Mysimba · 4.3 Contraindications · 1

HOS-096906 · has-adverse-reaction-information · PDF-Seite 11

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. 11 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

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HOS-096902 · has-contraindication-information · PDF-Seite 3

• 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, patients 3  treated 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 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)

HOS-096901 · has-indication-information · PDF-Seite 2

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).

HOS-096904 · has-interaction-information · PDF-Seite 8

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). 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 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. 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 8 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 ci

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HOS-096905 · has-pregnancy-information · PDF-Seite 10

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. 10 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).

HOS-096903 · has-warning-information · PDF-Seite 4

The safety and tolerability of naltrexone/bupropion should be assessed at regular intervals. The treatment should be discontinued if there are concerns with the safety or tolerability of ongoing treatment, including concerns about increased blood pressure (see section 4.8). Suicide and suicidal behaviour Naltrexone/bupropion contains bupropion. Bupropion is indicated for the treatment of depression in some countries. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult subjects with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in subjects less than 25 years old. Although in placebo-controlled clinical trials with naltrexone/bupropion for the treatment of obesity in adult subjects, no suicides or suicide attempts were reported in studies up to 56 weeks duration with naltrexone/bupropion, suicidality events (including suicidal ideation) have been reported in subjects of all ages treated with naltrexone/bupropion post-marketing. Close supervision of patients, particularly those at high risk, should accompany therapy with naltrexone/bupropion especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present. Seizures Bupropion is associated with a dose-related risk of seizures, with bupropion sustained release (SR) 300 mg yielding an estimated seizure incidence of 0.1%. Plasma concentrations of bupropion and metabolites of bupropion following single-dose administration of 180 mg of bupropion as naltrexone/bupropion tablets are comparable to concentrations observed after single-dose administration of bupropion SR 150 mg; however, no study has been conducted that determined the concentrations of bupropion and metabolites of bupropion after repeated dosing of naltrexone/bupropion tablets compared to bupropion SR tablets. As it is unknown whether the risk for seizure with bupropion is related to bupropion or a metabolite of bupropion, and there are no data demonstrating comparability of plasma concentrations with repeated dosing, there is uncertainty whether repeated-dose administration naltrexone/bupropion may be associated with a similar rate of seizures as bupropion SR 300 mg. The incidence of seizure in subjects receiving naltrexone/b

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