"Jan. 23, 2013 -- Women who smoke are now just as likely to die of lung cancer and other smoking-related diseases as men -- and smokers of both sexes die, on average, about a decade earlier than non-smokers.
These were among the findings fro"...
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Suicidal thoughts and behaviors in adolescents and young adults [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Seizure [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS]
- Psychosis and other neuropsychiatric reactions [see WARNINGS AND PRECAUTIONS]
- Angle-closure glaucoma [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading to Discontinuation of Treatment
Adverse reactions were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 subjects treated with ZYBAN and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with ZYBAN included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes.
Commonly Observed Adverse Reactions
The most commonly observed adverse reactions consistently associated with the use of ZYBAN were dry mouth and insomnia. The incidence of dry mouth and insomnia may be related to the dose of ZYBAN. The occurrence of these adverse reactions may be minimized by reducing the dose of ZYBAN. In addition, insomnia may be minimized by avoiding bedtime doses.
Adverse reactions reported in the dose-response and comparator trials are presented in Table 2 and Table 3, respectively. Reported adverse reactions were classified using a COSTART-based dictionary.
Table 2: Adverse Reactions Reported by at Least 1% of
Subjects and at a Greater Frequency than Placebo in the Dose-response Trial
|Adverse Reaction||ZYBAN 100 to 300 mg/day
(n = 461)
(n = 150)
|Neck pain||2||< 1|
|Increased appetite||2||< 1|
|Taste perversion||2||< 1|
Table 3: Adverse Reactions Reported by at Least 1% of
Subjects on Active Treatment and at a Greater Frequency than Placebo in the
|Adverse Experience (COSTART Term)||ZYBAN 300 mg/day
(n = 243)
|Nicotine Transdermal System (NTS) 21 mg/day
(n = 243)
|ZYBAN and NTS
(n = 244)
(n = 159)
|Chest pain||< 1||1||3||1|
|Neck pain||2||1||< 1||0|
|Facial edema||< 1||0||1||0|
|Thirst||< 1||< 1||2||0|
|Increased cough||3||5||< 1||1|
|Application site reactiona||11||17||15||7|
|a Subjects randomized to ZYBAN or placebo received placebo patches.|
Adverse reactions in a 1-year maintenance trial and a 12-week COPD trial with ZYBAN were quantitatively and qualitatively similar to those observed in the dose-response and comparator trials.
Other Adverse Reactions Observed during the Clinical Development of Bupropion
In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of bupropion.
Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with bupropion sustained-release tablets (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Tables 2 and 3, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.
Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps and twitching.
Nervous System: Frequent were agitation, depression, and irritability. Infrequent were abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare was bronchospasm.
Skin: Frequent was sweating.
The following adverse reactions have been identified during post-approval use of ZYBAN and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a relationship to drug exposure.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Glycosuria.
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.
Read the Zyban (bupropion hcl) Side Effects Center for a complete guide to possible side effects
Potential For Other Drugs To Affect ZYBAN
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between ZYBAN and drugs that are inhibitors or inducers of CYP2B6.
Inhibitors of CYP2B6
Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of ZYBAN may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see CLINICAL PHARMACOLOGY].
Inducers of CYP2B6
Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of ZYBAN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see CLINICAL PHARMACOLOGY] but should not exceed the maximum recommended dose.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see CLINICAL PHARMACOLOGY]. 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.
Potential For ZYBAN To Affect Other Drugs
Drugs Metabolized by CYP2D6
Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of ZYBAN with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with ZYBAN, 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 ZYBAN and such drugs may require increased doses of the drug [see CLINICAL PHARMACOLOGY].
Drugs That Lower Seizure Threshold
Use extreme caution when coadministering ZYBAN with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Dopaminergic Drugs (Levodopa and Amantadine)
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering ZYBAN concomitantly with these drugs.
Use With Alcohol
In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with ZYBAN. The consumption of alcohol during treatment with ZYBAN should be minimized or avoided.
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI and initiation of treatment with ZYBAN. Conversely, at least 14 days should be allowed after stopping ZYBAN before starting an MAOI intended to treat psychiatric disorders [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS].
Physiological changes resulting from smoking cessation, with or without treatment with ZYBAN, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
Drug Abuse And Dependence
Bupropion is not a controlled substance.
Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity.
In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered orally 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.
ZYBAN is intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.
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 behavior 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.
The possibility that bupropion may induce dependence should be kept in mind when evaluating the desirability of including the drug in smoking cessation programs of individual patients.
Read the Zyban Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/11/2016
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