Contrave black box warning
Contrave carries a black box warning, which is a strict label instruction that is issued by the FDA, warning users and medical professionals of an association with a serious adverse reaction which may occur. Significant evidence submitted to the FDA usually backs up such a warning and must be taken seriously by all medical professionals and patients using the medication.
In the case of Contrave, the black box warning stipulates that the drug may increase the occurrence of suicidal thoughts or behaviours, especially in adolescents and young adults using the medication. Thus, the medication is not approved for treating major depressive or psychiatric disorders. (3) The warning indicates that physicians prescribing the medication to any patient that has had such thoughts or tendencies toward suicidal behaviours in the past take extra precaution as risk may be elevated in these individuals.
Bupropion is the active ingredient responsible for Contrave’s black box warning. In general, many antidepressants are known to stimulate suicidal thoughts and behaviours in children, adolescents and young adults (i.e. those under 25 years of age) with major depressive or psychiatric disorders.
Due to the severity of the warning, all patients taking Contrave will be monitored closely for the duration of their treatment. Any indication of a low mood (depressive symptoms), restlessness, agitation or nervousness, irritability, hostility, impulsivity, mania and hypomania, insomnia, anxiety and panic attacks must be brought to the attention of the treating medical doctor. Should such symptoms worsen, especially if suicidal thoughts or behaviours occur, this must also be brought to the attention of the treating physician immediately.
Doctors will also advise close friends and family of a patient prescribed Contrave to be on the lookout for any potential changes in their loved one’s mood and behaviour and proactively inform the treating doctor should any concerns arise during treatment. This is especially important during the initial months of therapy or following any dosage adjustments (whether increased or decreased).
Should a person taking Contrave develop severe or abrupt suicidal tendencies (either thoughts, behaviours or both), major depression or worsened depression during the period of therapy, a doctor will recommend modified dosages or discontinuation of the drug.
Contrave in contraindicated in:
- Peoplewho have uncontrolled high blood pressure (hypertension)
- Those with diagnosed seizure disorders, such as epilepsy or who have a history of seizures
- People with diagnosed eating disorders such as bulimia and anorexia nervosa (*these may increase risk for seizures)
- Individuals in the process of discontinuing the use of various substances such as alcohol, anti-epileptic medications, barbiturates and benzodiazepines
- Individuals experiencing acute opioid medication withdrawal
- Individuals who are already using medications containing bupropion
- Individuals already using opioid medications or opiate agonists on a chronic / long-term basis
- Individuals taking prescribed monoamine oxidase inhibitor (MAOI) medications (Contrave may not be taken at the same time as these medications and can only be considered after discontinuing MAOIs for at least 14 days) (4)
- Individuals with allergies (or hypersensitivity) to any of the active or inactive ingredients of the medication
- Women who are pregnant
Medical concerns and adverse effects (physical conditions and diseases)
In patients with diagnosed cardiovascular difficulties, use of Contrave may:
If Contrave is prescribed, a physician will closely monitor the user, assessing their heart rate and blood pressure levels periodically.
|Diabetes mellitus (type 2)
Those with diagnosed and managed type 2 diabetic conditions intending to lose weight with Contrave treatment are at higher risk of hypoglycaemic (low blood sugar) episodes. Blood glucose levels when using Contrave along with insulin or insulin secretagogues (which stimulate insulin secretion from the pancreas) will need to be monitored closely. Dosage management is required, especially if signs of hypoglycaemia (low blood sugar) develop.
|Hepatoxicity (liver injury)
Problems with liver function may arise with use of this medication, largely due to the naltrexone content. Dysfunction can result in serious injury to the liver and cause hepatic transaminase elevations (which may be asymptomatic) or the development of hepatitis infections.
Contrave must be discontinued if symptoms of acute liver dysfunction develop, as any damage that may be incurred due to its use cannot be reversed or rectified.
Patients prone to sensitivity may experience adverse reactions following therapeutic use of Contrave. Hypersensitive reactions may include itching (pruritis), hives (urticaria), angioedema (swelling), breathing difficulties (shortness of breath or laboured breathing) and anaphylactic or anaphylactoid occurrences (i.e. adverse reactions to the medication that may be life-threatening).
In rare instances, the formation of bull’s-eye lesions (erythema multiforme) and Stevens-Johnson syndrome (a painful skin disorder) may develop.
Joint pain (arthralgia) and muscle pain (myalgia) may also occur.
|Impairment of the liver and kidneys
For patients with signs of hepatic (liver) or renal (kidney) function impairment, caution will be exercised. Lower dosages must be considered. Contrave will not be used in those with severe / end-stage dysfunction / impairment.
Mood changes, such as depression or even mania, paranoia, hallucinations, delusions, anxiety and panic, agitation, aggression or hostility and psychosis are associated with the use of this medication. Other associations include homicidal ideation (murderous thoughts), suicidal thoughts and behaviours (including attempts or suicide completion).
Mood changes may occur in individuals with or without any pre-existing psychiatric disorders, like bipolar disorder. Those with a pre-existing condition may find that symptoms worsen while on this medication.
This medication may influence normal ocular function. Notable changes may be pupillary dilation (widening of the pupils) which can result in narrow-angle glaucoma (a serious condition wherein the coloured area of the eyes, called the iris, is suddenly forced forwards or backwards – blindness can then occur within a handful of days).
|Opioid overdose (accidental)
Risk of opioid intoxication increases when Contrave is used concurrently with other opiate medications (on a chronic or intermittent basis). Lower doses of opioids may be considered but careful monitoring is required as overdosage scenarios can be life-threatening.
In those dependant on opioids for a period of time prior to Contrave treatment, a treating physician will usually initiate an opioid-free interval period before Contrave may be taken. If a patient was on short-acting varieties, an interval period of 7 – 10 days should be sufficient, but most doctors will wait for a period of 2 weeks before implementing Contrave therapy. This will allow time for opioid drug withdrawal symptoms which may include abdominal pain, nausea, vomiting and anxiety etc. to abate without risk of worsening side-effects and help to transition treatment practice safely.
The risk of seizures while on Contrave may be dose-related in some predisposed individuals. The medication is contraindicated for individuals with known susceptibility to seizures (i.e. those who have a diagnosed seizure disorder or a history of fits), but can also affect those using certain types of medications or undergoing withdrawal after discontinuing the use of specific substances such as:
Caution is advised during concurrent use with:
Seizure-potentiating metabolic conditions also warrant cautious use of this medication – such conditions can include:
Caution should also be exercised in instances where a person:
Contrave may be prescribed, but at low dosages and carefully monitored, so as to minimise any foreseeable risk factors. Discontinuation of treatment will be necessary should seizures occur. It is not recommended that therapy be re-initiated due to the high risk of seizure recurrence. (5)
Contrave medication interactions
All medications are manufactured to work with the body in a specific way. This means that the presence of a substance within the body will also affect or influence other bodily functions, structures and systems at the same time. Not all of these influences affect a person in non-harmful ways. Some adverse effects are transient (short-lived), while others can be somewhat serious.
For the most part, all medical practitioners have to take into account what may influence a person’s overall condition at the time a medication is considered for therapeutic use. Interactions and adverse effects can be expected to some degree. It is this degree, based on clinical analysis, that helps physicians weigh up the potential benefits against risk and determine the safest way to implement therapy.
Substances in the body’s system are likely to interact with one another. Interactions are thus typically classed in order to categorise the degree of risk involved. These are as follows:
- Major: Interactions experienced are determined as serious, severe or highly significant. Thus, taking Contrave with these substances is not recommended and should be avoided. The risk outweighs any significant benefit.
- Moderate: Interactions may be clinically notable, resulting in moderately significant adverse reactions. Combinations of these substances and Contrave may be avoided altogether to reduce unnecessary risk. Some combinations may be considered in specific circumstances where benefits outweigh the risks and a doctor deems it safe along with careful medical monitoring.
- Minor: Interactions experienced are considered clinically minor. Any foreseeable risks can be minimised with alternative therapy combinations where required.
The components of Contrave and how they interact with other substances
- Naltrexone and opioids: The therapeutic benefits of opioid-containing medications may be compromised by naltrexone, lessening the effects of these drugs. If intermittent opioid medication use is required, it is recommended that Contrave treatment be discontinued. Opioid therapy should also not exceed standard dosage recommendations. People in need of opioid therapy should only consider Contrave treatment after at least 7 to 10 days following discontinuation of these drugs. (6) This is to avoid severe withdrawal side-effects and possible opioid intoxication which can be life-threatening.
- Bupropion and monoamine oxidase inhibitors (MAOIs): The combination of medications is not recommended as the risk for hypertensive reactions (including high blood pressure and elevations in resting heart rate) is high. Bupropion and MAOI medications both interfere with the reuptake of norepinephrine and dopamine, and thereby increase the risk of these types of reactions. Acute toxicity of bupropion may also occur when these medication combinations are taken. Should a physician deem Contrave necessary for a patient who is currently taking MAOIs, the MAOI medication must be discontinued for at least 14 days before therapy is initiated.
- Bupropion and cytochrome P450 (CYP 450) 2D6 isozymes: Bupropion inhibits CYP4502D6 (and CYP2D6 substrates) which is mostly metabolised by the CYP2B6 isozyme. Basically, that is the medical way for saying Bupropion interferes with enzymes in the body that determine the way in which some drugs are metabolised. When this occurs, bupropion exposure increases and the therapeutic effect of the medication being taken at the same time decreases as the metabolic conversion of the other substance to its active metabolite is inhibited. If one is already taking medications metabolised by this isozyme, the lowest possible dosages must be considered when initiating Contrave therapy. Medications which are metabolised by CYP2D6 isozyme include some tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants, antipsychotics, beta-blockers used to treat high blood pressure and various cardiovascular abnormalities and antiarrhythmics.
Medications which are also classed as inducers of CYP2B6 reduce levels of bupropion and thereby decrease the efficacy of the drug. Combinations of these substances are best avoided.
- Bupropion and antidepressants, antipsychotics, xanthines and systemic corticosteroids: These medications tend to lower a person’s seizure threshold (i.e. make a person more susceptible to having a seizure). The Bupropion in Contrave can also cause seizures. When the drugs mentioned above are combined with bupropion, the seizure-inducing effects are compounded resulting in an increased risk of seizures. The severity of such occurrences is generally dose-dependent. Bupropion tends to inhibit the sufficient metabolism of tricyclic antidepressants. Increased blood serum concentrations can occur, resulting in elevated toxicity of tricyclic antidepressants.
- Bupropion and dopaminergic medications: Individuals under treatment for Parkinson’s disease can experience several problematic side-effects by combining bupropion with Levodopa or Amanadine. Side-effects can include agitation or restlessness, a lack of voluntary coordination of muscle movements (ataxia), tremors, gait difficulties, dizziness and vertigo (dopamine agonistic effects / central nervous system toxicity). Bupropion toxicity may be enhanced, stimulating adverse side-effects.
- Contrave and alcohol (ethanol): Consumption of alcohol / ethanol, especially in large quantities, should be avoided. Heavy drinkers should significantly reduce or discontinue the consumption of alcohol completely. Bupropion may reduce alcohol tolerance in some individuals.
- Bupropion and amphetamines: Urine immunoassay screening test results in individuals taking amphetamines and bupropion may lack any specificity (i.e. the drug may lead to false-positive results in these types of tests). Other testing procedures such as gas chromatography/mass spectrometry may be able to assist physicians with distinguishing between the two substances in a person’s system.
- Bupropion and nicotine: Combination of use of these two substances can result in blood pressure elevations. Indications of such an increase include chest pain (angina), dizziness, confusion and an irregular heartbeat. Dosage adjustments and periodic blood pressure readings may be required if therapy is initiated or continued.
Notable medications known to interact adversely (when co-administered with Contrave)
|Substances and medications
Eliglustat (for the treatment of Gaucher's disease)
The Bupropion content in Contrave affects the liver enzyme CYP2D6 during metabolism, elevating levels (serum concentration) of eliglustat in the system.
Pimozide (an antipsychotic used to treat abnormal excitement in the brain and severe tics)
Bupropion increases the therapeutic effect of pimozide by interacting with the metabolising enzyme, CYP2D6. This elevates levels of pimozide in the system (CYP2D6 inhibitor).
Bupropion and pimozide both reduce the threshold for seizures, making these more likely.
Isocarboxazid (monoamine oxidase inhibitor / antidepressant for the treatment of major depression)
Phenelzine (monoamine oxidase inhibitor / antidepressant for the treatment of major depression)
Rasagiline (a monoamine oxidase inhibitor for the treatment of Parkinson’s disease)
Selegiline (a monoamine oxidase inhibitor for the treatment of movement disorders and symptoms of Parkinson’s disease)
Selegiline transdermal (monoamine oxidase inhibitor for the treatment of depression)
Tranylcypromine (monoamine oxidase inhibitor for the treatment of depression)
Dopaminergic effects are increased due to bupropion monoamine oxidase inhibitors (MAOIs):
Risk of hypertensive reactions (increased blood pressure) is increased with these combinations.
Chlorpromazine (an antipsychotic used for the treatment of schizophrenia)
Clozapine (an antipsychotic used for the treatment of schizophrenia)
Dyphylline (a bronchodilator for the treatment of respiratory conditions such as asthma and bronchitis)
Escitalopram (an antidepressant for the treatment of major depression and generalised anxiety disorder)
Fluoxetine (an antidepressant for the treatment of major depression, panic disorder, obsessive compulsive disorder and some eating disorders)
Milnacipran (a selective serotonin and norepinephrine reuptake inhibitor for the treatment of fibromyalgia)
Nefazodone (a serotonin modulator for the treatment of depression)
These substances elevate toxicity levels of bupropion.
Clomipramine (a tricyclic antidepressant for the treatment of obsessive compulsive disorder, major depression, panic disorder and chronic pain)
Bupropion increases the therapeutic effect of clomipramine by interacting with the metabolising enzyme, CYP2D6. This elevates levels of clomipramine in the system (CYP2D6 inhibitor).
Cyclobenzaprine (a muscle relaxant for the treatment of skeletal muscle spasms pain symptoms of acute musculoskeletal conditions)
Linezolid (an antibiotic for the treatment of Gram-positive bacterial infections)
Lorcaserin (a serotonin receptor agonist for the treatment of obesity)
Methylene blue / methylthioninium chloride (for the treatment of methemoglobinemia)
When combined with Contrave these substances elevate serotonin levels in the body.
Fluvoxamine (an antidepressant for the treatment of obsessive compulsive disorder and major depression)
Bupropion increases the therapeutic effect of fluvoxamine by interacting with the metabolising enzyme, CYP2D6. This elevates levels of fluvoxamine in the system (CYP2D6 inhibitor).
Toxicity levels of bupropion are also elevated with combined use.
Iobenguane I 131 (for the treatment of metastatic pheochromocytoma or paraganglioma - adrenal gland tumours)
Bupropion decreases the therapeutic effect of iobenguane I 131 by reducing catecholamine uptake (depleting stores). This reduces the effectiveness of the medication.
Naldemedine (an opioid receptor antagonist for the treatment of constipation caused by opioid medication use – not related to chronic pain caused by cancer)
Naloxegol (an opioid receptor antagonist for the treatment of constipation caused by opioid medication use – not related to chronic pain caused by cancer)
The combination of Contrave with these medications elevates the effects of all medications (i.e. enhancing their adverse effects - pharmacodynamic synergism)
Acamprosate (for the treatment of alcohol dependence)
This medication elevates the toxicity levels of naltrexone found in Contrave.
Amantadine (used as an antiviral and for the treatment of Parkinson’s disease)
Levodopa (a central nervous system agent for the treatment of Parkinson’s disease symptoms)
Combined substances result in pharmacodynamic synergism.
Amitriptyline (a tricyclic antidepressant for the treatment of depression and anxiety)
Amoxapine (a tetracyclic / tricyclic antidepressant for the treatment of anxiety and depression)
Desipramine (a tricyclic antidepressant for the treatment of depression)
Dextroamphetamine (a stimulant of the central nervous system for the treatment of attention deficit hyperactivity disorder / ADHD and narcolepsy)
Doxepin (a tricyclic antidepressant for the treatment of major depression and anxiety)
Imipramine (a tricyclic antidepressant for the treatment of depression)
Lofepramine (a tricyclic antidepressant for the treatment of depression)
These substances elevate toxicity levels of bupropion in Contrave.Bupropion may also influence the therapeutic effect of the other medication by interfering with CYP2D6 enzyme metabolism.
Butabarbital (a barbiturate sleep aid used as a sedative)
Butalbital (a barbiturate, often combined aspirin or acetaminophen for the treatment of headaches and pain)
Hexobarbital (indicated as an anaesthetic agent / sedative)
The combination increases metabolism of all substances.
Apalutamide (a nonsteroidal antiandrogen for the treatment of non-metastatic prostate cancer)
This medication reduces the therapeutic effect of naltrexone found in Contrave by stimulating earlier expulsion of the substance from the body.
Aripiprazole (an atypical antipsychotic for the treatment of bipolar disorder and schizophrenia)
Atomoxetine (a norepinephrine reuptake inhibitor for the treatment of ADHD / attention deficit hyperactivity disorder)
Betaxolol (for the treatment of high blood pressure and glaucoma)
Brexpiprazole (an atypical antipsychotic for the treatment of major depression and schizophrenia)
Cannabidiol (a cannabinoid constituent of cannabis that is sometimes used to alleviate anxiety and symptoms associated with bipolar disorder, dystonia, multiple sclerosis, Parkinson’s disease, seizures and schizophrenia)
Carvedilol (for the treatment of high blood pressure and congestive heart failure)
Chloroquine (for the prevention and treatment of malaria)
Chlorpromazine (an antipsychotic medication for the treatment of schizophrenia)
Cinacalcet (a calcimimetic medication for the treatment of secondary hyperparathyroidism and individuals with detectably high levels of calcium in the blood)
Citalopram (a selective serotonin reuptake inhibitor / antidepressant for the treatment of major depression)
Clopidogrel (an antiplatelet medication used to reduce risk of stroke and heart disease)
Deutetrabenazine (a vesicular monoamine transporter 2 inhibitor for the treatment of abnormal involuntary movements / chorea associated with Huntington’s disease and tardive dyskinesia)
Dextromethorphan (a cough suppressant for the treatment of a cough)
Eluxadoline (for the treatment of diarrhoea and irritable bowel syndrome / IBS)
Fesoterodine (an antimuscarinic for the treatment of overactive bladder syndrome)
Flecainide (an antiarrhythmic agent to treat and prevent tachyarrhythmias)
Fluphenazine (an antipsychotic for the treatment of schizophrenia)
Galantamine (for the treatment of cognitive decline associated with Alzheimer’s disease and dementia)
Haloperidol (an antipsychotic for the treatment of schizophrenia, Tourette syndrome and bipolar disorder)
Hydromorphone (an opioid / analgesic for the treatment of pain)
Iloperidone (an atypical antipsychotic for the treatment of schizophrenia)
Loratadine (an antihistamine for the treatment of allergies)
Bupropion increases the therapeutic effect of these substances by interacting with the metabolising enzyme, CYP2D6. This elevates levels of these medications in the system (CYP2D6 inhibitor).
Benzhydrocodone/acetaminophen (short-term treatment combination for acute or severe pain)
Hydrocodone (a semisynthetic opioid for the treatment of pain)
The Bupropion in Contrave increases the therapeutic effect of these substances by interacting with the metabolising enzyme, CYP2D6. This elevates levels of these medications in the system (CYP2D6 inhibitor).
All of these substances combined also elevate levels of serotonin which can cause serotonin syndrome, resulting in a range of side-effects that include agitation, elevated body temperature, increased reflexes, tremor, sweating, dilated pupils, and diarrhoea.
Clomipramine (a tricyclic antidepressant for the treatment of obsessive compulsive disorder, major depression, panic disorder and chronic pain)
Cyclosporine (an immunosuppressant for the treatment of rheumatoid arthritis, psoriasis, Crohn’s disease and organ transplant rejection prevention)
Dosulepin (a tricyclic antidepressant for the treatment of depression)
Flucloxacillin (an antibiotic for the treatment of Gram-positive bacterial infections)
These substances elevate toxicity levels of the bupropion in Contrave.
Codeine (an opiate for the treatment of mild to moderate pain)
Bupropion decreases the therapeutic effect of codeine, influencing the metabolism of CYP2D6 in the liver.
Digoxin (for the treatment of congestive heart failure, atrial fibrillation and atrial flutter)
Bupropion decreases the therapeutic effect of Digoxin by stimulating renal elimination.
Dronabinol (man-made compound containing cannabinoids)
Nabilone (a synthetic cannabinoid for the treatment of neuropathic pain)
Naltrexone increases the therapeutic effect of these substances.
Efavirenz (an antiretroviral medication for the treatment of HIV/AIDS)
The therapeutic effectiveness of bupropion is decreased due to stimulated metabolism caused by Efavirenz.
Elvitegravir/cobicistat/emtricitabine/tenofovir df (a fixed dose combination medication for the treatment of HIV/AIDS)
These combined substances elevate levels of bupropion in Contrave in the body when taken concurrently.
Ioflupane I 123 (a neuro-imaging radiopharmaceutical used to help diagnose Parkinson’s disease)
Bupropion decreases the therapeutic effect of Ioflupane I 123 by binding to the dopamine transporter receptor and causing interference.
Lofexidine (an alpha2-adrenergic receptor agonist for the treatment of opioid withdrawal symptoms and high blood pressure)
Bupropion increases the therapeutic effect of this substance by interacting with the metabolising enzyme, CYP2D6. This elevates levels of lofexidine in the system (CYP2D6 inhibitor).
Lofexidine also reduces the therapeutic effect of naltrexone.
|Medications and substances which can result in minor interaction effects
Specific population precautions and Contrave7
The use of Contrave during pregnancy is contraindicated as harm to the developing foetus may occur. In addition, weight loss during pregnancy is not beneficial and may harm a developing baby, even for women who are already overweight or obese.
Should a woman fall pregnant while using Contrave, a doctor will recommend discontinuation and inform her of the potential risk to the healthy development of an unborn baby that continued use would pose.
Human and animal studies have not conclusively determined the exact adverse foetal effect which could be expected, nor to what extent harm or deformation may occur if Contrave is used during the various stages of pregnancy.
Bupropion and naltrexone components may be secreted in human breast milk. Thus, these substances can be passed on to breastfed infants. The manufacturer of Contrave therefore does not recommend that nursing mothers take this medication while breastfeeding their baby.
Food considerations when taking Contrave
It is recommended that Contrave not be administered along with the consumption of high-fat meals. The fat content can elevate systemic exposure to both the bupropion and naltrexone components of the medication. Risk of seizures may thus be increased if this medication is taken with a high-fat meal.
Types of medical monitoring parameters during treatment with Contrave
Physicians initiating treatment with contrave will consider the following in people where required:
- Periodic blood pressure, blood glucose, pulse and heart rate measurements (a baseline will be taken at the beginning of treatment to compare subsequent readings during the therapy period)
- BMI (body mass index) and weight measurements
- Liver and renal functionality assessments (baseline and periodic checks)
- Mental status assessments (at the beginning of therapy initiation, as well as when dosages are adjusted – increased or decreased) – key concerns include signs of depression, anxiety, suicidal ideation, social functioning difficulties, panic attacks, paranoia, hallucinations, delusions, homicidal ideation, aggression or hostility and mania.
3. DailyMed. 22 September 2014. LABEL: CONTRAVE- naltrexone hydrochloride and bupropion hydrochloride tablet, film coated, extended release: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed2da3a6-0614-4bea-8e82-962cbaae6428 [Accessed 23.08.2018]
4. Food and Drug Administration. Contrave - Drug Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200063s009lbl.pdf [Accessed 23.08.2018]
5. Orexigen. 4 August 2016. Orexigen Therapeutics Reports Business and Financial Results for the Second Quarter Ended June 30, 2016: https://www.sec.gov/Archives/edgar/data/1382911/000119312516671786/d172984dex991.htm [Accessed 23.08.2018]
6. Food and Drug Administration. Contrave - Drug Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200063s009lbl.pdf [Accessed 23.08.2018]
7. DailyMed. 22 September 2014. LABEL: CONTRAVE- naltrexone hydrochloride and bupropion hydrochloride tablet, film coated, extended release: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed2da3a6-0614-4bea-8e82-962cbaae6428 [Accessed 23.08.2018]