MYSIMBA 8mg / 90mg prolonged tablets medication leaflet

Mysimba 8 mg/90 mg prolonged-release tablets

Each tablet contains 8 mg naltrexone hydrochloride, equivalent to 7.2 mg of naltrexone, and 90 mgbupropion hydrochloride, equivalent to 78 mg of bupropion.

Each prolonged-release tablet contains 73.2 mg of lactose (see section 4.4).

For the full list of excipients, see section 6.1.

Prolonged-release tablet.

Blue, biconvex, round tablet of 12-12.2 mm diameter debossed with “NB-890” on one side.

Mysimba is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for themanagement 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-relatedco-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).

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 doseof 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. The cardiovascular risks of Mysimba when given for longer than a year have notbeen fully determined. Treatment with Mysimba should be discontinued after one year if patientshave not maintained a loss of at least 5% of their initial body weight (see Section 4.1). Annualassessment should be conducted by the healthcare professional in discussion with the patient whenconsidering treatment continuation to ensure no adverse change in their cardiovascular risk (see

Section 4.4) and maintenance of weight loss as defined in this section.

If a dose is missed, patients should not take an additional dose, but take the prescribed next dose atthe usual time.

Elderly patients (over 65 years)

Naltrexone/bupropion should be used with caution in patients over 65 years of age and is notrecommended in patients over 75 years of age (see sections 4.4, pct. 4.8 and 5.2).

Naltrexone/bupropion is contraindicated in patients with end-stage renal failure (see section 4.3). Inpatients with moderate or severe renal impairment, the maximum recommended daily dose fornaltrexone/bupropion is two tablets (one tablet in the morning and one tablet in the evening) (seesections 4.4, pct. 4.8 and 5.2). It is recommended that patients with moderate or severe renal impairmentinitiate treatment with one tablet in the morning for the first week of treatment, and escalate to onetablet in the morning and one tablet in the evening from week 2 onwards. Dose reduction is notnecessary in patients with mild renal impairment. For individuals who are at elevated risk for renalimpairment, in particular patients with diabetes or elderly individuals, estimated glomerular filtrationrate (eGFR) should be assessed prior to initiating therapy with naltrexone/bupropion.

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 (seesections 4.4 and 5.2). In patients with mild hepatic impairment, the maximum recommended dailydose 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 initiatetreatment with one tablet in the morning for the first week of treatment, and escalate to one tablet inthe morning and one tablet in the evening from week 2 onwards. Degree of hepatic impairmentshould be assessed using the Child-Pugh score.

The safety and efficacy of naltrexone/bupropion in children and adolescents below 18 have not yetbeen established. Therefore, naltrexone/bupropion should not be used in children and adolescentsbelow 18.

Oral use. The tablets should be swallowed whole with some water. The tablets should preferably betaken 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 opioids including opioid-containing medication, patientstreated with opioid agonists used in opioid dependence (e.g., methadone, buprenorphine),or patients in acute opioid withdrawal (see sections 4.4 and 4.5)

* Patients receiving concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14days should elapse between discontinuation of MAOI and initiation of treatment withnaltrexone/bupropion (see section 4.5)Patients with severe hepatic impairment (see sections 4.2 and5.2)

* Patients with end-stage renal failure (see sections 4.2 and 5.2)

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 ongoingtreatment, 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 insome countries. A meta-analysis of placebo-controlled clinical trials of antidepressants in adultsubjects with psychiatric disorders showed an increased risk of suicidal behaviour withantidepressants compared to placebo in subjects less than 25 years old.

Although in placebo-controlled clinical trials with naltrexone/bupropion for the treatment of obesityin adult subjects, no suicides or suicide attempts were reported in studies up to 56 weeks durationwith naltrexone/bupropion, suicidality events (including suicidal ideation) have been reported insubjects of all ages treated with naltrexone/bupropion post-marketing.

Close supervision of patients, particularly those at high risk, should accompany therapy withnaltrexone/bupropion especially in early treatment and following dose changes. Patients (andcaregivers 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 adviceimmediately if these symptoms present.

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 andmetabolites of bupropion following single-dose administration of 180 mg of bupropion asnaltrexone/bupropion tablets are comparable to concentrations observed after single-doseadministration of bupropion SR 150 mg; however, no study has been conducted that determined theconcentrations of bupropion and metabolites of bupropion after repeated dosing ofnaltrexone/bupropion tablets compared to bupropion SR tablets. As it is unknown whether the riskfor seizure with bupropion is related to bupropion or a metabolite of bupropion, and there are no datademonstrating comparability of plasma concentrations with repeated dosing, there is uncertaintywhether repeated-dose administration naltrexone/bupropion may be associated with a similar rate ofseizures as bupropion SR 300 mg. The incidence of seizure in subjects receivingnaltrexone/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 subjectswho received naltrexone/bupropion in a large cardiovascular outcomes trial (CVOT), was no higherthan 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 medicinalproducts, 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 seizurewhile being treated with the medicinal product. Caution should be used when prescribingnaltrexone/bupropion to patients with predisposing factors that may increase the risk of seizureincluding:

* 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 withdiabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed tominimise 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, systemicsteroids, quinolones and sedating antihistamines

The consumption of alcohol during naltrexone/bupropion treatment should be minimised or avoided.

Patients receiving opioids

Patients must be warned against the concomitant use of opioids during treatment with naltrexone/bupropion(see sections 4.3 and 4.5).

Naltrexone/bupropion must not be administered to patients currently dependent on opioids,including opioid-containing medication or patients treated with opioid agonists used in opioiddependence (e.g., methadone, buprenorphine) or patients in acute opioid withdrawal (see sections4.3 and 4.5).

Naltrexone/bupropion may be used with caution after opioid use has been stopped for at least 7 to10 days in order to prevent the precipitation of withdrawal symptoms. When opioid use issuspected, a test may be performed to ensure clearance of opioid medication before startingtreatment with naltrexone/bupropion. If opioid therapy is required after treatment initiation,naltrexone/bupropion treatment must be stopped. Serious life-threatening reactions, such as seizureand serotonin syndrome, have been observed after co-administration of naltrexone/bupropion andopioids. Insufficient intra-/post-operative opioid analgesia during treatment withnaltrexone/bupropion has been reported.

In patients requiring intermittent treatment with opioids (e.g., due to a surgical procedure),naltrexone/bupropion therapy should be discontinued for a minimum of 3 days before and theopioid dose should not be increased above the standard dose. During naltrexone/bupropion clinicalstudies, the use of concomitant opioid or opioid-like medicinal products, including analgesics orantitussives were excluded. However, approximately 12% of subjects took a concomitant opioid oropioid-like medicinal product while enrolled in the naltrexone/bupropion clinical studies, themajority 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 ofexogenous opioids is very dangerous and may lead to a fatal overdose or life endangering opioidintoxication (e.g., respiratory arrest, circulatory collapse). Patients should be aware that they may bemore sensitive to lower doses of opioids after naltrexone/bupropion treatment is discontinued.

Anaphylactoid/anaphylactic reactions characterised by symptoms such as pruritus, urticaria,angioedema, and dyspnoea requiring medical treatment have been reported in clinical trials withbupropion. In addition, there have been rare spontaneous postmarketing reports of erythemamultiforme, , and anaphylactic shock associated with bupropion. A patient should stop takingnaltrexone/bupropion and consult a doctor if experiencing allergic or anaphylactoid/anaphylacticreactions (e.g., skin rash, pruritus, hives, chest pain, oedema, and shortness of breath) duringtreatment.

Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivityhave 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. Ifserum sickness is suspected, naltrexone/bupropion should be discontinued.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and acute generalisedexanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in associationwith naltrexone/bupropion treatment.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs andsymptoms suggestive of these reactions appear, naltrexone/bupropion should be withdrawn immediately andan alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJSor AGEP with the use of naltrexone/bupropion, the treatment must not be restarted in this patient at any time.

Elevation of blood pressure

Early, transient mean increases from baseline in systolic and diastolic blood pressure of up to 1 mmHg wereobserved in naltrexone/bupropion Phase 3 clinical trials. In a cardiovascular outcomes trial (CVOT) ofpatients at increased risk of a cardiovascular event, mean increases from baseline in systolic and diastolicblood pressure of approximately 1 mmHg compared to placebo were also observed. In clinical practicewith other bupropion containing products, hypertension, in some cases severe and requiring acutetreatment, has been reported. Furthermore, post-marketing cases of hypertensive crisis have been reportedduring the initial titration phase with naltrexone/bupropion.

Blood pressure and pulse should be measured prior to initiation of therapy with naltrexone/bupropionand should be assessed at regular intervals consistent with usual clinical practice. If patientsexperience clinically relevant and sustained increases in blood pressure or pulse rate as a result ofnaltrexone/bupropion treatment, it should be discontinued.

Naltrexone/bupropion should be given with caution to those patients with controlled hypertensionand must not be given to patients with uncontrolled hypertension (see section 4.3).

There is no clinical experience establishing the safety of naltrexone/bupropion in patients with arecent history of myocardial infarction, unstable heart disease or NYHA class III or IV congestiveheart failure. Naltrexone/bupropion should be used with caution in patients with active coronaryartery disease (e.g., ongoing angina or recent history of myocardial infarction) or history ofcerebrovascular disease.

Brugada syndrome

Bupropion may unmask Brugada syndrome, a rare hereditary disease of the cardiac sodiumchannel with characteristic ECG changes (right bundle branch block and ST segment elevation inright precordial leads), which may lead to cardiac arrest or sudden death. Caution is advised inpatients with Brugada syndrome or a family history of cardiac arrest or sudden death.

In naltrexone/bupropion completed clinical studies, where naltrexone hydrochloride daily dosesranged from 16 mg to 48 mg, drug-induced liver injury (DILI) was reported. There have also beencases of elevated liver enzymes from post-marketing reporting. A patient with suspected DILI shouldstop taking naltrexone/bupropion.

Clinical studies of naltrexone/bupropion did not include sufficient numbers of subjects aged 65 andover to determine whether they respond differently than younger subjects. Elderly patients may bemore sensitive to the central nervous system adverse reactions of naltrexone/bupropion. Naltrexoneand bupropion are known to be substantially excreted by the kidney, and the risk of adverse reactionsto naltrexone/bupropion may be greater in patients with impaired renal function, a condition that ismore common in elderly individuals. Due to these reasons, naltrexone/bupropion should be used withcaution in patients over 65 years of age and is not recommended in patients over 75 years of age.

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 withmoderate or severe renal impairment, the maximum recommended daily dose fornaltrexone/bupropion should be reduced, as these patients may have higher drug concentrationswhich could result in an increase in adverse drug reactions (see sections 4.2, pct. 4.8, and 5.2). Forindividuals who are at elevated risk for renal impairment, in particular, individuals with diabetes orelderly individuals, estimated glomerular filtration rate (eGFR) should be assessed prior to initiatingtherapy with naltrexone/bupropion.

Naltrexone/bupropion has not been extensively evaluated in subjects with hepatic impairment.

Naltrexone/bupropion is contraindicated in patients with severe hepatic impairment, and notrecommended in patients with moderate hepatic impairment (see sections 4.2, pct. 4.3, and 5.2). Inpatients with mild hepatic impairment, the maximum recommended daily dose fornaltrexone/bupropion should be reduced, as these patients may have higher drug concentrationswhich 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-threateningcondition, when naltrexone/bupropion was co-administered with a serotonergic agent, such as

Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Re-uptake Inhibitors(SNRIs) and opioids (e.g. tramadol, methadone) (see sections 4.5 and 4.8). If concomitant treatmentwith 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), neuromuscularabnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g.nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, a discontinuation of therapyshould be considered.

Neuropsychiatric symptoms and activation of mania

Activation of mania and hypomania have been reported in patients with mood disorders who weretreated with other similar medicinal products for major depressive disorder. No activation of maniaor hypomania was reported in the clinical trials evaluating effects of naltrexone/bupropion in obesesubjects, which excluded subjects receiving antidepressants. Naltrexone/bupropion should be usedcautiously in patients with a history of mania.

Panic attacks, particularly in patients with a history of psychiatric disorders, have been reportedwith naltrexone/bupropion. The cases occurred mostly during the initial titration phase andfollowing dose changes. Naltrexone/bupropion should be used with caution in patients with ahistory of psychiatric disorders.

Data in animals suggest a potential for abuse of bupropion. However, studies on abuse liability inhumans 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 ofconsciousness, sometimes caused by seizure. Patients must be advised to exercise caution whiledriving or operating machines during treatment with naltrexone/bupropion, especially at thebeginning 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 operatingmachines until these adverse effects have resolved. Alternatively, treatment cessation might beconsidered (see sections 4.7 and 4.8).

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

All physicians who intend to prescribe Mysimba must ensure they have received and arefamiliar with the physician educational material. Physicians must explain and discuss thebenefits and risks of Mysimba therapy with the patient as provided in the SmPC and theprescriber guide (Physician Prescribing Checklist).

Monoamine oxidase inhibitors (MAOI)

Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by adifferent mechanism from bupropion, naltrexone/bupropion must not be used with MAOI (seesection 4.3).

Opioids

Naltrexone/bupropion is contraindicated in patients currently dependent on opioids including opioid-containing medication, patients treated with opioid agonists used in opioid dependence (e.g.,methadone, buprenorphine), or patients in acute opioid withdrawal (see sections 4.3 and 4.4). Due tothe antagonistic effect of naltrexone at the opioid receptor, patients taking naltrexone/bupropion maynot fully benefit from treatment with opioid-containing medicinal products, such as cough and coldremedies, antidiarrhoeal preparations and opioid analgesics.

Drugs metabolised by cytochrome P450 (CYP) enzymes

Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by thecytochrome P450 CYP2B6; thus, the potential exists for interaction when administered withmedicinal products that induce or inhibit CYP2B6. Although not metabolised by the CYP2D6isoenzyme, bupropion and its main metabolite, hydroxybupropion, inhibit the CYP2D6 pathway andthe potential exists to affect medicinal products metabolised by CYP2D6.

In a clinical study, naltrexone/bupropion (32 mg naltrexone hydrochloride /360 mg bupropionhydrochloride 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 increasedpharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a singlemedicinal product with desipramine and venlafaxine.

Co-administration of bupropion with drugs that are metabolised by CYP2D6 isozyme includingcertain 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 approachedwith caution and should be initiated at the lower end of the dose range of the concomitant medicinalproduct. Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropionincreased the Cmax and AUC of citalopram by 30% and 40%, respectively.

There have been post-marketing reports of serotonin syndrome, a potentially life-threateningcondition, when naltrexone/bupropion was co-administered with a serotonergic agent, such as

Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Re-uptake Inhibitors(SNRIs) and opioids (e.g. tramadol, methadone) (see sections 4.4 and 4.8).

Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g., tamoxifen), mayhave reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such asbupropion. If naltrexone/bupropion is added to the treatment regimen of a patient already receiving adrug metabolised by CYP2D6, the need to decrease the dose of the original medicinal product shouldbe considered, particularly for those concomitant medicinal products with a narrow therapeutic index.

When feasible, the option of therapeutic drug monitoring should be considered for medicinalproducts 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 CYP2B6isozyme. The potential exists for a drug interaction between naltrexone/bupropion and drugs thatinduce or are substrates of the CYP2B6 isozyme.

Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion isco-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 ofstudies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its majormetabolites in a dose dependent manner by 20 to 80%. Similarly, efavirenz 600 mg once daily fortwo 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 CYP2B6isoenzyme (e.g., CYP2B6 substrates: cyclophosphamide, ifosfamide, and CYP2B6 inhibitors:orphenadrine, ticlopidine, clopidogrel), may result in increased bupropion plasma levels and lowerlevels of active metabolite hydroxybupropion. The clinical consequences of the inhibition of themetabolism of bupropion via CYP2B6 enzyme and the consequent changes in thebupropion-hydroxybupropion ratio are currently unknown, but could potentially lead to reducedefficacy of naltrexone/bupropion.

OCT2 substrates

Bupropion and its metabolites competitively inhibit the OCT2 in the basolateral membrane of therenal tubule responsible for creatinine secretion, in a manner similar to the OCT2 substratecimetidine. Therefore, mild increases in creatinine observed after long-term treatment withnaltrexone/bupropion are likely due to inhibition of OCT2 and not indicative of changes in creatinineclearance. Use of naltrexone/bupropion with other OCT2 substrates (e.g., metformin) in clinicaltrials did not indicate the need for dose adjustment or other precautions.

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 inpatients drinking alcohol during bupropion treatment. There are no known pharmacokineticinteractions between naltrexone and alcohol. The consumption of alcohol duringnaltrexone/bupropion treatment should be minimised or avoided.

Caution should be used when prescribing naltrexone/bupropion to patients with predisposing factorsthat may increase the risk of seizure including:

* as treatment with naltrexone/bupropion may result in lowered glucose in patients withdiabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed tominimise 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, systemicsteroids, quinolones and sedating antihistamines

Naltrexone/bupropion is contraindicated in patients receiving concomitant treatment withmonoamine oxidase inhibitors, bupropion or naltrexone, patients undergoing acute alcohol, opioidor benzodiazepine withdrawal, patients currently dependent on opioids (see section 4.3).

Administration of naltrexone/bupropion to patients receiving either levodopa or amantadineconcurrently should be undertaken with caution. Limited clinical data suggest a higher incidence ofadverse reactions (e.g., nausea, vomiting, and neuropsychiatric adverse reactions - see section 4.8) inpatients receiving bupropion concurrently with either levodopa or amantadine.

Administration of naltrexone/bupropion with inhibitors or inducers of UGT 1A2 and 2B7 should beundertaken with caution as these may alter the exposure of naltrexone.

Coadministration of naltrexone/bupropion with digoxin may decrease plasma digoxin levels. Monitorplasma digoxin levels in patients treated concomitantly with naltrexone/bupropion and digoxin.

Clinicians should be aware that digoxin levels may rise on discontinuation of naltrexone/bupropionand the patient should be monitored for possible digoxin toxicity.

Naltrexone/bupropion has not been studied in conjunction with alpha-adrenergic blockers orclonidine.

Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion isco-administered with medicinal products known to inhibit metabolism (e.g. valproate), as these mayaffect its clinical efficacy and safety.

Naltrexone/bupropion should preferably be taken with food, as it is known that both naltrexone andbupropion plasma concentrations are increased with food and the safety and efficacy data fromclinical trials is based on dosing with food.

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 inanimals have shown reproductive toxicity (see section 5.3); animal studies with bupropion show noclear evidence of reproductive harm. The potential risk for humans is unknown.

Naltrexone/bupropion should not be used during pregnancy or in women currently attempting tobecome pregnant.

Naltrexone and bupropion and their metabolites are excreted in human milk.

Since there is limited information on the systemic exposure to naltrexone and bupropion ininfants/newborns being breast-fed, a risk to the newborns/infants cannot be excluded.

Naltrexone/bupropion should not be used during breast-feeding.

There are no data on fertility from the combined use of naltrexone and bupropion. No effect onfertility in reproductive toxicity studies have been observed with bupropion. Naltrexone administeredorally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates atapproximately 30 times the naltrexone dose provided by naltrexone/bupropion. The relevance ofthese 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 vehiclesor using machines, it should be taken into account that dizziness, somnolence, loss of consciousnessand seizure may occur during treatment.

Patients should be cautioned about driving or operating hazardous machinery in casenaltrexone/bupropion may affect their ability to engage in such activities (see sections 4.4 and 4.8)

In clinical studies, 23.8% of subjects receiving naltrexone/bupropion and 11.9% of subjects receivingplacebo discontinued treatment due to an adverse reaction. The most frequent adverse reactions fornaltrexone/bupropion are nausea (very common), constipation (very common), vomiting (verycommon), dizziness (common), and dry mouth (common). The most frequent adverse reactionsleading to discontinuation with naltrexone/bupropion were nausea (very common), headache (verycommon), dizziness (common) and vomiting (very common).

The safety profile of naltrexone/bupropion (NB) summarised in Table 1 below is based on clinicalstudies 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 providesinformation 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

Nervous system disorders Very common Headache

Common Dizziness

Tremor

Dysgeusia

Lethargy

Somnolence

Uncommon Intention tremor

Balance disorder

Rare Loss of consciousness

Paraesthesia

Presyncope

Seizure**

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

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 Not known Coughdisorders Dysphonia

Nasal congestion

Nasal discomfort

Oropharyngeal pain

Rhinorrhea

Sinus disorder

Sneezing

Yawning

Gastrointestinal disorders Very common Nausea

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

Not known Acne

Erythema multiforme and Stevens

Johnson syndrome

Cutaneous lupus erythematosus

Systemic lupus erythematosus syndromeaggravated

Acute generalised exanthematouspustulosis (AGEP)

Musculoskeletal and connective tissue Rare Jaw paindisorders Not known Arthralgia

Groin pain

Myalgia

Renal and urinary disorders Uncommon Blood creatinine increased

Rare Micturition urgency

Not known Dysuria,

Pollakiuria

Urinary frequency and/or retention

Reproductive system and breast Uncommon Erectile Dysfunctiondisorders

Rare Irregular menstruation

Vaginal haemorrhage

Vulvovaginal dryness

General disorders and administration Common Fatiguesite conditions Feeling jittery

Irritability

Uncommon Asthenia

Feeling abnormal

Feeling hot

Increased appetite

Thirst

Rare Chest pain

Peripheral coldness

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

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

**** Serotonin syndrome may occur as a consequence of an interaction between bupropion and a serotonergicmedicinal product (e.g., Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) and opioids (see sections 4.4 and 4.5).

*****Post-marketing cases of hypertensive crisis have been reported during the initial titration phase.

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. Theadditional undesirable effects occurring with either of the individual components (bupropion ornaltrexone) when used for non-obesity indications are summarized in Table 2.

Table 2. Adverse reactions of the individual components naltrexone and bupropion identifiedin the respective approved SmPCs.

System Organ Class Frequency Adverse Reaction

Infections and infestations Uncommon Oral herpes (N)

Tinea pedis (N)

Blood and lymphatic system Uncommondisorders Idiopathic thrombocytopenic purpura (N)

Immune system disorders Very rare More severe hypersensitivity reactionsincluding angioedema, dyspnoea/bronchospasm and anaphylactic shock.

Arthralgia, myalgia and fever have alsobeen reported in association with rash andother symptoms suggestive of delayedhypersensitivity. These symptoms mayresemble 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 Uncommon Sputum increased (N)mediastinal disorders

Gastrointestinal disorders Common Taste disorders (B)

Hepatobiliary disorders Uncommon Blood bilirubin increased (N)

Jaundice (B)

Skin and subcutaneous tissue Uncommon Exacerbation of psoriasis (B)disorders Seborrhea (N)

Musculoskeletal and connective Uncommon Twitching (B)tissue disorders

Reproductive system and breast Commondisorders Ejaculation delayed (N)

General disorders and administration Uncommon Weight gain (N)site conditions

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 ofseizures were considered as serious and led to treatment discontinuation (see section 4.4). There wereno cases of seizures in the placebo group.

The vast majority of subjects treated with naltrexone/bupropion who experienced nausea reported theevent within 4 weeks of starting treatment. Events were generally self-limited; the majority of eventsresolved within 4 weeks and almost all resolved by week 24. Similarly, the majority of events ofconstipation in subjects treated with naltrexone/bupropion were reported during the dose escalationphase. The time to resolution of constipation was similar between subjects treated withnaltrexone/bupropion and subjects treated with placebo. Approximately half of the subjects treatedwith naltrexone/bupropion who experienced vomiting first reported the event during the doseescalation phase. Time to resolution for vomiting was typically rapid (within one week) and almostall events resolved within 4 weeks. The incidence of these common gastrointestinal adverse reactionsin 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, severeconstipation, and severe vomiting was low, but was higher in subjects treated withnaltrexone/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 ofnausea, 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 maybe associated with toothache and dental caries; in the subset of patients with dry mouth, a higherincidence of toothache and dental caries were observed in subjects treated with naltrexone/bupropioncompared to subjects treated with placebo. The incidence of severe headache, severe dizziness, andsevere insomnia was low, but was higher in subjects treated with naltrexone/bupropion compared tosubjects treated with placebo (severe headache: naltrexone/bupropion (1.1%), placebo (0.3%); severedizziness: 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 subjectstreated with naltrexone/bupropion were considered serious.

Elderly patients may be more sensitive to some of the central nervous system-related adversereactions of naltrexone/bupropion (primarily dizziness and tremor). There is an increased incidenceof gastrointestinal disorders with higher age categories. Common events leading to withdrawalamong elderly were nausea, vomiting, dizziness, constipation.

Type 2 diabetes

Patients with type 2 diabetes treated with naltrexone/bupropion demonstrated a higher incidence ofgastrointestinal adverse reactions, primarily nausea, vomiting, and diarrhoea, than subjects withoutdiabetes. Patients with type 2 diabetes may be more prone to these events due to concomitantmedicinal product use (e.g., metformin) or may be more likely to have underlying gastrointestinaldisorders (e.g., gastroparesis) predisposing to gastrointestinal symptoms.

Patients with moderate renal impairment had a higher incidence of gastrointestinal and centralnervous system-related adverse reactions, thus these patients generally had lower tolerability ofnaltrexone/bupropion at a total daily dose of 32 mg naltrexone hydrochloride/360 mg bupropionhydrochloride, which is thought to be due to higher plasma concentrations of active metabolites. Thetypes of tolerability events were similar to the events observed in patients with normal renal function(see sections 4.2, pct. 4.4, and 5.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Human overdose experience

There is no clinical experience with overdose with combined use of bupropion and naltrexone. Themaximum daily dose of combined use of bupropion and naltrexone administered in clinical trialscontained 50 mg naltrexone hydrochloride and 400 mg bupropion hydrochloride. The most seriousclinical implications of combined use of bupropion and naltrexone overdose are likely related tobupropion.

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 ofnaltrexone/bupropion) has been reported. Seizure was reported in approximately one third of theseoverdose cases. Other serious reactions reported with overdoses of bupropion alone includedhallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conductiondisturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis,hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion waspart of multiple drug overdoses.

Although most subjects recovered without sequelae, deaths associated with overdoses of bupropionalone have been reported in subjects ingesting large doses of the drug. Serotonin syndrome has alsobeen reported.

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 recommendeddaily 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 signsshould 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 notrecommended.

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 bupropionand naltrexone overdoses. No specific antidotes for combined use of bupropion and naltrexone areknown.

Due to the dose-related risk of seizures with bupropion, hospitalisation following suspected overdosewith naltrexone/bupropion should be considered. Based on studies in animals, it is recommended thatseizures be treated with intravenous benzodiazepine administration and other supportive measures, asappropriate.

Pharmacotherapeutic group: Antiobesity preparations excluding diet products, centrally actingantiobesity products, ATC code: A08AA62.

Mechanism of action and pharmacodynamic effects

The exact neurochemical appetite suppressant effects of naltrexone/bupropion are not fullyunderstood. The medicinal product has two components: naltrexone, a mu-opioid antagonist, andbupropion, a weak inhibitor of neuronal dopamine and norepinephrine reuptake. These componentsaffect two principal areas of the brain, specifically the arcuate nucleus of the hypothalamus and themesolimbic 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 andstimulates melanocortin 4 receptors (MC4-R). When α-MSH is released, POMC neuronssimultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptors. Binding ofβ-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMCneurons leading to a decrease in the release of α-MSH. Blocking this inhibitory feedback loop withnaltrexone 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 thatnaltrexone and bupropion may have greater than additive effects in this region to reduce food intakewhen administered together.

The effects of naltrexone/bupropion on weight loss, weight maintenance, waist circumference, bodycomposition, obesity-related markers for cardiovascular and metabolic parameters and patientreported assessments were examined in double-blind, placebo-controlled obesity Phase 2 and Phase 3trials (BMI range 27-45 kg/m2) with study durations of 16 to 56 weeks randomised to naltrexonehydrochloride (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 conjunctionwith 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 primaryendpoint at week 28, but continued for 56 weeks. Studies NB-301, NB-303, and NB-304 includedperiodic 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 counselingsessions over 56 weeks, as well as a prescribed rigorous diet and exercise regimen. NB-304 evaluatedsubjects with type 2 diabetes not achieving glycaemic goal of HbA1c <7% (53 mmol/mol) with oralanti-diabetes agents or on diet and exercise alone. NB-303 included a re-randomisation in a blindedmanner and the addition of a higher dose of naltrexone (naltrexone hydrochloride 48 mg/bupropionhydrochloride 360 mg) at week 28 to half of the cohort of subjects in the active treatment arm whodid not adequately respond to treatment, and as such the primary endpoint comparing weight changewith 32 mg naltrexone hydrochloride /360 mg bupropion hydrochloride vs. placebo was evaluated atweek 28.

Of the overall population of 4,536 subjects in the naltrexone/bupropion Phase 3 studies, 25% hadhypertension, 33% had fasting glucose levels ≥100 mg/dL (5.6 mmol/L) at baseline, 54% haddyslipidaemia 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 waistcircumference was 110 cm. The two co-primary endpoints were percent change from baseline bodyweight and the proportion of subjects achieving ≥5% total decreased body weight. Data summariesfor mean change in body weight reflect the Intent-to-Treat (ITT) population, defined as subjects whowere randomised, had a baseline body weight measurement, and had at least one post-baseline bodyweight 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 similarbetween 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% placeboat 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 ofat least 5% baseline body weight was observed more frequently for subjects treated withnaltrexone/bupropion (31%) compared to placebo (12%) (Table 3). More pronounced weight losswas observed in the cohort of subjects who completed 56 weeks of treatment withnaltrexone/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 innaltrexone/bupropion -treated subjects compared to placebo at the week 28 primary endpoint, andsustained through 56 weeks from baseline (Table 3).

Naltrexone/bupropion was also evaluated in combination with intensive behavioural modificationcounseling in the NB-302 study. Correspondingly, there was greater mean weight loss from baselinefor naltrexone/bupropion treatment (-8.1%) compared to study NB-301 (-5.4%) at week 56, and forplacebo (-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 3study NB-30356-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)% -5.4* -1.3 -8.1* -4.9 -3.7* -1.7 -5.7* -1.9(-2.4, -(-6.0, -4.8) (-1.9, -0.7) (-8.8, -7.4) (-6.1, -3.7) (-4.3, -3.1) (-2.5, -0.9) (-6.1, -5.3)

Change 1.4)

From

Baseline

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) -11.5

- 2.4% -8.1 -1.8 -7.3 -5.9 -2.2 -7.8(-12.6, - (-3.0, -

Change (-9.0, -7.2) (-2.7, -0.9) (-9.0, -5.6) (-6.8, -5.0) (-3.4, -1.0) (-8.3, -7.3)10.4) 1.8)

From

Baseline

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 obesewith comorbidities. Study NB-302 had a more intensive behavioural modification program, while theprimary endpoint of Study NB-303 was at week 28 to allow for re-randomization to different doses in thelatter portion of the study. Study NB-304 was conducted in subjects who were overweight or obese and hadtype 2 diabetes mellitus.

The percentages of subjects with ≥ 5% or ≥ 10% body weight loss from baseline were greater withnaltrexone/bupropion compared to placebo in all four Phase 3 obesity trials (Table 4).

Table 4. Percentage (%) of subjects losing ≥5% and ≥10% of body weight from baseline toweek 56 in phase 3 studies NB-301, NB-302, and NB-304 and from baseline to week 28 in phase3 study NB-30356-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 withcomorbidities. Study NB-302 had a more intensive behavioural modification program, while the primaryendpoint of Study NB-303 was at week 28 to allow for re-randomisation to different doses in the latter portion ofthe study. Study NB-304 was conducted in subjects who were overweight or obese and had type 2 diabetesmellitus.

Of the subjects with observed data at week 16 in the four Phase 3 clinical trials, 50.8% of thoserandomised to receive naltrexone/bupropion had lost ≥5% of their baseline body weight, compared to19.3% 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 was11.3%, with 55% losing ≥10% bodyweight. Additionally, week 16 Responders who receivednaltrexone/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 predictivevalue 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 tohave increased tolerability or safety issues relative to patients who did have a favourable earlyresponse.

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-Cratio were seen in naltrexone/bupropion-treated subjects diagnosed with baseline dyslipidaemiairrespective 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/bupropionexhibited 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 treatedwith naltrexone/bupropion compared to subjects on placebo -0.14% (p<0.001). In subjects withbaseline HbA1c >8% (64 mmol/mol), HbA1c changes at endpoint were -1.1% and -0.5% fornaltrexone/bupropion compared to placebo, respectively. Improvements were observed for fastingglucose, fasting insulin, HOMA-IR and percent of subjects requiring rescue diabetes medicinalproducts for subjects treated with naltrexone/bupropion vs. placebo.

Table 5. Change in cardiovascular and metabolic parameters from baseline to week 56 in phase3 studies NB-301, NB-302, and NB-304 and from baseline to week 28 in phase 3 study NB-30356-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

Waistcircumference, -6.2* -2.5 -10.0* -6.8 -5.0* -2.9 -6.2* -2.7cm

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-Cratio -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 withcomorbidities. Study NB-302 had a more intensive behavioural modification program, while the primaryendpoint of Study NB-303 was at week 28 to allow for re-randomisation to different doses in the latter portion ofthe study. Study NB-304 was conducted in subjects who were overweight or obese and had type 2 diabetesmellitus.

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 computedtomography (CT) scan (naltrexone/bupropion = 34 subjects and placebo = 24 subjects). The DEXAassessment showed that treatment with naltrexone/bupropion was associated with greater reductionsfrom 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 withplacebo-treated subjects in percent of total body lean mass. These results suggest that most of thetotal weight loss was attributable to a reduction in adipose tissue, including visceral adipose.

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 forinformation 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 thatnaltrexone/bupropion tablets, when dose adjusted, are bioequivalent based on AUC0-∞ mean ratio and90% confidence intervals to naltrexone immediate release (IR) or bupropion prolonged release (PR)administered as single agents.

Following single oral administration of naltrexone/bupropion tablets to healthy subjects, peakconcentrations of naltrexone and bupropion occurred approximately 2 and 3 hours postadministration of naltrexone/bupropion, respectively. There were no differences in bioavailability, asmeasured by AUC, of naltrexone or bupropion when administered in combination compared to eachadministered alone. However, given the prolonged nature of the drug release fornaltrexone/bupropion, Cmax for naltrexone was markedly reduced compared to the 50 mg naltrexonehydrochloride 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 ofbupropion PR (150 mg bupropion hydrochloride), indicating that the bupropion Cmax achieved withnaltrexone/bupropion (360 mg bupropion hydrochloride /day) is comparable to that achieved withcommercially 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, withonly 5-6% reaching the systemic circulation intact.

When naltrexone/bupropion was given with a high-fat meal the AUC and Cmax for naltrexoneincreased 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-foldfor naltrexone, and 1.1- and 1.3-fold for bupropion, respectively. Clinical experience includedvarying prandial conditions and supports the use of naltrexone/bupropion tablets with food.

The mean volume of distribution at steady state of oral naltrexone and bupropion given asnaltrexgone/bupropion, Vss /F, was 5697 liters and 880 liters, respectively.

Plasma protein binding is not extensive for naltrexone (21%) or bupropion (84%) indicating lowpotential for drug interactions by displacement.

Following single oral administration of naltrexone/bupropion tablets to healthy subjects, mean T½elimination 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 thannaltrexone. Naltrexone and 6-beta-naltrexol are not metabolised by cytochrome P450 enzymes and invitro 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 metabolites2-hydroxy-3-O-methyl naltrexone and 2-hydroxy-3-O-methyl-6-beta-naltrexol, believed to bemediated by catechol-O-methyl transferases (COMT), and glucuronidation, thought to be mediatedby UGT1A1 and UGT2B7.

Naltrexone and its metabolites are excreted primarily by the kidney (37 to 60% of the dose). Thederived value for renal excretion of naltrexone after oral administration, adjusting for plasma proteinbinding, 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-livesthan bupropion and accumulate to a greater extent. In vitro findings suggest that CYP2B6 is theprincipal isozyme involved in the formation of hydroxybupropion, while CYP1A2, 2A6, 2C9, 3A4and 2E1 are less involved. In contrast, formation of threohydrobupropion has been reported in theliterature to be mediated by 11-beta-hydroxysteroid dehydrogenase 1. The metabolic pathwayresponsible for the formation of erythrohydrobupropion is unknown.

Bupropion and its metabolites inhibit CYP2D6. Plasma protein binding of hydroxybupropion issimilar to that of bupropion (84%) whereas the other two metabolites have approximately half thebinding.

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 oraldose of bupropion excreted unchanged was 0.5%, a finding consistent with the extensive metabolismof bupropion.

Accumulation

Following twice daily administration of naltrexone/bupropion, naltrexone does not accumulate, while6-beta-naltrexol accumulates over time. Based on its half-life, 6-beta-naltrexol is estimated to reachsteady state concentrations in approximately 3 days. Metabolites of bupropion (and to a lesser extentunmetabolised bupropion) accumulate and reach steady state concentrations in approximately oneweek. No study has been performed comparing AUC or Cmax of naltrexone/bupropionprolonged-release tablets with bupropion PR or naltrexone IR administered as single agents in themultiple dose setting (i.e., under steady state conditions).

Pooled analysis of naltrexone/bupropion data revealed no meaningful gender or race-relateddifferences in the pharmacokinetic parameters of bupropion or naltrexone. However, only Caucasianand Black subjects were investigated to a significant extent. No dosage adjustment is necessary basedon 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 peopleare more likely to have decreased renal function, care should be taken in dose selection, and it maybe useful to monitor renal function. Naltrexone/bupropion is not recommended in patients over 75years of age.

Smokers

Pooled analysis of naltrexone/bupropion data revealed no meaningful differences in the plasmaconcentrations of bupropion or naltrexone in smokers compared to nonsmokers. The effects ofcigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and femalevolunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oraladministration of a single 150 mg dose of bupropion hydrochloride, there was no statisticallysignificant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its activemetabolites between smokers and nonsmokers.

A single-dose pharmacokinetic study has been conducted with naltrexone/bupropion in patients withhepatic impairment. The results from this study demonstrated that in patients with mild hepaticimpairment (Child-Pugh scores of 5-6 [Class A]), there was a modest increase in naltrexoneconcentrations, but concentrations of bupropion and most other metabolites were mostly comparableand no more than doubled to those in patients with normal hepatic function. In patients withmoderate (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-foldwere 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 wereobserved for patients with moderate and severe impairment respectively. There were no consistentchanges 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 patientswith mild hepatic impairment, the maximum recommended daily dose for naltrexone/bupropionshould be reduced (see section 4.2).

A single-dosepharmacokinetic study has been conducted for naltrexone/bupropion in subjects withmild, 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 andmetabolites and for plasma bupropion and metabolites was increased by less than two-fold in patientswith moderate and severe renal impairment, and smaller increases were observed for patients withmild renal impairment. Based on these results, there are no dose adjustments recommended forpatients with mild renal impairment. For patients with moderate or severe renal impairment, themaximum 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).

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 onconventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicpotential. Any effects in non-clinical studies were observed only at exposures considered sufficientlyin excess of the maximum human exposure indicating little relevance to clinical use. However, thereis some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymeshave been found in humans with therapeutic and higher doses (see section 4.4 and 4.8). Liverchanges are seen in animal studies with bupropion but these reflect the action of a hepatic enzymeinducer. At recommended doses in humans, bupropion does not induce its own metabolism. Thissuggests that the hepatic findings in laboratory animals have only limited importance in theevaluation and risk assessment of bupropion.

Reproduction toxicity

Naltrexone (100 mg/kg/day, approximately 30 times the dose of naltrexone in naltrexone/bupropionon a mg/m2 basis) caused a significant increase in pseudo-pregnancy in the rat. A decrease in thepregnancy rate of mated female rats also occurred. There was no effect on male fertility at this doselevel. 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 ofnaltrexone (30 times the naltrexone/bupropion dose) prior to and throughout gestation, and in rabbitstreated with 60 mg/kg/day of naltrexone (36 times the naltrexone/bupropion dose) during the periodof organogenesis.

A fertility study of bupropion in rats at doses up to 300 mg/kg/day, or 8 times the bupropion doseprovided by naltrexone/bupropion revealed no evidence of impaired fertility.

Naltrexone was negative in the following in vitro genotoxicity studies: bacterial reverse mutationassay (Ames test), the heritable translocation assay, CHO cell sister chromatid exchange assay, andthe mouse lymphoma gene mutation assay. Naltrexone was also negative in an in vivo mousemicronucleus assay. In contrast, naltrexone tested positive in the following assays: Drosophilarecessive lethal frequency assay, non-specific DNA damage in repair tests with E. coli and WI-38cells, and urinalysis for methylated histidine residues. The clinical relevance of these equivocalfindings is unknown.

Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mammalianmutagen, and therefore is of no concern as a human genotoxic agent. Mouse and rat studies confirmthe absence of carcinogenicity in these species.

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

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.

Orexigen Therapeutics Ireland Limited9-10 Fenian Street,

Dublin 2,

D02 RX24

Ireland

EU/1/14/988/001-002

Date of first authorisation: 26 March 2015

Date of latest renewal: 16 January 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.