [{'Text': 'mysimba', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'mysimba', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 7}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 17, 'EndOffset': 18}, {'Id': 1, 'BeginOffset': 38, 'EndOffset': 62, 'Score': 0.9869837760925293, 'Text': 'naltrexone hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 67, 'EndOffset': 90, 'Score': 0.9900054335594177, 'Text': 'bupropion hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 106, 'EndOffset': 111, 'Score': 0.47020187973976135, 'Text': 'obese', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 4, 'BeginOffset': 115, 'EndOffset': 125, 'Score': 0.8562110662460327, 'Text': 'overweight', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8529129028320312}]}, {'Text': 'a reduced calorie diet', 'Type': 'TREATMENT', 'BeginOffset': 164, 'EndOffset': 186}, {'Id': 13, 'BeginOffset': 191, 'EndOffset': 208, 'Score': 0.5053680539131165, 'Text': 'physical exercise', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 210, 'EndOffset': 223}, {'Id': 0, 'BeginOffset': 246, 'EndOffset': 251, 'Score': 0.803848147392273, 'Text': 'brain', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 5, 'BeginOffset': 315, 'EndOffset': 322, 'Score': 0.9717678427696228, 'Text': 'obesity', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9088674187660217}]}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 338, 'EndOffset': 340}, {'Text': 'a body mass index', 'Type': 'TEST', 'BeginOffset': 368, 'EndOffset': 385}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 414, 'EndOffset': 416}, {'Id': 7, 'BeginOffset': 421, 'EndOffset': 431, 'Score': 0.4503856897354126, 'Text': 'overweight', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 447, 'EndOffset': 449}, {'Text': 'a body mass index', 'Type': 'TEST', 'BeginOffset': 477, 'EndOffset': 494}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 520, 'EndOffset': 522}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 537, 'EndOffset': 540}, {'Text': 'the body mass index', 'Type': 'TEST', 'BeginOffset': 541, 'EndOffset': 560}, {'Text': 'an initial body mass index', 'Type': 'TEST', 'BeginOffset': 698, 'EndOffset': 724}, {'Text': '30', 'Type': 'NUMBER', 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'BeginOffset': 1028, 'EndOffset': 1030}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 1067, 'EndOffset': 1068}, {'Id': 20, 'BeginOffset': 1093, 'EndOffset': 1104, 'Score': 0.34573015570640564, 'Text': 'body weight', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1146, 'EndOffset': 1155}, {'Id': 12, 'BeginOffset': 1184, 'EndOffset': 1208, 'Score': 0.39883747696876526, 'Text': 'increased blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6759194135665894}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1263, 'EndOffset': 1276}]}
{'Title': '2. what you need to know before you take mysimba', 'Section_Content': '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; 36 - 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 chronic opiates or opiate agonists (for example methadone), 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 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. 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). you should talk to your doctor, especially if: you have high blood pressure before taking mysimba, 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 before you start mysimba. you have any kidney problems before you start mysimba. you have a history of mania (feeling elated or over-excited, which causes unusual behaviour). 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"). opiates and opiate-containing medicines for example to treat cough and cold (such as mixtures containing dextromethorphan or codeine), opiate addiction (such as methadone), pain (for example, morphine and codeine), diarrhoea (for example, paregoric). you must have stopped taking any opiate medicines at least 7-10 days before starting mysimba. your doctor may carry out a blood test to ensure that your body has cleared these medicines before starting your treatment. naltrexone blocks the effects of opiates; if you take higher doses of opiates to overcome these effects of naltrexone, you may suffer from an acute opiate intoxication which may be life threatening. after you stop treatment with mysimba you may be more sensitive to low doses of opiates (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 tramadol (a painkiller belonging to the class of opiates); 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 desipramine, venlafaxine, imipramine, paroxetine, citalopram) or other mental health problems (such as risperidone, haloperidol, thioridazine); 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 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.', 'Entity_Recognition': [{'Text': 'mysimba', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 3, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.9969601631164551, 'Text': 'naltrexone', 'Category': 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{'Title': '3. how to take mysimba', 'Section_Content': '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 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects 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 and stevens johnson syndrome 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. stevens johnson syndrome is a rare skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals. - 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. 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 40 - 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 41 - 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 - 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 - fluctuating blood pressure - 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.', 'Entity_Recognition': [{'Text': 'mysimba', 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0.9642877578735352}]}, {'Text': 'increased energy', 'Type': 'PROBLEM', 'BeginOffset': 5513, 'EndOffset': 5529}, {'Id': 283, 'BeginOffset': 5543, 'EndOffset': 5555, 'Score': 0.7820613980293274, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8449028134346008}]}, {'Id': 284, 'BeginOffset': 5571, 'EndOffset': 5583, 'Score': 0.8971427083015442, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8273629546165466}]}, {'Id': 285, 'BeginOffset': 5647, 'EndOffset': 5659, 'Score': 0.9568579196929932, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.751708447933197}]}, {'Id': 286, 'BeginOffset': 5708, 'EndOffset': 5720, 'Score': 0.8792758584022522, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7579959630966187}]}, {'Id': 287, 'BeginOffset': 5774, 'EndOffset': 5785, 'Score': 0.3713447153568268, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7129642367362976}]}, {'Id': 288, 'BeginOffset': 5799, 'EndOffset': 5811, 'Score': 0.8689178228378296, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7922943234443665}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5867, 'EndOffset': 5880}]}
{'Title': '5. how to store mysimba', 'Section_Content': '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. 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.', 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': '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.', 'Entity_Recognition': [{'Text': 'mysimba', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 50, 'EndOffset': 74, 'Score': 0.9821027517318726, 'Text': 'naltrexone hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 79, 'EndOffset': 102, 'Score': 0.9947596192359924, 'Text': 'bupropion hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.19861716032028198, 'RelationshipScore': 0.9978830218315125, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 2, 'BeginOffset': 104, 'EndOffset': 115, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 125, 'EndOffset': 126}, {'Id': 4, 'BeginOffset': 141, 'EndOffset': 165, 'Score': 0.9956662654876709, 'Text': 'naltrexone 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