4.1. Therapeutic indications

Mysimba is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adult patients (≥18 years) with an initial Body Mass Index (BMI) of

• ≥ 30 kg/m2 (obese), or

• ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of one or more weight-related co-morbidities (e.g., type 2 diabetes, dyslipidaemia, or controlled hypertension)

Treatment with Mysimba should be discontinued after 16 weeks if patients have not lost at least 5% of their initial body weight (see section 5.1).

4.2. Posology and method of administration

Posology

Upon initiating treatment, the dose should be escalated over a 4-week period as follows:

• Week 1: One tablet in the morning

• Week 2: One tablet in the morning and one tablet in the evening

• Week 3: Two tablets in the morning and one tablet in the evening

• Week 4 and onwards: Two tablets in the morning and two tablets in the evening

The maximum recommended daily dose of Mysimba is two tablets taken twice daily for a total dose of 32 mg naltrexone hydrochloride and 360 mg bupropion hydrochloride.

The need for continued treatment should be evaluated after 16 weeks (see section 4.1) and re- evaluated annually.

Missed dose

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

Special populations

Elderly patients (over 65 years)

Naltrexone/bupropion should be used with caution in patients over 65 years of age and is not recommended in patients over 75 years of age (see sections 4.4, 4.8 and 5.2).

Patients with renal impairment

Naltrexone/bupropion is contraindicated in patients with end-stage renal failure (see section 4.3). In patients with moderate or severe renal impairment, the maximum recommended daily dose for naltrexone/bupropion is two tablets (one tablet in the morning and one tablet in the evening) (see sections 4.4, 4.8 and 5.2). It is recommended that patients with moderate or severe renal impairment initiate treatment with one tablet in the morning for the first week of treatment, and escalate to one tablet in the morning and one tablet in the evening from week 2 onwards. Dose reduction is not necessary in patients with mild renal impairment. For individuals who are at elevated risk for renal impairment, in particular patients with diabetes or elderly individuals, estimated glomerular filtration rate (eGFR) should be assessed prior to initiating therapy with naltrexone/bupropion.

Patients with hepatic impairment

Naltrexone/bupropion is contraindicated in patients with severe hepatic impairment (see section 4.3). Naltrexone/bupropion is not recommended in patients with moderate hepatic impairment (see sections 4.4 and 5.2). In patients with mild hepatic impairment, the maximum recommended daily dose for naltrexone/bupropion is two tablets (one tablet in the morning and one tablet in the evening) (see sections 4.4 and 5.2). It is recommended that patients with mild hepatic impairment initiate treatment with one tablet in the morning for the first week of treatment, and escalate to one tablet in the morning and one tablet in the evening from week 2 onwards. Degree of hepatic impairment should be assessed using the Child-Pugh score.

Paediatric population

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

Method of administration

Oral use. The tablets should be swallowed whole with some water. The tablets should preferably be taken with food (see section 5.2). The tablets should not be cut, chewed, or crushed.

4.3. Contraindications

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

• Patients with uncontrolled hypertension (see section 4.4)

• Patients with a current seizure disorder or a history of seizures (see section 4.4)

• Patients with a known central nervous system tumour

• Patients undergoing acute alcohol or benzodiazepine withdrawal

• Patients with a history of bipolar disorder

• Patients receiving any concomitant treatment containing bupropion or naltrexone

• Patients with a current or previous diagnosis of bulimia or anorexia nervosa

• Patients currently dependent on chronic opioids (see sections 4.4 and 4.5) or opiate agonists (e.g., methadone), or patients in acute opiate withdrawal

• Patients receiving concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with naltrexone/bupropion (see section 4.5)

• Patients with severe hepatic impairment (see sections 4.2 and 5.2)

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

4.4. Special warnings and precautions for use

The safety and tolerability of naltrexone/bupropion should be assessed at regular intervals.

The treatment should be discontinued if there are concerns with the safety or tolerability of ongoing treatment, including concerns about increased blood pressure (see section 4.8).

Suicide and suicidal behaviour

Naltrexone/bupropion contains bupropion. Bupropion is indicated for the treatment of depression in some countries. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult subjects with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in subjects less than 25 years old.

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

Close supervision of patients, particularly those at high risk, should accompany therapy with naltrexone/bupropion especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Seizures

Bupropion is associated with a dose-related risk of seizures, with bupropion sustained release (SR) 300 mg yielding an estimated seizure incidence of 0.1%. Plasma concentrations of bupropion and metabolites of bupropion following single-dose administration of 180 mg of bupropion as naltrexone/bupropion tablets are comparable to concentrations observed after single-dose administration of bupropion SR 150 mg; however, no study has been conducted that determined the concentrations of bupropion and metabolites of bupropion after repeated dosing of naltrexone/bupropion tablets compared to bupropion SR tablets. As it is unknown whether the risk for seizure with bupropion is related to bupropion or a metabolite of bupropion, and there are no data demonstrating comparability of plasma concentrations with repeated dosing, there is uncertainty whether repeated-dose administration naltrexone/bupropion may be associated with a similar rate of seizures as bupropion SR 300 mg. The incidence of seizure in subjects receiving naltrexone/bupropion in clinical trials was approximately 0.06% (2/3,239 subjects) vs. 0.0% (0/1,515 subjects) on placebo. This incidence of seizure, along with incidence of seizure in subjects who received naltrexone/bupropion in a large cardiovascular outcomes trial (CVOT), was no higher than the seizure rate with bupropion as a single agent at approved doses.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medicinal products, which must be considered in the selection of patients treated with naltrexone/bupropion. Naltrexone/bupropion should be discontinued and not restarted in patients who experience a seizure while being treated with the medicinal product. Caution should be used when prescribing naltrexone/bupropion to patients with predisposing factors that may increase the risk of seizure including:

• history of head trauma

• excessive use of alcohol or addiction to cocaine or stimulants

• as treatment with naltrexone/bupropion may result in lowered glucose in patients with diabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed to minimise the risk of hypoglycaemia, which could predispose patients to seizure

• 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, 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.

Severe cutaneous adverse reactions (SCARs)

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

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, naltrexone/bupropion should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or 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 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.

4.5. Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAOI)

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

Opioid analgesics

Naltrexone/bupropion is contraindicated in patients currently dependent on chronic opioid or opiate agonist therapy (e.g., methadone), or patients in acute opiate withdrawal (see section 4.3). Due to the antagonistic effect of naltrexone at the opioid receptor, patients taking naltrexone/bupropion may not fully benefit from treatment with opioid-containing medicinal products, such as cough and cold remedies, antidiarrhoeal preparations and opioid analgesics. In patients requiring intermittent opiate treatment, naltrexone/bupropion therapy should be temporarily discontinued and opiate dose should not be increased above the standard dose (see section 4.4). If chronic opiate therapy is required, naltrexone/bupropion treatment must be stopped. Naltrexone/bupropion may be used with caution after chronic opioid use has been stopped for 7 to 10 days in order to prevent precipitation of withdrawal.

Drugs metabolised by cytochrome P450 (CYP) enzymes

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

CYP2D6 substrates

In a clinical study, naltrexone/bupropion (32 mg naltrexone hydrochloride /360 mg bupropion hydrochloride daily) was co-administered with a 50 mg dose of metoprolol (a CYP2D6 substrate). Naltrexone/bupropion increased metoprolol AUC and Cmax by approximately 4- and 2-fold, respectively, relative to metoprolol alone. Similar clinical drug interactions resulting in increased pharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a single medicinal product with desipramine and venlafaxine.

Co-administration of bupropion with drugs that are metabolised by CYP2D6 isozyme including certain antidepressants (SSRIs and many tricyclic antidepressants, e.g. desipramine, imipramine, paroxetine), antipsychotics (e.g., haloperidol, risperidone and thioridazine), beta-blockers (e.g., metoprolol) and Type 1C antiarrhythmics (e.g., propafenone and flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medicinal product. Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.

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 (SSRI) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.4 and 4.8).

Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g., tamoxifen), may have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. If naltrexone/bupropion is added to the treatment regimen of a patient already receiving a drug metabolised by CYP2D6, the need to decrease the dose of the original medicinal product should be considered, particularly for those concomitant medicinal products with a narrow therapeutic index. When feasible, the option of therapeutic drug monitoring should be considered for medicinal products with a narrow therapeutic index, such as tricyclic antidepressants.

CYP2B6 inducers, inhibitors and substrates

Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the CYP2B6 isozyme. The potential exists for a drug interaction between naltrexone/bupropion and drugs that induce or are substrates of the CYP2B6 isozyme.

Since bupropion is extensively metabolised, caution is advised when naltrexone/bupropion is co-administered with medicinal products known to induce CYP2B6 (e.g., carbamazepine, phenytoin, ritonavir, efavirenz) as these may affect the clinical efficacy of naltrexone/bupropion. In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by 20 to 80%. Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers.

Co-administration of medicinal products that may inhibit the metabolism of bupropion via CYP2B6 isoenzyme (e.g., CYP2B6 substrates: cyclophosphamide, ifosfamide, and CYP2B6 inhibitors: orphenadrine, ticlopidine, clopidogrel), may result in increased bupropion plasma levels and lower levels of active metabolite hydroxybupropion. The clinical consequences of the inhibition of the metabolism of bupropion via CYP2B6 enzyme and the consequent changes in the bupropion-hydroxybupropion ratio are currently unknown, but could potentially lead to reduced efficacy of naltrexone/bupropion.

OCT2 substrates

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

Other interactions

Although clinical data do not identify a pharmacokinetic interaction between bupropion and alcohol, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during bupropion treatment. There are no known pharmacokinetic interactions between naltrexone and alcohol. The consumption of alcohol during naltrexone/bupropion treatment should be minimised or avoided.

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

• as treatment with naltrexone/bupropion may result in lowered glucose in patients with diabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed to minimise the risk of hypoglycaemia, which could predispose patients to seizure

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

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

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

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

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

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

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

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

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amounts of data from the use of naltrexone/bupropion in pregnant women. The combination has not been tested in reproductive toxicity studies. Studies with naltrexone in animals have shown reproductive toxicity (see section 5.3); animal studies with bupropion show no clear evidence of reproductive harm. The potential risk for humans is unknown. Naltrexone/bupropion should not be used during pregnancy or in women currently attempting to become pregnant.

Breast-feeding

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

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

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

Fertility

There are no data on fertility from the combined use of naltrexone and bupropion. No effect on fertility in reproductive toxicity studies have been observed with bupropion. Naltrexone administered orally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates at approximately 30 times the naltrexone dose provided by naltrexone/bupropion. The relevance of these observations to human fertility is not known (see section 5.3).

4.7. Effects on ability to drive and use machines

Naltrexone/bupropion has influence on the ability to drive and use machines. When driving vehicles or using machines, it should be taken into account that dizziness, somnolence, loss of consciousness and seizure may occur during treatment.

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

The safety profile of naltrexone/bupropion (NB) summarised in Table 1 below is based on clinical studies performed with the fixed-dose combination (adverse reactions at an incidence of at least 0.1% and twice that of placebo) 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

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

Amnesia

Rare

Loss of consciousness

Paraesthesia

Presyncope

Seizure**

Syncope

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 disorders

Not known

Cough

Dysphonia

Dyspnoea

Nasal congestion

Nasal discomfort

Oropharyngeal pain

Rhinorrhea

Sinus disorder

Sneezing

Yawning

Gastrointestinal disorders

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***

Not known

Diarrhoea

Flatulence

Haemorrhoids

Ulcer

Hepatobiliary disorders

Uncommon

Cholecystitis

ALT increased

AST increased

Hepatic enzyme increased

Rare

Drug induced liver injury

Not known

Hepatitis

Skin and subcutaneous tissue disorders

Common

Hyperhidrosis

Pruritus

Alopecia

Rash

Not known

Acne

Erythema multiforme and Stevens Johnson syndrome

Cutaneous lupus erythematosus

Systemic lupus erythematosus syndrome aggravated

Acute generalised exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare

Jaw pain

Not known

Arthralgia

Groin pain

Myalgia

Rhabdomyolysis

Renal and urinary disorders

Uncommon

Blood creatinine increased

Rare

Micturition urgency

Not known

Dysuria,

Pollakiuria

Urinary frequency and/or retention

Reproductive system and breast disorders

Uncommon

Erectile Dysfunction

Rare

Irregular menstruation

Vaginal haemorrhage

Vulvovaginal dryness

General disorders and administration site conditions

Common

Fatigue

Feeling jittery

Irritability

Uncommon

Asthenia

Feeling abnormal

Feeling hot

Increased appetite

Thirst

Rare

Chest pain

Peripheral coldness

Pyrexia

Not known

Chills

Energy increased

* Cases of suicidal ideation and suicidal behaviour have been reported during NB therapy (see section 4.4).

** The incidence of seizures is approximately 0.1% (1/1,000). The most common type of seizures is generalised tonic-clonic seizures, a seizure type which can result in some cases in post-ictal confusion or memory impairment (see section 4.4).

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

**** Serotonin syndrome may occur as a consequence of an interaction between bupropion and a serotonergic medicinal product such as Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 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. The additional undesirable effects occurring with either of the individual components (bupropion or naltrexone) when used for non-obesity indications are summarized in Table 2.

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

System Organ Class

Frequency

Adverse Reaction

Infections and infestations

Uncommon

Oral herpes (N)

Tinea pedis (N)

Blood and lymphatic system disorders

Uncommon

Idiopathic thrombocytopenic purpura (N)

Immune system disorders

Very rare

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

Metabolism and nutrition disorders

Common

Decreased appetite (N)

Uncommon

Anorexia (B)

Blood glucose disturbances (B)

Psychiatric disorders

Common

Concentration disturbance (B)

Uncommon

Delusions (B)

Depersonalisation (B)

Libido disorder (N)

Paranoid ideation (B)

Nervous system disorders

Uncommon

Ataxia (B)

Incoordination (B)

Eye disorders

Uncommon

Visual disturbance (B)

Cardiac disorders

Common

Electrocardiogram change (N)

Vascular disorders

Uncommon

Postural hypotension (B)

Vasodilatation (B)

Respiratory, thoracic and mediastinal disorders

Uncommon

Sputum increased (N)

Gastrointestinal disorders

Common

Taste disorders (B)

Hepatobiliary disorders

Uncommon

Blood bilirubin increased (N)

Jaundice (B)

Skin and subcutaneous tissue disorders

Uncommon

Exacerbation of psoriasis (B)

Seborrhea (N)

Musculoskeletal and connective tissue disorders

Uncommon

Twitching (B)

Reproductive system and breast disorders

Common

Ejaculation delayed (N)

General disorders and administration site conditions

Uncommon

Weight gain (N)

Description of selected adverse reactions

Seizures

The incidence of seizure in naltrexone/bupropion over the course of the clinical program was 0.06% (2/3,239 subjects). Among the group of subjects treated with naltrexone/bupropion, both cases of seizures were considered as serious and led to treatment discontinuation (see section 4.4). There were no cases of seizures in the placebo group.

Gastrointestinal adverse reactions

The vast majority of subjects treated with naltrexone/bupropion who experienced nausea reported the event within 4 weeks of starting treatment. Events were generally self-limited; the majority of events resolved within 4 weeks and almost all resolved by week 24. Similarly, the majority of events of constipation in subjects treated with naltrexone/bupropion were reported during the dose escalation phase. The time to resolution of constipation was similar between subjects treated with naltrexone/bupropion and subjects treated with placebo. Approximately half of the subjects treated with naltrexone/bupropion who experienced vomiting first reported the event during the dose escalation phase. Time to resolution for vomiting was typically rapid (within one week) and almost all events resolved within 4 weeks. The incidence of these common gastrointestinal adverse reactions in naltrexone/bupropion versus placebo was as follows: nausea (31.8% vs. 6.7%), constipation (18.1% vs. 7.2%), and vomiting (9.9% vs. 2.9%). The incidence of severe nausea, severe constipation, and severe vomiting was low, but was higher in subjects treated with naltrexone/bupropion compared to subjects treated with placebo (severe nausea: naltrexone/bupropion (1.9%), placebo (<0.1%); severe constipation: naltrexone/bupropion (0.6%), placebo (0.1%); severe vomiting: naltrexone/bupropion (0.7%), placebo (0.3%)). No events of nausea, constipation, or vomiting were considered serious.

Other frequent adverse reactions

The majority of subjects treated with naltrexone/bupropion who reported dizziness, headache, insomnia, or dry mouth, first reported these events during the dose escalation phase. Dry mouth may be associated with toothache and dental caries; in the subset of patients with dry mouth, a higher incidence of toothache and dental caries were observed in subjects treated with naltrexone/bupropion compared to subjects treated with placebo. The incidence of severe headache, severe dizziness, and severe insomnia was low, but was higher in subjects treated with naltrexone/bupropion compared to subjects treated with placebo (severe headache: naltrexone/bupropion (1.1%), placebo (0.3%); severe dizziness: naltrexone/bupropion (0.6%), placebo (0.2%); severe insomnia: naltrexone/bupropion (0.4%), placebo (<0.1%)). No events of dizziness, dry mouth, headache, or insomnia in subjects treated with naltrexone/bupropion were considered serious.

Elderly patients

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

Type 2 diabetes

Patients with type 2 diabetes treated with naltrexone/bupropion demonstrated a higher incidence of gastrointestinal adverse reactions, primarily nausea, vomiting, and diarrhoea, than subjects without diabetes. Patients with type 2 diabetes may be more prone to these events due to concomitant medicinal product use (e.g., metformin) or may be more likely to have underlying gastrointestinal disorders (e.g., gastroparesis) predisposing to gastrointestinal symptoms.

Renal impairment

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system on Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Human overdose experience

There is no clinical experience with overdose with combined use of bupropion and naltrexone. The maximum daily dose of combined use of bupropion and naltrexone administered in clinical trials contained 50 mg naltrexone hydrochloride and 400 mg bupropion hydrochloride. The most serious clinical implications of combined use of bupropion and naltrexone overdose are likely related to bupropion.

Bupropion

Acute ingestion of doses in excess of 10 times the maximum therapeutic dose of bupropion (equivalent to approximately in excess of 8 times the recommended daily dose of naltrexone/bupropion) has been reported. Seizure was reported in approximately one third of these overdose cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.

Although most subjects recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in subjects ingesting large doses of the drug. Serotonin syndrome has also been 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 recommended daily dose of naltrexone/bupropion) for up to one week showing no evidence of toxicity.

Overdose management

An adequate airway, oxygenation, and ventilation should be ensured. Cardiac rhythm and vital signs should be monitored. EEG monitoring is also recommended for the first 48 hours post-ingestion.

General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended.

Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of combined use of bupropion and naltrexone overdoses. No specific antidotes for combined use of bupropion and naltrexone are known.

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