Bupropion

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Bupropion
Skeletal formula of bupropion
Ball-and-stick model of the (S) isomer of the bupropion molecule
1 : 1 mixture (racemate)
Clinical data
Pronunciation/bjˈprpiɒn/
bew-PROH-pee-on
Trade namesWellbutrin, Zyban, others
Other namesAmfebutamone; 3-Chloro-N-tert-butyl-β-keto-α-methylphenethylamine;
3- Chloro-N-tert-butyl-β-ketoamphetamine;
Bupropion hydrochloride[1]
AHFS/Drugs.comMonograph
MedlinePlusa695033
License data
Pregnancy
category
Routes of
administration
Medical: By mouth
Recreational: by mouth, insufflation, intravenous
Drug classAntidepressants
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding84% (bupropion), 77% (hydroxybupropion metabolite), 42% (threohydrobupropion metabolite)[3]
MetabolismLiver (mostly CYP2B6-mediated hydroxylation, but with some contributions from CYP1A2, CYP2A6, CYP2C9, CYP3A4, CYP2E1 and CYP2C19)[3][6][4][7]
Elimination half-life12–30 hours[4][5]
ExcretionRenal (87%; 0.5% unchanged), faecal (10%)[3][6][4]
Identifiers
  • (RS)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO
Molar mass239.74 g·mol−1
3D model (JSmol)
  • O=C(C(C)NC(C)(C)C)C1=CC=CC(Cl)=C1
  • InChI=1S/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3 checkY
  • Key:SNPPWIUOZRMYNY-UHFFFAOYSA-N checkY
  (verify)

Bupropion, sold under the brand names Wellbutrin and Zyban among others, is a medication primarily used to treat major depressive disorder and to support smoking cessation.[8] It is an effective antidepressant on its own, but it is also used as an add-on medication in cases of incomplete response to first-line antidepressants.[8][9] Bupropion is taken in tablet form and is available only by prescription in industrialized countries.[8]

Common side effects of bupropion include a dry mouth, difficulty sleeping, agitation, and headaches.[8] Serious side effects include an increased risk for epileptic seizures and suicide.[8] In comparison to some other antidepressants, bupropion may have a lower rate of sexual dysfunction or sleepiness and may result in weight loss.[10] It is unclear if its use during pregnancy or breastfeeding is safe.[8][2]

Bupropion is an atypical antidepressant.[11] It acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) and a nicotinic receptor antagonist.[10][12][13] Chemically, it is an aminoketone that belongs to the class of substituted cathinones and more generally that of substituted amphetamines and substituted phenethylamines.[1][14]

Bupropion was first made by chemist Nariman Mehta in 1969, and patented by Burroughs Wellcome in 1974.[15] It was first approved for medical use in the United States in 1985.[8] It was originally called by the generic name amfebutamone, before being renamed in 2000.[16] In 2018, it was the 27th most commonly prescribed medication in the United States, with more than 24 million prescriptions.[17][18]

Medical uses[edit]

Wellbutrin XL

Depression[edit]

A majority of controlled clinical trials support efficacy of bupropion for the treatment of depression.[19][20][21] However, the overall quality of the evidence is low,[21][20] with one meta-analysis, for example, finding small[21] effect size of bupropion in depression and another - large[20] effect size. Comparative head-to-head clinical trials indicate that bupropion is similar in efficacy against depression to fluoxetine, sertraline, paroxetine, and venlafaxine.[20]

Given over the fall and winter months, bupropion prevents development of depression in those who suffer from recurring seasonal affective disorder: 15% of participants on bupropion experienced a major depressive episode vs 27% of those on placebo.[22] Bupropion also improves depression in bipolar disorder, with the efficacy and risk of affective switch being similar to other antidepressants.[23]

Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo.[20][24] Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants.[20] Bupropion treatment also is not associated with the sleepiness that may be produced by other antidepressants.[25] Bupropion is more effective than selective serotonin reuptake inhibitors (SSRIs) at improving symptoms of hypersomnia and fatigue in depressed patients.[26][27] There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of depression with high anxiety; they are equivalent for the depression with moderate or low anxiety.[28]

The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI,[29] and it is supported by clinical trials;[20] however, it appears to be inferior to the addition of atypical antipsychotic aripiprazole.[30]

Smoking cessation[edit]

Prescribed as an aid for smoking cessation bupropion reduces the severity of craving for tobacco and withdrawal symptoms[31][32][33] such as depressed mood, irritability, difficulty concentrating, and increased appetite.[34] Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible.[34]

The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course.[34][35] After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year.[36] It is unclear whether extending bupropion treatment helps to prevent relapse of smoking.[37]

Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6 fold as compared to placebo. In this respect, bupropion is as effective as nicotine replacement therapy but inferior to varenicline. Combining bupropion and nicotine replacement therapy does not improve the quitting rate.[38]

In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits.[39] The evidence for its use to aid smoking cessation in pregnant women is insufficient.[40]

Attention deficit hyperactivity disorder[edit]

The treatment of ADHD is not an approved indication of bupropion, and it is not mentioned in the current (2019) guideline on the ADHD treatment from the American Academy of Pediatrics.[41] Systematic reviews of bupropion for the treatment of ADHD in both adults and children note that bupropion may be effective for ADHD but warn that this conclusion has to be interpreted with caution, because clinical trials were of low quality due to small sizes and risk of bias.[42][43][44][45]

Sexual dysfunction[edit]

Bupropion is less likely than other antidepressants to cause sexual dysfunction.[46] A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction[47] including sexual dysfunction induced by SSRI antidepressants.[48] There have also been small studies suggesting that bupropion or a bupropion/trazodone combination may improve some measures of sexual function in women who have hypoactive sexual desire disorder (HSDD) and are not depressed.[49] According to an expert consensus recommendation from the International Society for the Study of Women's Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data.[50]

Obesity[edit]

Bupropion, when used for treating obesity over a period of 6 to 12 months, results in an average weight loss of 2.7 kg (5.9 lbs) over placebo.[51] This is not much different from the weight loss produced by several other weight-loss medications such as sibutramine or orlistat.[51] The combination drug naltrexone/bupropion has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of obesity.[52][53]

Other uses[edit]

Bupropion is not effective in the treatment of cocaine dependence,[54] but it is showing promise in reducing drug use in light methamphetamine users.[55] Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease, psoriasis, and other autoimmune conditions, but very little clinical evidence is available.[56][57][58] Bupropion is not effective in treating chronic low back pain.[59]

Contraindications[edit]

The drug label advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as anorexia nervosa, bulimia nervosa, benzodiazepine or alcohol withdrawal. It should be avoided in individuals who are taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications.[4] The label recommends that caution should be exercised when treating people with liver damage, severe kidney disease, and severe hypertension, and in children, adolescents and young adults due to the increased risk of suicidal ideation.[4]

Side effects[edit]

The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, insomnia, tremor, excessive sweating and tinnitus.[35] Bupropion has highest incidence of insomnia of all second-generation antidepressants, bar desvenlafaxine.[60]It is also associated with about 20% increased risk of headache.[61]

Bupropion rises systolic blood pressure by 6 mm Hg and the heart rate by 7 beats per minute.[62] The prescribing information notes that hypertension, sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension.[63] Safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remain unclear due to the lack of data.[64][65]

Seizure is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300-450 mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600 mg.[63] For comparison, the incidence of unprovoked seizure in the general population is 0.07 to 0.09%, and the risk of seizure for a variety of other antidepressants is generally between 0 and 0.5% at the recommended doses.[66]

The prescribing information warns about bupropion triggering an angle-closure glaucoma attack.[4] On the other hand, bupropion may decrease the risk of development of open angle glaucoma.[67]

Bupropion use by mothers in the first trimester of pregnancy is associated with 23% increase of the odds in congenital heart defects in their children.[68]

Psychiatric[edit]

The FDA requires all antidepressants, including bupropion, to carry a boxed warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in suicidal thought and behavior in children and adolescents, and 1.5-fold increase in the 18–24 age group.[69] For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.[69]

Bupropion prescribed for smoking cessation results in 25% increase of the risk of psychiatric side effects, in particular, anxiety (about 40% increase) and insomnia (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behavior. [70]

Bupropion-induced psychosis may develop in select populations, or worsen a pre-existing psychotic syndrome.[71] Symptoms may include delusions, hallucinations, paranoia, and confusion. In most cases these symptoms can be reduced or eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication.[4][71] However, adding a benzodiazepine to treat psychosis, instead of an antipsychotic, may become a valid alternative according to the model of amphetamine-induced psychosis.[72] Psychotic symptoms are associated with factors such as higher doses of bupropion, a history of bipolar disorder or psychosis, concomitant medications, for example, lithium or benzodiazepines, old age, or substance abuse.[71][73] In a large-scale study of programs where bupropion was used for smoking cessation or treatment of depression, no withdrawal symptoms were observed.[74] As of 2002 there were two case reports of people experiencing withdrawal symptoms when discontinuing bupropion taken to aid smoking cessation;[75] the prescribing information states that dose tapering is not required when discontinuing treatment for smoking cessation.[3]

Overdose[edit]

Bupropion is considered moderately dangerous in overdose.[76][77] According to an analysis of US National Poison Data System, adjusted for the number of prescriptions, bupropion and venlafaxine are the two new generation antidepressants (that is excluding tricyclic antidepressants) that result in the highest mortality and morbidity.[78] For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and abnormal heart rhythms. When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, and before they died suffered multiple uncontrolled seizures and heart attacks.[4]

In the majority of childhood exploratory ingestions involving one or two tablets, children show no apparent symptoms.[79]

Interactions[edit]

Since bupropion is metabolized to hydroxybupropion by the enzyme CYP2B6, drug interactions with CYP2B6 inhibitors are possible: this includes medications like paroxetine, sertraline, fluoxetine, diazepam, clopidogrel, and orphenadrine. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers, such as carbamazepine, clotrimazole, rifampicin, ritonavir, St John's wort, phenobarbital, phenytoin and others.[80] Indeed, carbamazepine decreases exposure to bupropion by 90% and increases exposure to hydroxybupropion by 94%.[81] Ritonavir, lopinavir/ritonavir, and efavirenz have been shown to decrease levels of bupropion and/or its metabolites.[82] Ticlopidine and clopidogrel, both potent CYP2B6 inhibitors, have been found to considerably increase bupropion levels as well as decrease levels of its metabolite hydroxybupropion.[82]

Conversely, because bupropion is itself a strong inhibitor of CYP2D6 (Ki = 21 μM),[3][83] as is its active metabolite, hydroxybupropion (Ki = 13.3 μM), it can slow the clearance of other drugs metabolized by this enzyme.[3][6][4][80] For instance, bupropion has been found to increase levels of desipramine, a CYP2D6 substrate, by 5-fold in the case of area-under-the-curve levels and by 2-fold in the case of peak levels.[82] Bupropion has also been found to increase levels of atomoxetine by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold.[84] As another example, the ratio of dextromethorphan (a drug that is mainly metabolized by CYP2D6) to its major metabolite dextrorphan increased approximately 35-fold when it was administered to people being treated with 300 mg/day bupropion.[80] When people on bupropion are given MDMA, about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased heart rate effects of MDMA.[85][86] Interactions with other CYP2D6 substrates, such as metoprolol, imipramine, and nortriptyline have also been reported.[86]

Bupropion lowers the threshold for epileptic seizures,[87] and therefore can potentially interact with other medications that also lower it, such as carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline, systemic corticosteroids (e.g., prednisone), and some tricyclic antidepressants (e.g., clomipramine).[4] The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold.[4] Also, bupropion should not be taken by individuals undergoing abrupt cessation of alcohol or benzodiazepine use.

Caution should be observed when combining bupropion with a monoamine oxidase inhibitor (MAOI), as it may result in hypertensive crisis.[88]

Pharmacology[edit]

Abbreviations
DA: dopamine
NE: norepinephrine
5-HT: serotonin
ND: no data
Human pharmacology effects of bupriopion[89][90][91][92][93]
  Bupropion R,R-
Hydroxy
bupropion
S,S-
Hydroxy
bupropion
Threo-
hydro
bupropion
Erythro-
hydro
bupropion
Exposure (concentration over time; bupropion exposure = 100%) and half-life
Exposure 100% 800% 160% 310% 90%
Half-life 10 h (IR)
17 h (SR)
21 h 25 h 26 h 26 h
Inhibition potency (potency of DA reuptake inhibition by bupropion = 100%)
DA reuptake 100% ND ND ND ND
NE reuptake 27% ND ND ND ND
5-HT reuptake 2% ND ND ND ND
α3β4 nicotinic 53% 15% 10% ND ND
α4β2 nicotinic 8% 3% 29% ND ND
α1* nicotinic 12% 13% 13% ND ND

Pharmacodynamics[edit]

Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI).[12] It has also been found to act as a releasing agent of dopamine and norepinephrine (NDRA), similarly to other cathinones.[94][95][96] However, when ingested orally by humans, bupropion is extensively converted in the body into several active metabolites with differing activities and influences on the effects of the drug during first-pass metabolism.[12][94] These metabolites are present in much higher concentrations in the body compared to bupropion itself.[12][94][97] The most important example is the major metabolite of bupropion, hydroxybupropion, a selective norepinephrine reuptake inhibitor (and likely releasing agent) and nicotinic acetylcholine receptor (nAChR) antagonist that lacks significant dopaminergic actions, and which, with oral bupropion treatment, can reach area under the curve (AUC) plasma concentrations that are as much as 16–20 times greater than those of bupropion itself.[12] Hence, the effects of bupropion cannot be understood unless its metabolism is also considered.[12][94][98]

Dopaminergic activity[edit]

Bupropion inhibits the reuptake of dopamine through the human dopamine transporter and norepinephrine transporter;[99][100][101] the inhibition of dopamine reuptake through the norepinephrine transporter is most pronounced in the prefrontal cortex of humans.[99] The binding affinity (Ki) and inhibitory potency (i.e., the half maximal inhibitory concentration or IC50) of bupropion at the human dopamine transporter are 526 nanomolar (nM) and 443 nM, respectively.[100][101]

Antinicotinic and other activities[edit]

Bupropion is also known to act as a non-competitive antagonist of the α3β2, α3β4, α4β2, and, very weakly, α7 nACh receptors,[94][102] and these actions appear to be importantly involved in its beneficial properties not only in smoking cessation, but in depression as well.[12][94][97][103] The metabolites of bupropion also act as non-competitive antagonists of these nACh receptors, and hydroxybupropion is even more potent in comparison.[12][104][105][106][107] At therapeutically-relevant concentrations bupropion and hydroxybupropion act as negative allosteric modulators of the serotonin 5-HT3A receptor.[108] Pharmacological data on bupropion and its metabolites are shown in the table. Bupropion is known to weakly inhibit the α1 adrenergic receptor, with a 14% potency of its dopamine uptake inhibition, and the H1 receptor, with a 9% potency.[89]

Mechanism of action[edit]

Bupropion causes antidepressant activity as it selectively inhibits dopamine and norepinephrine re-uptake.[109] Bupropion can also stimulate the release of norepinephrine and dopamine from the presynaptic neuron. The primary metabolite, hydroxybupropion has the same effect as bupropion to block norepinephrine and dopamine re-uptake, so it extends the drug's duration of action.[109] Bupropion is also a non-competitive antagonist of nicotinic acetylcholine receptors so it helps people to stop smoking as binding of the drug to these receptors causes their activation and reduces the craving for cigarettes.[110]

Pharmacokinetics[edit]

Phase I Metabolism of racemic bupropion. The carbonyl reductase enzyme that is responsible for producing erythro-bupropion is unknown as of March 2015.

Bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6.[111] It has several active metabolites: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Both bupropion and its primary metabolite hydroxybupropion act in the liver as potent inhibitors of the enzyme CYP2D6, which metabolizes not only bupropion itself but also a variety of other drugs and biologically active substances.[83] This mechanism creates the potential for a variety of drug interactions.

The biological activity of bupropion can be attributed to a significant degree to its active metabolites, in particular to S,S-hydroxybupropion. GlaxoSmithKline developed this metabolite as a separate drug called radafaxine,[112] but discontinued development in 2006 due to "an unfavourable risk/benefit assessment".[113]

Bupropion is metabolized to hydroxybupropion by CYP2B6, an isozyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. Bupropion is metabolized to threo-hydrobupropion via cortisone reductase.[114] The metabolic pathway responsible for the creation of erythro-hydrobupropion remains elusive.

The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (with a half-life of 12–30 hours), while the effective doses of hydroxybupropion may differ by as much as 7.5 times (with a half-life of 15–25 hours).[4][5][115] Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.[116] The half-lives of erythrohydrobupropion and threohydrobupropion are roughly 23–43 hours and 24–50 hours respectively.[3][4]

There have been reported cases of false-positive urine amphetamine tests in persons taking bupropion.[117][118][119]

In 2016, three new major metabolites of bupropion, all formed exclusively by CYP2C19, were identified.[120] These include 4'-OH-bupropion, erythro-4'-OH-hydrobupropion and threo-4'-OH-hydrobupropion, and represent 24% of a dose of bupropion excreted in urine.[120] For comparison, bupropion and its three previously known primary metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion represent 23% of a dose of bupropion excreted in urine.[120]

Chemistry[edit]

Bupropion is a unicyclic aminoketone that belongs to the class of substituted cathinones and the more general class of substituted phenethylamines.[1][14] Although two optical isomers on bupropion can be separated at 20 oC,[121] they spontaneously racemize even during storage of solid samples. FDA-approved and commercially available bupropion is racemic.

Synthesis[edit]

It is synthesized in two chemical steps starting from 3'-chloro-propiophenone. The alpha position adjacent to the ketone is first brominated followed by nucleophilic displacement of the resulting alpha-bromoketone with t-butylamine and treated with hydrochloric acid to give bupropion as the hydrochloride salt in 75–85% overall yield.[15][122]

Bupropion synthesis diagram
3'-Chloro-propiophenone
3'-Chloro-2-bromopropiophenone
Bupropion hydrochloride
This diagram shows the synthesis of bupropion via 3'-chloro-propiophenone.

History[edit]

A bioequivalency profile comparison of 150 mg extended-release bupropion as produced by Impax Laboratories for Teva and Biovail for GlaxoSmithKline.

Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974.[15] It was approved by the U.S. Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin.[123][124] However, a significant incidence of epileptic seizures at the originally recommended dosage caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose.[125]

In 1996, the FDA approved a sustained-release formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin).[126] In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing.[127] Wellbutrin SR and XL are available in generic form in the United States and Canada. In Canada, generic XR bupropion is distributed by Mylan. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban.[128][126] In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.[129][130]

In France, marketing authorization was granted for Zyban on 3 August 2001, with a maximum daily dose of 300 mg;[131] only sustained-release bupropion is available, and only as a smoking cessation aid. Bupropion was granted a licence for use in adults with major depression in the Netherlands in early 2007, with GlaxoSmithKline expecting subsequent approval in other European countries.[132] Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder (SAD).[133] In some countries (including Australia, New Zealand and the UK) depression treatment and SAD prevention are off-label uses.[134][135]

On 11 October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People's Pharmacy, released the results of comparative tests of different brands of bupropion.[136] The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that "one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab."[137] The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL.[138] On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg."[139] The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013.[139] As of October 2013 the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.[139]

In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by Sanofi-Aventis.[140][141][142]


In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide.[143] This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years.[144] Based on the results of follow-up trials this warning was removed in 2016.[145]

In 2012, the U.S. Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3-billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.[146]

In 2017, the European Medicines Agency recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India.[147] The products recommended for suspension included several 300 mg modified-release Bupropion tablets.[148]

Society and culture[edit]

Recreational use[edit]

While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of bupropion's pharmacology.[149] Bupropion misuse is uncommon.[149] There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion via the oral route are markedly different from those of addictive stimulants such as cocaine or amphetamine.[150] That said, bupropion, via non-conventional routes of administration (e.g., injection, insufflation), is reported to be abused in the United States and Canada, notably in prisons.[151][152][153][154]

Brands[edit]

It is sold under many trade names worldwide and in combinations with naltrexone.[155]

It is sold under many trade names worldwide including Aplenzin, Budeprion SR, Bup, Bupredol, Buproban, Bupropion GSK, BuPROPion HCL SR Watson, Bupropion Hydrochloride Anchen, Bupropion Hydrochloride Apotex, BuPROPion Hydrochloride Cadista, Bupropion Hydrochloride Mylan, Bupropion Hydrochloride Sandoz, buPROPion Hydrochloride SR actavis, Bupropion Hydrochloride Sun Pharma, buPROPion Hydrochloride Torrent Pharma, Bupropion Hydrochloride Wockhardt, buPROPion Hydrochloride XL actavis, BuPROPion Hydrochloride XL Watson, Bupropion SR Sanis Health, Bupropionhydrochlorid HEXAL, Bupropionhydrochloride GSK, Buprotrin, Butrin, Buxon, Carmubine, Depnox-SR, Elontril, Elontril XL, Forfivo XL, Funnix, Global buPROPion HCL, Le Fu Ting, Odranal, PMS-Bupropion SR, Prewell, Quomem, ratio-Bupropion SR, Sandoz Bupropion SR, Voxra, Wellbutrin, Wellbutrin Retard, Wellbutrin SR, Wellbutrin XL, Wellbutrin XR, Yue Ting, Zetron, Zyban, Zyban LP, Zybex SR, ZyGenerics Bupropion Hydrochloride XL, and Zyntabac.[155]

It is sold as a combination drug with naltrexone as Contrave.[155]

Legal status[edit]

In Russia bupropion is banned as a narcotic drug, yet not per se but rather as a derivative of methcathinone.[156] In Australia and the UK, smoking cessation is the only licensed use of bupropion.[134][135] In the US, the FDA granted approval for marketing of bupropion for depression and smoking cessation.[157]

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