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).

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. 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.

• 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) • 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.

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 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. Furthermore, post-marketing cases of hypertensive crisis have been reported during the initial titration phase with naltrexone/bupropion. 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). 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. Brugada syndrome Bupropion may unmask Brugada syndrome, a rare hereditary disease of the cardiac sodium channel with characteristic ECG changes (right bundle branch block and ST segment elevation in right precordial leads), which may lead to cardiac arrest or sudden death. Caution is advised in patients with Brugada syndrome or a family history of cardiac arrest or sudden death. 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). Serotonin Syndrome There have been post-marketing reports of serotonin syndrome, a potentially life-threatening condition, when naltrexone/bupropion was co-administered with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.5 and 4.8). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, a discontinuation of therapy should be considered. 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. Panic attacks, particularly in patients with a history of psychiatric disorders, have been reported with naltrexone/bupropion. The cases occurred mostly during the initial titration phase and following dose changes. Naltrexone/bupropion should be used with caution in patients with a history of psychiatric disorders. 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. 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.

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

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).

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. 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)

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) and/or post marketing data sources.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 Panic attack Not known Affective disorders Aggression Confusional state Delusions Depression Disorientation Disturbance in attention Hostility Loss of libido Nightmares Paranoia Psychotic disorder Suicidal ideation* Suicide attempt Suicidal behaviour Very common Headache Common Dizziness Tremor Dysgeusia Lethargy Somnolence Uncommon Intention tremor Balance disorder Amnesia Rare Loss of consciousness Paraesthesia Presyncope Seizure** Syncope Nervous system disorders Not known Dystonia Memory impairment Parkinsonism Restlessness Serotonin syndrome**** Eye disorders Not known Eye irritation Eye pain or asthenopia Eye swelling Lacrimation increased Photophobia Vision blurred Common Tinnitus Vertigo Uncommon Motion sickness Ear and labyrinth disorders Not known Ear discomfort Ear pain Common Palpitations Heart rate increased Cardiac disorders Uncommon Tachycardia Common Hot flush Hypertension***** Blood pressure increased Vascular disorders 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 Very common Nausea Constipation Vomiting Common Dry mouth Abdominal pain upper Abdominal pain Uncommon Abdominal discomfort Dyspepsia Eructation Rare Haematochezia Hernia Lip swelling Lower abdominal pain Dental caries*** Toothache*** Gastrointestinal disorders Not known Diarrhoea Flatulence Haemorrhoids Ulcer Uncommon Cholecystitis ALT increased AST increased Hepatic enzyme increased Rare Drug induced liver injury Hepatobiliary disorders Not known Hepatitis Common Hyperhidrosis Pruritus Alopecia Rash Skin and subcutaneous tissue disorders Not known Acne Erythema multiforme and Stevens Johnson syndrome Cutaneous lupus erythematosus Systemic lupus erythematosus syndrome aggravated Musculoskeletal and connective Rare Jaw pain tissue disorders Not known Arthralgia Groin pain Myalgia Rhabdomyolysis Uncommon Blood creatinine increased Rare Micturition urgency Renal and urinary disorders Not known Dysuria, Pollakiuria Urinary frequency and/or retention Uncommon Erectile Dysfunction Reproductive system and breast disorders Rare Irregular menstruation Vaginal haemorrhage Vulvovaginal dryness Common Fatigue Feeling jittery Irritability Uncommon Asthenia Feeling abnormal Feeling hot Increased appetite Thirst Rare Chest pain Peripheral coldness Pyrexia General disorders and administration site conditions 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. **** Serotonin syndrome may occur as a consequence of an

Human experience There is no clinical experience with 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 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 cases. Other serious reactions reported with s 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 s. Although most subjects recovered without sequelae, deaths associated with s of bupropion alone have been reported in subjects ingesting large doses of the drug. Serotonin syndrome has also been reported. Naltrexone There is limited experience with 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. 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 and naltrexone s. 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 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.

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 (a-MSH), which in turn binds to and stimulates melanocortin 4 receptors (MC4-R). When a-MSH is released, POMC neurons simultaneously release ß-endorphin, an endogenous agonist of the mu-opioid receptors. Binding of ß-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMC neurons leading to a decrease in the release of a-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 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. 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). 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 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.

The results of a single dose relative bioavailability study in healthy subjects demonstrated that naltrexone/bupropion tablets, when dose adjusted, are bioequivalent based on AUC0-8 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

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. 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.

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)

Not Applicable

30 months

Do not store above 30°C.

PVC/PCTFE/PVC/Aluminium blisters. Pack sizes: 28, 112 tablets. Not all pack sizes may be marketed.

No special requirements.

Feb. 16, 2026

spc-doc_PLGB 50742-0001.pdf

Bulk SPC upload Feb2026