"The U.S. Food and Drug Administration today approved the first generic versions of Cymbalta (duloxetine delayed-release capsules), a prescription medicine used to treat depression and other conditions.
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The following risks are discussed in greater detail in other sections of the labeling:
- Clinical worsening and suicide risk [see WARNINGS AND PRECAUTIONS]
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see WARNING AND PRECAUTIONS]
- Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNING AND PRECAUTIONS]
- Psychosis, and other neuropsychiatric events [see WARNINGS AND PRECAUTIONS]
- Severe hypertension [see WARNINGS AND PRECAUTIONS]
- Agitation and insomnia [see WARNINGS AND PRECAUTIONS]
- Altered appetite and weight [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Commonly Observed Adverse Reactions in Controlled Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse reactions from Table 5 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion hydrochloride and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day dose groups.
FORFIVO XL is bioequivalent to three 150 mg tablets of WELLBUTRIN XL®, which has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion. The information included under this subsection and under subsections 6.2 and 6.3 is based primarily on data from controlled clinical trials with the sustained-release formulation of bupropion hydrochloride.
Adverse Reactions Leading to Discontinuation of Treatment with Bupropion Immediate Release or Bupropion Sustained Release
In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion hydrochloride and 4% of patients treated with placebo discontinued treatment due to adverse reactions. The specific adverse reactions in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of the sustained-release formulation of bupropion hydrochloride, and at a rate at least twice the placebo rate are listed in Table 4.
Table 4: Treatment Discontinuations Due to Adverse Reactions
in Placebo-Controlled Trials for Major Depressive Disorder using Bupropion Hydrochloride
Sustained Release Formulation
|Adverse Reaction||Bupropion HCl 300 mg/day
(n = 376)
|Bupropion HCl 400 mg/day
(n = 114)
(n = 385)
In clinical trials with the immediate-release formulation of bupropion, 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 of bupropion hydrochloride, include vomiting, seizures, and sleep disturbances.
Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated With Bupropion Immediate release or Bupropion Sustained Release
Table 5 enumerates adverse reactions that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion hydrochloride and with placebo in controlled trials. Reactions that occurred in either the 300- or 400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo group are included. Reported adverse reactions were classified using a COSTART-based Dictionary.
Accurate estimates of the incidence of adverse reactions associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward reactions in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the reactions. A better perspective on the serious adverse reactions associated with the use of bupropion is provided in the WARNINGS AND PRECAUTIONS.
Table 5: Adverse Reactions in Placebo-Controlled Trials*
for Major Depressive Disorder
|Body System/ Adverse Reaction||Bupropion HCl 300 mg/day
(n = 376)
|Bupropion HCl 400 mg/day
(n = 114)
(n = 385)
|Central nervous system stimulation||2%||1%||1%|
|Blurred vision or diplopia||3%||2%||2%|
|Urinary tract infection||1%||0%||—|
|* Adverse reactions that occurred in at least
1% of patients treated with either 300 or 400 mg/day of the sustained-release
formulation of bupropion hydrochloride, but equally or more frequently
in the placebo group, were: abnormal dreams, accidental injury, acne,
appetite increased, back pain, bronchitis, dysmenorrhea, dyspepsia, flatulence,
flu syndrome, hypertension, neck pain, respiratory disorder, rhinitis,
and tooth disorder.
† Incidence based on the number of female patients.
— Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.
Additional reactions to those listed in Table 5 that occurred at an incidence of at least 1% in controlled clinical trials of the immediate-release formulation of bupropion hydrochloride (300 to 600 mg/day) and that were numerically more frequent than placebo were: cardiac arrhythmias (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), tachycardia (11% vs. 9%), appetite increase (4% vs. 2%), dyspepsia (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%).
Other adverse reactions occurring < 1% in clinical trials
Chills, facial edema, postural hypotension, stroke, syncope, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, mouth ulcers, stomatitis, edema of tongue, ecchymosis, edema, abnormal coordination, decreased libido, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, ataxia, and derealization, bronchospasm, accommodation abnormality, dry eye, impotence, and prostate disorder.
The following adverse reactions have been identified during post-approval use of Bupropion hydrochloride. 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 causal relationship to drug exposure.
Only those adverse reactions not previously listed for bupropion are included. The extent to which these reactions may be associated with FORFIVO XL is unknown.
Metabolic and Nutritional—glycosuria.
Musculoskeletal-muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System—abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, delirium,dysarthria, dyskinesia, dystonia, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, and unmasking tardive dyskinesia.
Read the Forfivo XL (bupropion hydrochloride) Side Effects Center for a complete guide to possible side effects
Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.
Potential for Other Drugs to Affect FORFIVO XL
Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity.
Substrates or Inhibitors/Inducers of Cytochrome P450IIB6 (CYP2B6): In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between FORFIVO XL and drugs that are substrates or inhibitors/inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine and clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, inhibit the hydroxylation of bupropion.
Ticlopidine, Clopidogrel: In a study in healthy male volunteers, 75 mg clopidogrel once daily or 250 mg ticlopidine twice daily increased exposures (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, by 38% and 85% for ticlopidine, respectively. The exposures of hydroxybupropion were decreased. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation. Coadministration of FORFIVO XL with ticlopidine or clopidogrel is not recommended.
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased Cmax and AUC values of bupropion by 14% and 18%, respectively, and decreased Cmax and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively. The inhibition of prasugrel on bupropion metabolism is not considered clinically significant.
Ritonavir, Lopinavir, Efavirenz: In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir (KALETRA) 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. Similarly, efavirenz 600 mg once daily for 2 weeks reduced the exposure of bupropion by approximately 55%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving any of these drugs with bupropion may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded [see CLINICAL PHARMACOLOGY].
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg tablets of the sustained-release formulation of bupropion hydrochloride with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.
Potential for FORFIVO XL to Affect Other Drugs
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion hydrochloride, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, 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.
Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
Drugs Metabolized by Cytochrome P450IID6 (CYP2D6)
Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion hydrochloride given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax, 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.
Therefore, coadministration of bupropion with drugs that are metabolized by the CYP2D6 isoenzyme including certain 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), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.
CYP2D6 in order to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion.
Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.
Nicotine Transdermal System
Data from a smoking cessation study suggest that a higher incidence of hypertension in patients who received the combination of sustained-release bupropion hydrochloride and nicotine transdermal system (NTS). Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement. [see WARNINGS AND PRECAUTIONS].
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 test such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
Drugs that Lower Seizure Threshold
Since there is no lower strength for FORFIVO XL, concurrent administration of FORFIVO XL tablets and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with caution [see WARNINGS AND PRECAUTIONS].
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 bupropion. Alcohol increased the release rate of FORFIVO XL in vitro. The consumption of alcohol during treatment with FORFIVO XL should be avoided.
Levodopa and Amantadine
Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine. Since there is no lower strength for FORFIVO XL, administration of FORFIVO XL tablets to patients receiving either levodopa or amantadine concurrently should be undertaken with caution.
Drug Abuse And Dependence
Bupropion is not a controlled substance.
Controlled clinical studies of bupropion hydrochloride (immediate-release formulation) conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion hydrochloride 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 especially reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Studies in rodents and primates have shown 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 to assess 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.
Last reviewed on RxList: 11/28/2011
This monograph has been modified to include the generic and brand name in many instances.
Additional Forfivo XL Information
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