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 Adverse Reactions).
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 Contraindications). If chronic opiate therapy is required, naltrexone/bupropion treatment must be stopped. In patients requiring intermittent opiate treatment, naltrexone/bupropion therapy should be temporarily discontinued and opiate dose should not be increased above the standard dose. During naltrexone/bupropion clinical studies, the use of concomitant opioid or opioid-like medicinal products, including analgesics or antitussives were excluded. However, approximately 12% of subjects took a concomitant opioid or opioid-like medicinal product while enrolled in the naltrexone/bupropion clinical studies, the majority of whom continued study treatment without interruption of naltrexone/bupropion dose, without untoward consequences.
Attempt to overcome blockade: The attempt to overcome any naltrexone opioid blockade by administering large amounts of exogenous opioids is very dangerous and may lead to a fatal overdose or life endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be aware that they may be more sensitive to lower doses of opioids after naltrexone/bupropion treatment is discontinued.
Allergic reactions: Anaphylactoid/anaphylactic reactions characterised by symptoms such as pruritus, urticaria, angioedema, and dyspnoea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking naltrexone/bupropion and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, oedema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness. Patients should be advised to notify their prescribing physician if they experience these symptoms. If serum sickness is suspected, naltrexone/bupropion should be discontinued.
Elevation of blood pressure: Early, transient mean increases from baseline in systolic and diastolic blood pressure of up to 1 mmHg were observed in naltrexone/bupropion Phase 3 clinical trials. In a cardiovascular outcomes trial (CVOT) of patients at increased risk of a cardiovascular event, mean increases from baseline in systolic and diastolic blood pressure of approximately 1 mmHg compared to placebo were also observed. In clinical practice with other bupropion containing products, hypertension, in some cases severe and requiring acute treatment, has been reported.
Blood pressure and pulse should be measured prior to initiation of therapy with naltrexone/bupropion and should be assessed at regular intervals consistent with usual clinical practice. If patients experience clinically relevant and sustained increases in blood pressure or pulse rate as a result of naltrexone/bupropion treatment, it should be discontinued.
Naltrexone/bupropion should be given with caution to those patients with controlled hypertension and must not be given to patients with uncontrolled hypertension (see Contraindications).
Cardiovascular disease: There is no clinical experience establishing the safety of naltrexone/bupropion in patients with a recent history of myocardial infarction, unstable heart disease or NYHA class III or IV congestive heart failure. Naltrexone/bupropion should be used with caution in patients with active coronary artery disease (e.g., ongoing angina or recent history of myocardial infarction) or history of cerebrovascular disease.
Hepatotoxicity: In naltrexone/bupropion completed clinical studies, where naltrexone hydrochloride daily doses ranged from 16 mg to 48 mg, drug-induced liver injury (DILI) was reported. There have also been cases of elevated liver enzymes from post-marketing reporting. A patient with suspected DILI should stop taking naltrexone/bupropion.
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 Dosage & Administration, Adverse Reactions, and Pharmacology: Pharmacokinetics under Actions). 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 Dosage & Administration, Contraindications, and Pharmacology: Pharmacokinetics under Actions). 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 Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Neuropsychiatric symptoms and activation of mania: Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar medicinal products for major depressive disorder. No activation of mania or hypomania was reported in the clinical trials evaluating effects of naltrexone/bupropion in obese subjects, which excluded subjects receiving antidepressants. Naltrexone/bupropion should be used cautiously in patients with a history of mania.
Data in animals suggest a potential for abuse of bupropion. However, studies on abuse liability in humans and extensive clinical experience show that bupropion has low abuse potential.
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 Effects on ability to drive and use machines as follows and Adverse Reactions).
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 as previously mentioned and Adverse Reactions).
Use in the Elderly: 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.