Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been foun ...

, an opioid antagonist, and

bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...

, an aminoketone antidepressant. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight. In September 2014, a

sustained release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

formulation of the drug was approved for marketing in the United States under the brand name Contrave. The combination was subsequently approved in the

European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are located primarily in Europe, Europe. The union has a total area of ...

in the spring of 2015, where it is sold under the name Mysimba. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. It was approved in Canada under the Contrave brand name in 2018.

Medical uses

Naltrexone/bupropion is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, as

Anti-obesity medication Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control weight. These medications alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absor ...

for the management of weight in adults with an initial

body mass index Body mass index (BMI) is a value derived from the mass ( weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and ...

(BMI) of: * 30 kg/m² (obese), or * 27 kg/m² to < 30 kg/m², (overweight) in the presence of one or more weight-related comorbidities, like

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...

dyslipidaemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

, or controlled

high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

Available forms

Each Contrave tablet contains 8 mg naltrexone and 90 mg bupropion.https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf Once full dosing is reached (after 4 weeks of administration), the total dosage of Contrave for overweightness or obesity is two tablets twice daily or 32 mg naltrexone and 360 mg bupropion per day.

Contraindications

The manufacturer recommends against its use in people that have/are: * History of

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

* History of an eating disorder such as

bulimia nervosa Bulimia nervosa, also known as simply bulimia, is an eating disorder characterized by binge eating followed by purging or fasting, and excessive concern with body shape and weight. The aim of this activity is to expel the body of calories eaten ...

anorexia nervosa Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

* Taking opioid pain medicines, taking medicines to stop opioid addiction, or are in opiate withdrawal * Taking an MAOI or have taken an MAOI in the last 14 days *

Pregnant Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

* Abruptly stopped using: alcohol,

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

barbiturates Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...

, or

antiepileptic drugs Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

Adverse effects

The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) has put a

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that i ...

onto this medicine because it may affect mood and increase the likelihood of suicidal thoughts in people under 25 years old. This is attributed to the bupropion component, as antidepressants have been associated with increased risk of suicidal thoughts, but not suicide, and only in people younger than 25. The safety and effectiveness in children under the age of 18 has not been studied.

Mechanism of action

Individually, naltrexone and bupropion each target pathways in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

that influence appetite and energy use. *Bupropion is a

reuptake inhibitor Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

and

releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the synapse, release of a monoamine neurotransmitter from the synapse, presynaptic neuron into the synapse, leading to an increase in the extracellular conc ...

of both

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

and

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...

, and a

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

, and it activates

proopiomelanocortin Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the ...

(POMC) neurons in the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

which give an effect downstream, resulting in loss of appetite and increased energy output. The POMC is regulated by endogenous opioids via opioid-mediated

negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

. *Naltrexone is a pure opioid antagonist, which further augments bupropion's activation of the POMC. Combined, naltrexone/bupropion has an effect on the reward pathway that results in reduced food craving. In 2009,

Monash University Monash University () is a public research university based in Melbourne, Victoria, Australia. Named for prominent World War I general Sir John Monash, it was founded in 1958 and is the second oldest university in the state. The university has ...

physiologist Michael Cowley was awarded one of

Australia Australia, officially the Commonwealth of Australia, is a sovereign country comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands. With an area of , Australia is the largest country by ...

's top research honors, the Commonwealth Science Minister's Prize for Life Scientist of the Year, in recognition of his elucidation of these pathways, which led to the development of the combination medication.

History

Orexigen submitted a New Drug Application (NDA) for this drug combination to the U.S.

(FDA) on 31 March 2010. Having paid a fee under the

Prescription Drug User Fee Act The ''Prescription Drug User Fee Act'' (PDUFA) was a law passed by the United States Congress in 1992 which allowed the Food and Drug Administration (FDA) to collect fees from drug manufacturers to fund the new drug approval process. The Act prov ...

, Orexigen was given a deadline for the FDA to approve or reject the drug of 31 January 2011. On 7 December 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave, and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study. Subsequently, on 2 February 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered. It was ultimately approved in the United States in the fall of 2014. In December 2014, the EU's

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regardin ...

(CHMP) endorsed the combination for licensure as an obesity medication when used alongside diet and exercise. Approval was granted in late March 2015. In May 2015, Orexigen ended a safety study of its diet drug earlier than planned, because an independent panel of experts says the drug maker “inappropriately” compromised the trial by prematurely releasing interim data. The early data release reported a reduction in heart attacks that was no longer observed when a more complete view of the data was analyzed. In 2018, Orexigen sold its assets, including Contrave, to Nalpropion Pharmaceuticals. On 22 September 2020, the FDA issued a Warning Letter to Nalpropion Pharmaceuticals LLC on concerns of a sponsored Google link making "false or misleading claims about the risks associated with and efficacy of Contrave" on multiple issues. Nalproprion subsequently issued "An important correction from CONTRAVE® (naltrexone HCl/bupropion HCl) Extended-Release Tablets" https://www.correctiveadvertisementforcontrave.com/

Marketing and sales

The sustained-release formulation, Contrave, is marketed by

Takeda is a Japanese family name.1990 Census Name Files< ...

under license from the combination medication's developer, Orexigen Therapeutics. As of 2015, Orexigen received 20% of net sales from Takeda. At the time of its approval by the FDA,

Wells Fargo Wells Fargo & Company is an American multinational financial services company with corporate headquarters in San Francisco, California; operational headquarters in Manhattan; and managerial offices throughout the United States and intern ...

analyst Matthew Andrews estimated that Contrave's U.S. sales would reach approximately in 2016, exceeding that of the dominant alternative obesity medications lorcaserin and phentermine/topiramate. Despite being initially impeded by technical issues, the growth in filled prescriptions in the first months after approval was very rapid — substantially exceeding the equivalent early uptake of either of the two alternative medications just cited. The first quarter of sales for Contrave (Q1 2015) showed net sales of . Despite having been approved for use in Europe in March 2015, sales of Contrave have not begun as Orexigen has not yet found a marketing partner.

References

External links

* {{DEFAULTSORT:Naltrexone Bupropion Anorectics Antiobesity drugs Combination drugs Kappa-opioid receptor antagonists Mu-opioid receptor antagonists Norepinephrine releasing agents Norepinephrine reuptake inhibitors Nicotinic antagonists