Bupropion and Naltrexone interacts in the following cases:
Administration of naltrexone/bupropion with inhibitors or inducers of UGT1A2 and UGT2B7 should be undertaken with caution as these may alter the exposure of naltrexone.
In patients with moderate or severe renal impairment, the maximum recommended daily dose for naltrexone/bupropion is 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the morning and 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the evening. It is recommended that patients with moderate or severe renal impairment initiate treatment with 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the morning for the first week of treatment, and escalate to 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the morning and in the evening from week 2 onwards.
In patients with mild hepatic impairment, the maximum recommended daily dose for naltrexone/bupropion is 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the morning and 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the evening). It is recommended that patients with mild hepatic impairment initiate treatment with 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the morning for the first week of treatment, and escalate to 8 mg naltrexone hydrochloride / 90 mg bupropion hydrochloride in the morning and in the evening from week 2 onwards. Degree of hepatic impairment should be assessed using the Child-Pugh score.
Naltrexone/bupropion is not recommended in patients with moderate hepatic impairment.
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.
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.
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.
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.
Naltrexone/bupropion should be given with caution to those patients with controlled hypertension.
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.
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; 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.
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.
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.
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.
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).
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). 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 fixeddose 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.
** 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.
*** 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).
***** 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) |
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. There were no cases of seizures in the placebo group.
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.
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 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.
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.
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.
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