Incidence of Seizure with Bupropion Use
The incidence of seizure with bupropion hydrochloride extended-release tablets (XL) has not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.
Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the bupropion hydrochloride extended-release tablets (XL) dose does not exceed 450 mg once daily and the titration rate is gradual.
Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride
Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below.
300 mg/
day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
400 mg/
day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
Bupropion hydrochloride extended-release tablets (XL) has been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under the subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended release formulations of bupropion hydrochloride.
Major Depressive Disorder
Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials
In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2.
Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD| Adverse Reaction Term | Placebo
(n=385)
| Bupropion HCl Sustained-Release 300 mg/day
(n=376)
| Bupropion HCl Sustained-Release 400 mg/day
(n=114)
|
|---|
| Rash | 0.0% | 2.4% | 0.9% |
| Nausea | 0.3% | 0.8% | 1.8% |
| Agitation | 0.3% | 0.3% | 1.8% |
| Migraine | 0.3% | 0.0% | 1.8% |
In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation, (in addition to those listed above for the sustained-release formulation), included vomiting, seizures, and sleep disturbances.
Adverse Reactions Occurring at an Incidence of >1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD
Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group are included.
Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD| Body System/Adverse Reaction | Placebo
(n=385)
| Bupropion HCl Sustained-Release 300 mg/day
(n=376)
| Bupropion HCl Sustained-Release 400 mg/day
(n=114)
|
|---|
| Body (General) | | | |
| Headache | 23% | 26% | 25% |
| Infection | 6% | 8% | 9% |
| Abdominal pain | 2% | 3% | 9% |
| Asthenia | 2% | 2% | 4% |
| Chest Pain | 1% | 3% | 4% |
| Pain | 2% | 2% | 3% |
| Fever | – | 1% | 2% |
| Cardiovascular | | | |
| Palpitation | 2% | 2% | 6% |
| Flushing | – | 1% | 4% |
| Migraine | 1% | 1% | 4% |
| Hot flashes | 1% | 1% | 3% |
| Digestive | | | |
| Dry mouth | 7% | 17% | 24% |
| Nausea | 8% | 13% | 18% |
| Constipation | 7% | 10% | 5% |
| Diarrhea | 6% | 5% | 7% |
| Anorexia | 2% | 5% | 3% |
| Vomiting | 2% | 4% | 2% |
| Dysphagia | 0% | 0% | 2% |
| Musculoskeletal | | | |
| Myalgia | 3% | 2% | 6% |
| Arthralgia | 1% | 1% | 4% |
| Arthritis | 0% | 0% | 2% |
| Twitch | – | 1% | 2% |
| Nervous System | | | |
| Insomnia | 6% | 11% | 16% |
| Dizziness | 5% | 7% | 11% |
| Agitation | 2% | 3% | 9% |
| Anxiety | 3% | 5% | 6% |
| Tremor | 1% | 6% | 3% |
| Nervousness | 3% | 5% | 3% |
| Somnolence | 2% | 2% | 3% |
| Irritability | 2% | 3% | 2% |
| Memory decreased | 1% | – | 3% |
| Paresthesia | 1% | 1% | 2% |
| Central nervous system stimulation | 1% | 2% | 1% |
| Respiratory | | | |
| Pharyngitis | 2% | 3% | 11% |
| Sinusitis | 2% | 3% | 1% |
| Increased cough | 1% | 1% | 2% |
| Skin | | | |
| Sweating | 2% | 6% | 5% |
| Rash | 1% | 5% | 4% |
| Pruritus | 2% | 2% | 4% |
| Urticaria | 0% | 2% | 1% |
| Special Senses | | | |
| Tinnitus | 2% | 6% | 6% |
| Taste perversion | – | 2% | 4% |
| Blurred vision of diplopia | 2% | 3% | 2% |
| Urogenital | | | |
| Urinary frequency | 2% | 2% | 5% |
| Urinary urgency | 0% | – | 2% |
| Vaginal hemorrhage
Incidence based on the number of female patients. | – | 0% | 2% |
| Urinary tract infection | –
Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients | 1% | 0% |
The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%).
Seasonal Affective Disorder
In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion hydrochloride extended-release tablets (XL) and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. <1%) and headache (1% vs. <1%).
Table 4 summarizes the adverse reactions that occurred in patients treated with bupropion hydrochloride extended-release tablets (XL) for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group.
Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD| System Organ Class/Preferred Term | Placebo
(n=511)
| Bupropion HCl Extended-Release
(n=537)
|
|---|
| Gastrointestinal Disorder | | |
| Dry mouth | 15% | 26% |
| Nausea | 8% | 13% |
| Constipation | 2% | 9% |
| Flatulence | 3% | 6% |
| Abdominal pain | <1% | 2% |
| Nervous System Disorders | | |
| Headache | 26% | 34% |
| Dizziness | 5% | 6% |
| Tremor | <1% | 3% |
| Infections and Infestations | | |
| Nasopharyngitis | 12% | 13% |
| Upper respiratory tract infection | 8% | 9% |
| Sinusitis | 4% | 5% |
| Psychiatric Disorders | | |
| Insomnia | 13% | 20% |
| Anxiety | 5% | 7% |
| Abnormal dreams | 2% | 3% |
| Agitation | <1% | 2% |
| Musculoskeletal and Connective | | |
| Tissue Disorders | 2% | 3% |
| Myalgia | | |
| Pain in extremity | 2% | 3% |
| Respiratory, Thoracic, and Mediastinal Disorders | 3% | 4% |
| Cough | | |
| General Disorders and Administration Site Conditions | 2% | 3% |
| Feeling jittery | | |
| Skin and Subcutaneous | | |
| Tissue Disorders | 2% | 3% |
| Rash | | |
| Metabolism and Nutrition Disorders | | |
| Decreased appetite | 1% | 4% |
| Reproductive System and Breast Disorders | <1% | 2% |
| Dysmenorrhea | | |
| Ear and Labyrinth Disorders | | |
| Tinnitus | <1% | 3% |
| Vascular Disorders | | |
| Hypertension | 0% | 2% |
Changes in Body Weight
Table 5 presents the incidence of body weight changes (≥5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight.
Table 5: Incidence of Weight Gain or Weight Loss (≥5 lbs.) in MDD Trials Using Bupropion HCl Sustained-Release| Weight Change | Bupropion HCl Sustained-Release 300 mg/day
(n=339)
| Bupropion HCl Sustained-Release 400 mg/day
(n=112)
| Placebo
(n=347)
|
|---|
| Gained >5 lbs | 3% | 2% | 4% |
| Lost >5 lbs | 14% | 19% | 6% |
Table 6 presents the incidence of body weight changes (≥5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥5 lbs., compared to the placebo group (11%). These were relatively long-term trials (up to 6 months).
Table 6: Incidence of Weight Gain or Weight Loss (≥5 lbs) in SAD Trials Using Bupropion HCl Extended-Release| Weight Change | Bupropion HCl Extended-Release 150 to 300 mg/day
(n=537)
| Placebo
(n=511)
|
|---|
| Gained >5 lbs | 11% | 21% |
| Lost >5 lbs | 23% | 11% |
Body (General)
Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.
Cardiovascular
Postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.
Digestive
Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine
Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.
Hemic and Lymphatic
Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional
Glycosuria.
Musculoskeletal
Leg cramps, fever/rhabdomyolysis, and muscle weakness.
Nervous System
Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory
Bronchospasm and pneumonia.
Skin
Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism.
Special Senses
Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.
Urogenital
Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
Inhibitors of CYP2B6
Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see
Clinical Pharmacology (12.3)].
Inducers of CYP2B6
Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [see
Clinical Pharmacology (12.3)].
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce metabolism of bupropion and may decrease bupropion exposure. [see
Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion but the maximum recommended dose should not be exceeded.
Drugs Metabolized by CYP2D6
Bupropion and its metabolites (erythohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion hydrochloride extended-release tablets (XL) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g. haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g. propafenone, and flecainide). When used concomitantly with bupropion hydrochloride extended-release tablets (XL), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen), theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride extended-release tablets (XL) and such drugs may require increased doses of the drug [see
Clinical Pharmacology (12.3)].
Risk Summary
Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies regardless of drug exposure have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion hydrochloride extended-release tablets (XL) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data
Data from international bupropion Pregnancy registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7) and the Slone Epidemiology case control study did not find increased risk for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find an increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.
Animal Data
In studies conducted in rats and rabbits, bupropion was administered orally at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m
2 basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m
2 basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater. When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m
2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
Humans
Controlled clinical studies of bupropion HCl immediate-release conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients demonstrated an increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg bupropion produced mild amphetamine-like activity as compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.
Animals
Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
Absorption
Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion w as approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion.
Distribution
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that of bupropion.
Metabolism
Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the
tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group.
In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance, because the plasma concentrations of the metabolites are as high or higher than those of bupropion.
At steady state, peak plasma concentration of hydroxybupropion occurred approximately 7 hours after administration of bupropion hydrochloride extended-release tablets (XL), and it was approximately 7 times the peak level of the parent drug. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion. However, the elimination half-lives of erythrohydrobupropion and threohydrobupropion are longer, approximately 33 (±10) and 37 (±13) hours, respectively and steady-state AUCs were 1.4 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.
Elimination
Following oral administration of 200 mg of
14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.
Population Subgroups
Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function, because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.
Renal Impairment
There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug C
max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second study, comparing normal subjects and subjects with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that after a single 150 mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see
Dosage and Administration (2. 7) and
Use in Specific Populations (8.6)].
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild to severe cirrhosis. The first trial demonstrated that the half-life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 groups were minimal.
The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C
max, and T
max) and its active metabolites (t
1/2) in subjects with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion C
max and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in subjects with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean C
max was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean C
max was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median T
max was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers [see
Dosage and Administration (2.6) and
Use in Specific Populations (8.7)].
Left Ventricular Dysfunction
During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy volunteers.
Age
The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that in younger subjects. These data suggest that there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetic study suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see
Use in Specific Populations (8.5)].
Gender
A single-dose study involving 12 healthy male and 12 healthy female volunteers, revealed no sex-related differences in the pharmacokinetic parameters of bupropion. In addition, pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared to female volunteers.
Smokers
The effects of cigarette smoking on the pharmacokinetics of bupropion hydrochloride were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no statistically significant difference in C
max, half-life, T
max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.
Drug Interactions
Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (XL)
In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL)and drugs that are inhibitors or inducers of CYP2B6. In addition,
in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir, inhibit the hydroxylation of bupropion.
Inhibitors of CYP2B6
Ticlopidine Clopidogrel: In a study in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C
max and AUC) of bupropion by 40% and 60% for clopidogrel, by 38% and 85% for ticlopidine, respectively. The exposures of hydroxybupropion were decreased.
Prasugrel: In healthy subjects, prasugrel increased bupropion C
max and AUC values by 14% and 18%, respectively, and decreased C
max and AUC values of hydroxybupropion, by 32% and 24%, respectively.
Cimetidine: Following oral administration of bupropion 300 mg with and without cimetidine 800 mg in 24 healthy young male volunteers, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C
max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.
Inducers of CYP2B6
Ritonavir and Lopinavir: In a healthy volunteer study, ritonavir 100 mg twice daily reduced the AUC and C
max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%. In a second healthy volunteer study, ritonavir 600 mg twice daily decreased the AUC and C
max of bupropion by 66% and 62% respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%.
In another healthy volunteer study, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and C
max by 57%. The AUC and C
max of hydroxybupropion metabolite were decreased by 50% and 31%, respectively.
Efavirenz: In a study of healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and C
max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C
max of hydroxybupropion was increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.
Potential for Bupropion Hydrochloride Extended-Release Tablets (XL) to Affect Other Drugs
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In a study of 8 healthy male volunteers, following a 14-day administration of bupropion 100 mg three times per day, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.
Drugs Metabolized by CYP2D6
In vitro, bupropion and hydroxybupropion are CYP2D6 inhibitors. In a clinical study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the C
max, AUC, and T½ of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the C
max and AUC of citalopram by 30% and 40%, respectively.
Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
Suicidal Thoughts and Behaviors
Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
Although bupropion hydrochloride extended-release tablets (XL) are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN
® which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g. including depression or agitation), or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and to discontinue bupropion hydrochloride extended-release tablets (XL)if they have a severe allergic reaction.
Seizure
Instruct patients to discontinue and not restart bupropion hydrochloride extended-release tablets (XL)if they experience a seizure while on treatment. Advise patients that the excessive use or the abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid the use of alcohol.
Angle Closure Glaucoma
Patients should be advised that taking bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see
Warnings and Precautions (5.7)].
Bupropion-Containing Products
Educate patients that bupropion hydrochloride extended-release tablets (XL)contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (XL)should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation, and APLENZIN, a bupropion hydrobromide formulation). In addition, there are a number of generic bupropion HCl products for the immediate, sustained, and extended-release formulations.
Potential for Cognitive and Motor Impairment
Advise patients that any CNS-active drug like bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that bupropion hydrochloride extended-release tablets (XL) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion hydrochloride extended-release tablets (XL) treatment may lead to decreased alcohol tolerance.
Concomitant Medications
Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs, because bupropion hydrochloride extended-release tablets (XL) and other drugs may affect each other's metabolism.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Precautions for Nursing Mothers
Communicate with the patient and pediatric healthcare provider regarding the infant's exposure to bupropion through human milk. Instruct patients to immediately contact the infant's healthcare provider if they note any side effect in the infant that concerns them or is persistent.
Administration Information
Instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole so that the release rate is not altered. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure.
Instruct patients that bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may be taken with or without food.
Mfg. by:
IMPAX Laboratories, Inc.
Hayward, CA 94544 USA
Dist. by:
Global Pharmaceuticals
Division of IMPAX Laboratories, Inc.
Philadelphia, PA 19124 USA
ZYBAN
® , WELLBUTRIN
® , AND WELLBUTRIN SR
® are registered trademarks of GlaxoSmithKline.
662-14
Rev. 03/2015
