Naltrexone Hydrochloride/ Bupropion Hydrochloride

Registered South African indications:

• Management of weight

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• End-stage renal failure
• Severe hepatic impairment
• Uncontrolled hypertension
• Current seizure disorder
• History of seizures
• Known central nervous system tumour
• Acute alcohol or benzodiazepine withdrawal
• Acute opiate withdrawal
• History of bipolar disorder
• Current or previous diagnosis of bulimia or anorexia nervosa
• Current dependence on chronic opioids or opiate agonists (e.g., methadone)
• Children <18 years of age (South African manufacturer recommendations)
• Coadministration with treatment containing bupropion or naltrexone
• Coadministration of monoamine oxidase inhibitors or within 14 days of their use

Cautions

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment
• Mild to moderate hepatic impairment
  - Suspected drug-induced liver injury (DILI)
• Elderly (>65 years)
• Psychiatric disorders
  - Mood disorders
• History of mania
• High risk of suicide and suicidal behaviour
  - Clinical worsening
  - Unusual changes in behaviour
• Predisposing factors that increase risk of seizures
  - History of head trauma
  - Excessive use of alcohol
  - Cocaine or stimulant addiction
  - Diabetes mellitus
  - Hypoglycaemia
  - Coadministration with antidiabetic agents
  - Coadministration with agents that lower seizure threshold
• Controlled hypertension
• Active coronary artery disease
  - Ongoing angina
  - Recent history of myocardial infarction 
• Unstable heart disease 
• NYHA class III or IV congestive heart failure
• History of cerebrovascular disease
• Risk of serotonin syndrome
   (See additional prescribing points)
• Attempts to overcome blockade
  (See additional prescribing points)
• Use of opioids after discontinuation of treatment
• Galactose intolerance (e.g. galactosaemia)
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Fructose intolerance
• Coadministration with chronic or intermittent opiate therapy
   (See additional prescribing points)
• Coadministration with serotonergic agents
   (See additional prescribing points)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment
• Mild to moderate hepatic impairment
  - Suspected drug-induced liver injury (DILI)
• Elderly (>65 years)
• Psychiatric disorders
  - Mood disorders
• History of mania
• High risk of suicide and suicidal behaviour
  - Clinical worsening
  - Unusual changes in behaviour
• Predisposing factors that increase risk of seizures
  - History of head trauma
  - Excessive use of alcohol
  - Cocaine or stimulant addiction
  - Diabetes mellitus
  - Hypoglycaemia
  - Coadministration with antidiabetic agents
  - Coadministration with agents that lower seizure threshold
• Controlled hypertension
• Active coronary artery disease
  - Ongoing angina
  - Recent history of myocardial infarction
• Unstable heart disease
• NYHA class III or IV congestive heart failure
• History of cerebrovascular disease
• Risk of serotonin syndrome
  (See additional prescribing points)
• Attempts to overcome blockade
  (See additional prescribing points)
• Use of opioids after discontinuation of treatment
• Alcohol abuse
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• Coadministration with chronic or intermittent opiate therapy
   (See additional prescribing points)
• Coadministration with serotonergic agents
   (See additional prescribing points)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Management of weight
- With an initial body mass index (BMI) of >30kg/m² (obese)
- With an initial BMI of >27-30kg/m2 (overweight) in the presence of one or more weight-related co-morbidities

Naltrexone Hydrochloride/ Bupropion Hydrochloride
8/90 (mg)

• Oral (tab): Week 1: 1 tab, dly in the morning; Week 2: 1 tab, 12hrly in the morning and evening; Week 3: 2 tab, in the morning and 1 tab, in the evening; Maintenance: Week 4 onwards: 2 tab, 12hrly in the morning and evening; Max: 4 tab/24hrs

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Should be administered as an adjunct to a reduced calorie diet and increased physical activity

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Weight related comorbidities include type 2 diabetes mellitus, dyslipidaemia or controlled hypertension

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Upon initiating treatment, the dose should be escalated over a 4 week period

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Treatment of naltrexone hydrochloride/ bupropion hydrochloride should be discontinued after 16 weeks if patients have not lost at least 5% of their initial body weight

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The need for continued treatment should be evaluated after 16 weeks and re-evaluated annually

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

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The tablets should be swallowed whole with some water. The tablets should preferably be taken with food. The tablets should not be cut, chewed or crushed

Not established for use in children below 18 years

Pregnancy

• Caution; positive evidence of risk in animal studies
• There are no or limited amounts of data from the use of naltrexone hydrochloride/ bupropion hydrochloride 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 hydrochloride/ bupropion hydrochloride should not be used during pregnancy or in women currently attempting to become pregnant

Breastfeeding

• Caution; not recommended 
• 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 breastfed, a risk to the newborns/ infants cannot be excluded
• Naltrexone hydrochloride/ bupropion hydrochloride should not be used during breastfeeding

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 hydrochloride/ bupropion hydrochloride. The relevance of these observations to human fertility is not known

Renal Impairment

South African manufacturer recommendations

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; dose adjustment recommended 
  Oral (tab): 1 tab, 12hrly in the morning and evening; Max: 2 tab/24hrs
  For individuals who are at elevated risk for renal impairment, in particular patients with diabetes or elderly individuals, eGFR should be assessed prior to initiating therapy with naltrexone hydrochloride/ bupropion hydrochloride
• End-stage renal failure: Contraindicated 

International manufacturer recommendations

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; dose adjustment recommended 
  Oral (tab): Week 1: 1 tab, dly in the morning; Week 2 onwards: 1 tab, 12hrly in the morning and evening; Max: 2 tab/24hrs
  For individuals who are at elevated risk for renal impairment, in particular patients with diabetes or elderly individuals, eGFR should be assessed prior to initiating therapy with naltrexone hydrochloride/ bupropion hydrochloride
• End-stage renal failure: Contraindicated 

Hepatic Impairment

South African manufacturer recommendations

• Mild to moderate: Caution; not recommended
  Naltrexone hydrochloride/ bupropion hydrochloride is not recommended in patients with mild to moderate hepatic impairment
• Severe: Contraindicated 

International manufacturer recommendations

• Mild: Caution; dose adjustment recommended 
  Oral (tab): Week 1: 1 tab, dly in the morning; Week 2 onwards: 1 tab, 12hrly in the morning and evening; Max: 2 tab/24hrs
• Moderate: Caution; not recommended for use
  Naltrexone hydrochloride/ bupropion hydrochloride is not recommended in patients with moderate hepatic impairment
• Severe: Contraindicated 
  Degree of hepatic impairment should be assessed using the Child-Pugh score

Elderly

• >65 years: Caution; no dose adjustment recommended 
• >75 years: Caution; not recommended for use 
  For individuals who are at elevated risk for renal impairment, in particular patients with diabetes or elderly individuals, eGFR should be assessed prior to initiating therapy with naltrexone hydrochloride/ bupropion hydrochloride

Drugs in Sport

• Permitted - No warnings

Naltrexone hydrochloride/ bupropion hydrochloride
Central Nervous System Disorders

• Headache
• Anxiety
• Insomnia
• Dizziness
• Tremor
• Dysgeusia
• Lethargy
• Somnolence
• Feeling jittery
• Irritability
• Abnormal dreams
• Agitation
• Mood swings
• Nervousness
• Tension
• Dissociation (feeling spacey)
• Intention tremor
• Balance disorder
• Amnesia
• Feeling abnormal
• Feeling hot
• Hallucination
• Loss of consciousness
• Paraesthesia
• Presyncope
• Seizure
  - Generalised tonic-clonic seizures
• Post-ictal confusion
• Memory impairment
• Syncope
• 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
• Dystonia
• Parkinsonism
• Restlessness
• Serotonin syndrome

Cardiovascular Disorders

• Palpitations
• Increased heart rate
• Hot flush
• Hypertension
  - Increased blood pressure
  - Hypertensive crisis
• Tachycardia
• Chest pain
• Blood pressure fluctuation

Respiratory Disorders

• Cough
• Dysphonia
• Dyspnoea
• Nasal congestion
• Nasal discomfort
• Oropharyngeal pain
• Rhinorrhea
• Sinus disorder
• Sneezing
• Yawning

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Dry mouth
• Abdominal pain
  - Upper abdominal pain
  - Lower abdominal pain
  - Abdominal discomfort
• Dyspepsia
• Eructation
• Haematochezia
• Hernia
• Lip swelling
• Dental caries
• Toothache
• Diarrhoea
• Flatulence
• Haemorrhoids
• Ulcer

Hepatobiliary Disorders

• Cholecystitis
• Increased hepatic enzymes
  - Increased alanine aminotransferase (ALT)
  - Increased aspartate aminotransferase (AST)
• Drug-induced liver injury (DILI)
• Hepatitis

Genitourinary Disorders

• Increased blood creatinine
• Erectile dysfunction
• Micturition urgency
• Dysuria
• Pollakiuria
• Urinary frequency and/or retention
• Irregular menstruation
• Vaginal haemorrhage
• Vulvovaginal dryness

Endocrine and Metabolic Disorders

• Dehydration
• Increased appetite
• Thirst
• Increased energy

Musculoskeletal Disorders

• Jaw pain
• Arthralgia
• Groin pain
• Myalgia
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Pruritus
• Alopecia
• Rash
• Urticaria
• Acne
• Erythema multiforme
• Stevens Johnson syndrome
• Cutaneous lupus erythematosus
• Aggravated systemic lupus erythematosus syndrome

Immune, Blood and Lymphatic System Disorders

• Decreased haematocrit
• Decreased lymphocyte count
• Hypersensitivity
• Lymphadenopathy
• Angioedema
• Peripheral coldness
• Pyrexia
• Chills

Sensory Disorders

• Tinnitus
• Vertigo
• Motion sickness
• Ear discomfort
• Ear pain
• Eye irritation
• Eye pain or asthenopia
• Eye swelling
• Increased lacrimation
• Photophobia
• Blurred vision

Naltrexone hydrochloride
Central Nervous System Disorders

• Libido disorder

Cardiovascular Disorders

• Change in electrocardiogram

Respiratory Disorders

• Increased sputum

Gastrointestinal Disorders

• Oral herpes

Hepatobiliary Disorders

• Increased blood bilirubin

Genitourinary Disorders

• Delayed ejaculation

Endocrine and Metabolic Disorders

• Decreased appetite
• Weight gain

Skin and Subcutaneous Tissue Disorders

• Tinea pedis
• Seborrhea

Immune, Blood and Lymphatic System Disorders

• Idiopathic thrombocytopenic purpura

Bupropion hydrochloride
Central Nervous System Disorders

• Concentration disturbance
• Delusions
• Depersonalisation
• Ataxia
• Incoordination 
• Paranoid ideation

Cardiovascular Disorders

• Postural hypotension
• Vasodilatation

Hepatobiliary Disorders

• Jaundice

Endocrine and Metabolic Disorders

• Anorexia
• Blood glucose disturbances

Musculoskeletal Disorders

• Twitching

Skin and Subcutaneous Tissue Disorders

• Exacerbation of psoriasis

Immune, Blood and Lymphatic System Disorders

• More severe hypersensitivity reactions
  - Angioedema
  - Dyspnoea
  - Bronchospasm
  - Anaphylactic shock
• Delayed hypersensitivity
  - Arthralgia
  - Myalgia
  - Fever
  - Rash
  - Other symptoms suggestive of delayed hypersensitivity
• Anaphylactoid/ anaphylactic reactions
  - Pruritus
  - Urticaria
  - Rash
  - Angioedema
  - Dyspnoea
  - Hives
  - Chest pain
  - Shortness of breath
  - Oedema
•  Erythema multiforme
• Stevens-Johnson syndrome
• Anaphylactic shock

Sensory Disorders

• Visual disturbance
• Taste disorders

• CYP2D6 substrates
• Venlafaxine
• Antipsychotics
• Haloperidol
• Risperidone
• Thioridazine
• Tricyclic antidepressants
• Desipramine
• Imipramine
• Paroxetine
• Beta-blockers
• Metoprolol
• Tamoxifen
• Monoamine oxidase inhibitors
• Opioid containing preparations
  (See additional prescribing points)
• Opiate agonists
• Methadone
• Levodopa
• Amantadine
• Cocaine
• Stimulants
• Agents that lower the seizure threshold
  (See additional prescribing points)
• Antimalarial agents
• Tramadol
• Theophylline
• Systemic steroids
• Quinolones
• Sedating antihistamines
• Insulin
• Oral diabetic agents
• Selective serotonin reuptake inhibitors
• Selective norepinephrine reuptake inhibitors
• CYP2B6 substrates
• Cyclophosphamide
• Ifosfamide
• CYP2B6 inhibitors
• Orphenadrine
• Ticlopidine
• Clopidogrel
• CYP2B6 inducers
• Carbamazepine
• Phenytoin
• Ritonavir
• Efavirenz
• Type 1C antiarrhythmics
• Propafenone
• Flecainide
• UGT 1A2 inhibitors
• UGT 1A2 inducers
• UGT 2B7 inhibitors
• UGT 2B7 inducers
• Agents known to inhibit metabolism
• Valproate
• Digoxin

Other interactions

• Alcohol

• Blood pressure
• Heart rate
• Blood glucose
• Weight
• Body mass index (BMI)
• Renal function
• Hepatic function

Additional observations

• Mental status for depression
• Suicidal ideation at initiation or when doses are adjusted
• Clinical worsening
• Unusual changes in behaviour
• Anxiety
• Social functioning
• Mania
• Panic attacks

Opioid analgesics

• Naltrexone hydrochloride/ bupropion hydrochloride is contraindicated in patients currently dependent on chronic opioid or opiate agonist therapy (e.g., methadone), or patients in acute opiate withdrawal
• Due to the antagonistic effect of naltrexone at the opioid receptor, patients taking naltrexone hydrochloride/ bupropion hydrochloride 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 hydrochloride/ bupropion hydrochloride therapy should be temporarily discontinued and opiate dose should not be increased above the standard dose
• If chronic opiate therapy is required, naltrexone hydrochloride/ bupropion hydrochloride treatment must be stopped
• Naltrexone hydrochloride/ bupropion hydrochloride may be used with caution after chronic opioid use has been stopped for 7 to 10 days in order to prevent precipitation of withdrawal
• 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 treatment is discontinued

Serotonin Syndrome

• There have been post-marketing reports of serotonin syndrome, a potentially life threatening condition, when naltrexone hydrochloride/ bupropion hydrochloride was coadministered with a serotonergic agent, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine re-uptake inhibitors (SNRIs)
• 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, discontinuation of therapy should be considered

Predisposing factors that may increase the risk of seizures

• Caution should be used when prescribing naltrexone hydrochloride/ bupropion hydrochloride to patients with predisposing factors that may increase the risk of seizures including; history of head trauma, excessive use of alcohol or addiction to cocaine or stimulants
• The risk of seizure is also related to patient factors, clinical situations, and concomitant medicinal agents, which must be considered in the selection of patients treated with naltrexone hydrochloride/ bupropion hydrochloride
• Therapy should be discontinued and not restarted in patients who experience a seizure while being treated with naltrexone hydrochloride/ bupropion hydrochloride
• As treatment with naltrexone hydrochloride/ bupropion hydrochloride may result in lowered glucose in patients with diabetes, the dose of insulin and/or oral diabetic agents should be assessed to minimise the risk of hypoglycaemia, which could predispose patients to seizure
• Coadministration of agents that may lower the seizure threshold include antipsychotics, antidepressants, antimalarial agents, tramadol, theophylline, systemic steroids, quinolones and sedating antihistamines
• The consumption of alcohol during treatment should be minimised or avoided

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 agents for major depressive disorder
• No activation of mania or hypomania was reported in the clinical trials evaluating effects of naltrexone hydrochloride/ bupropion hydrochloride in obese subjects, which excluded subjects receiving antidepressants
• Naltrexone hydrochloride/ bupropion hydrochloride 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

The exact neurochemical appetite suppressant effects of naltrexone hydrochloride/ bupropion hydrochloride are not fully understood. The medicinal product has two components: naltrexone hydrochloride, a mu-opioid antagonist, and bupropion hydrochloride, a weak inhibitor of neuronal dopamine and norepinephrine reuptake. These components affect two principal areas of the brain, specifically the arcuate nucleus of the hypothalamus and the mesolimbic dopaminergic reward system.

In the arcuate nucleus of the hypothalamus, bupropion hydrochloride stimulates pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α-MSH), which in turn binds to and stimulates melanocortin 4 receptors (MC4-R). When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptors. Binding of β-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMC neurons leading to a decrease in the release of α-MSH. Blocking this inhibitory feedback loop with naltrexone hydrochloride is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying the effects of bupropion hydrochloride on energy balance. Preclinical data suggests that naltrexone hydrochloride and bupropion hydrochloride may have greater than additive effects in this region to reduce food intake when administered together.

COMBINATION PREPARATIONS

Naltrexone hydrochloride/ Bupropion hydrochloride

Tablet 8mg/90mg

• Contrave (Acino Pharma) originator