Forfivo
bupropion hydrochloride · Tablet, Film Coated, Extended Release · Oral
Uses
(bupropion hydrochloride extended-release tablets) is indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The efficacy of the sustained-release formulation of bupropion in the maintenance treatment of MDD was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [see Clinical Studies ( 14 )] . The physician who elects to use FORFIVO XL for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. FORFIVO XL is an aminoketone antidepressant indicated for the treatment of major depressive disorder (MDD) ( 1 ). The efficacy was established in two 4-week trials, one 6-week trial with bupropion immediate-release formulation, and one maintenance trial with bupropion sustained-release formulation, all in adults ( 14 ). Periodically re-evaluate long-term usefulness for the individual patient ( 1 ).
Dosage and administration
• Use one tablet (450 mg) once daily without regard to food ( 2.1 ).
• Swallow the tablet whole. Do not chew, divide, or crush ( 2.1 ).
• Do not initiate treatment with FORFIVO XL. Use another bupropion formulation for initial dose titration ( 2.2 ).
• Can be used in patients who are receiving 300 mg/day of another bupropion formulation for at least 2 weeks, and require a dosage of 450 mg/day ( 2.2 ).
• Patients who are currently being treated with other bupropion products at 450 mg/day can be switched to equivalent dose of FORFIVO XL once daily ( 2.2 ). 2.1 General Instructions for Use One tablet (450 mg) of FORFIVO XL should be taken once daily without regard to meals. FORFIVO XL should be swallowed whole and not crushed, divided, or chewed. 2.2 Initial Treatment with FORFIVO XL Do not initiate treatment with FORFIVO XL because the 450 mg tablet is the only available dose formulation. Use another bupropion formulation for initial dose titration (referring to prescribing information of other bupropion products). FORFIVO XL can be used in patients who are receiving 300 mg/day of another bupropion formulation for at least 2 weeks, and require a dosage of 450 mg/day. Patients who are currently being treated with other bupropion products at 450 mg/day can be switched to an equivalent dose of FORFIVO XL once daily. 2.3 Maintenance Treatment with FORFIVO XL It is generally agreed that acute episodes of depression require several months or longer of sustained antidepressant treatment beyond the response in the acute episode. It is unknown whether the 450 mg dose needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. 2.4 To Discontinue FORFIVO XL, Taper the Dose Because the 450 mg tablet is the only available dose formulation, use another bupropion formulation for tapering the dose prior to discontinuation (referring to prescribing information of other bupropion products). 2.5 Patients with Impaired Hepatic Function Because there is no lower dose strength for FORFIVO XL, FORFIVO XL is not recommended in patients with hepatic impairment [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . 2.6 Patients with Impaired Renal Function Because there is no lower dose strength for FORFIVO XL, FORFIVO XL is not recommended in patients with renal impairment [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . 2.7 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with FORFIVO XL. Conversely, at least 14 days should be allowed after stopping FORFIVO XL before starting an MAOI antidepressant [see Contraindications ( 4 ) and Drug Interactions ( 7.6 )] . 2.8 Use of FORFIVO XL with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start FORFIVO XL in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, nonpharmacological interventions, including hospitalization, should be considered [see Contraindications ( 4 )] . In some cases, a patient already receiving therapy with FORFIVO XL may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, FORFIVO XL should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with FORFIVO XL may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by nonintravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with FORFIVO XL is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications ( 4 ) and Drug Interactions ( 7.6 )] .
Dosage forms and strengths
Extended-Release Tablets, 450 mg of bupropion hydrochloride, are white to off-white, oblong-shaped tablets with the logo “Forfivo” printed on one side.
• Extended-release tablets: 450 mg ( 3 )
Contraindications
• FORFIVO XL is contraindicated in patients with a seizure disorder [see Warnings and Precautions ( 5.3 )] .
• FORFIVO XL is contraindicated in patients treated currently with other bupropion products because the incidence of seizure is dose dependent [see Warnings and Precautions ( 5.3 )] .
• FORFIVO XL is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because a higher incidence of seizures was observed in such patients treated with bupropion [see Warnings and Precautions ( 5.3 )] .
• FORFIVO XL is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions ( 5.3 ) and Drug Interactions ( 7.3 )] .
• The use of MAOIs (intended to treat psychiatric disorders) concomitantly with FORFIVO XL or within 14 days of discontinuing treatment with FORFIVO XL is contraindicated. There is an increased risk of hypertensive reactions when FORFIVO XL is used concomitantly with MAOIs. The use of FORFIVO XL within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting FORFIVO XL in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration ( 2.8 ), Warnings and Precautions ( 5.4 ), and Drug Interactions ( 7.6 )] .
• FORFIVO XL is contraindicated in patients with known hypersensitivity to bupropion or the other ingredients of FORFIVO XL tablets. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions ( 5.8 )] .
• Seizure disorder ( 4 , 5.3 )
• Current use of other bupropion products ( 4 , 5.3 )
• Current or prior diagnosis of bulimia or anorexia nervosa ( 4 , 5.3 )
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs ( 4 , 5.3 )
• Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with FORFIVO XL or within 14 days of stopping treatment with FORFIVO XL. Do not use FORFIVO XL within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start FORFIVO XL in a patient who is being treated with linezolid or intravenous methylene blue ( 4 , 7.6 ).
• Known hypersensitivity to bupropion or other ingredients of FORFIVO XL ( 4 , 5.8 )
Warnings and precautions
Neuropsychiatric Adverse Events During Smoking Cessation: Postmarketing reports of serious or clinically significant neuropsychiatric adverse events have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients attempting to quit smoking with FORFIVO XL for the occurrence of such symptoms and instruct them to discontinue FORFIVO XL and contact a healthcare provider if they experience such adverse events ( 5.2 ). Seizure Risk: The risk is dose dependent. Discontinue if seizure occurs ( 4 , 5.3 , 7.3 ). Hypertension: FORFIVO XL can increase blood pressure. Monitor blood pressure before initiating treatment and periodically during treatment ( 5.4 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder and monitor for these symptoms ( 5.5 ). Psychosis and Other Neuropsychiatric Reactions: Discontinue if such reactions occur ( 5.6 ). Angle-closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.7 ). 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1 . Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (Years) Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases [see Boxed Warning and Use in Specific Populations ( 8.4 )]. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Side effects
The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Suicidal thoughts and behaviors in children, adolescents, and young adults [see Warnings and Precautions ( 5.1 )]
• Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see Warnings and Precautions ( 5.2 )]
• Seizure [see Warnings and Precautions ( 5.3 )]
• Hypertension [see Warnings and Precautions ( 5.4 )]
• Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )]
• Psychosis and other neuropsychiatric events [see Warnings and Precautions ( 5.6 )]
• Angle-closure Glaucoma [see Warnings and Precautions ( 5.7 )]
• Hypersensitivity reactions [see Warnings and Precautions ( 5.8 )] Most common adverse reactions are (incidence ≥ 5%; ≥ 2 times placebo rate): dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 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 hydrochloride sustained-release (300 and 400 mg/day) and at a rate at least twice the placebo rate are listed below. 300 mg/day of bupropion hydrochloride sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion hydrochloride sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. 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 and the sustained-release formulations of bupropion. The information included under this subsection and under 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 Hydrochloride Immediate-release, Bupropion Hydrochloride Sustained-release, and Bupropion Hydrochloride Extended-release Formulations in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion hydrochloride 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 Major Depressive Disorder Adverse Reaction Term Placebo (N = 385) Bupropion Hydrochloride Sustained-release 300 mg/day (N = 376) Bupropion Hydrochloride 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 hydrochloride 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 Hydrochloride Immediate-release or Bupropion Hydrochloride Sustained-release Formulations in Major Depressive Disorder Trials Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion hydrochloride sustained-release at 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg/day or 400 mg/day group at an incidence of 1% or more and were more frequent than in the placebo group. Table 3. Adverse Reactions in Placebo-controlled Trials for Major Depressive Disorder a = Incidence based on the number of female patients. — = Denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.
Drug interactions
• CYP2B6 Inhibitors: Ticlopidine or clopidogrel may increase bupropion exposure. Coadministration of FORFIVO XL with ticlopidine or clopidogrel is not recommended ( 7.1 ).
• CYP2B6 Inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based on clinical exposure, but should not exceed the maximum recommended dose ( 7.1 ).
• Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). Consider dose reduction when using with bupropion ( 7.2 ).
• Drugs That Lower Seizure Threshold: Dose FORFIVO XL with extreme caution ( 5.3 , 7.3 ).
• Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with FORFIVO XL ( 7.4 ).
• MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with FORFIVO XL ( 7.6 ).
• Drug-Laboratory Test Interactions: FORFIVO XL can cause false-positive urine test results for amphetamines ( 7.7 ). 7.1 Potential for Other Drugs to Affect FORFIVO XL Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between FORFIVO XL and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Coadministration of FORFIVO XL with ticlopidine or clopidogrel is not recommended [see Clinical Pharmacology ( 12.3 )] . Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. 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 ( 12.3 )] . Carbamazepine, Phenobarbital, and Phenytoin: Although 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. 7.2 Potential for FORFIVO XL to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, and hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion 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, 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 FORFIVO XL and such drugs may require increased doses of the drug [see Clinical Pharmacology ( 12.3 )] . 7.3 Drugs that Lower Seizure Threshold Because there is no lower strength for FORFIVO XL, concurrent administration of FORFIVO XL tablets and agents that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids) should be undertaken only with extreme caution [see Warnings and Precautions ( 5.3 )] . 7.4 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. Because 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. 7.5 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 bupropion. Alcohol increased the release rate of FORFIVO XL in vitro . The consumption of alcohol during treatment with FORFIVO XL should be avoided. 7.6 Monoamine Oxidase Inhibitors (MAOIs) 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 MAOI phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with FORFIVO XL. Conversely, at least 14 days should be allowed after stopping FORFIVO XL before starting an MAOI antidepressant [see Dosage and Administration ( 2.7 , 2.8 ) and Contraindications ( 4 )] . 7.7 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.
Use in specific populations
• Renal Impairment: Because there is no lower dose strength for FORFIVO XL, FORFIVO XL is not recommended in patients with renal impairment ( 8.6 ).
• Hepatic Impairment: Because there is no lower dose strength for FORFIVO XL, FORFIVO XL is not recommended in patients with hepatic impairment ( 8.7 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data) . There are risks to the mother associated with untreated depression (see Clinical Considerations) . When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. When given to pregnant rabbits during organogenesis, non-dose-related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater (see Data) . The estimated background risk for major birth defects and miscarriage are unknown for the indicated population. All pregnancies have a background rate of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. Data Human Data Data from the 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. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. 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, which has a limited number of exposed cases with cardiovascular malformations, 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 for 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 odds ratio (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 drug 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 pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 10 and 6 times the MRHD, respectively, on a mg/m 2 basis). There was no evidence of fetal malformations in rats. When given to pregnant rabbits, during organogenesis, non-dose-related increases in incidence 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 doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m 2 basis) and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data) . There are risks to the mother associated with untreated depression (see Clinical Considerations) . When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. When given to pregnant rabbits during organogenesis, non-dose-related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater (see Data) . The estimated background risk for major birth defects and miscarriage are unknown for the indicated population. All pregnancies have a background rate of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. Data Human Data Data from the 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. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. 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, which has a limited number of exposed cases with cardiovascular malformations, 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 for 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 odds ratio (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 drug 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 pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 10 and 6 times the MRHD, respectively, on a mg/m 2 basis). There was no evidence of fetal malformations in rats. When given to pregnant rabbits, during organogenesis, non-dose-related increases in incidence 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 doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m 2 basis) and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the MRHD on a mg/m 2 basis) from embryonic implantation through lactation had no effect on pup growth or development.
Pediatric use
8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established. When considering the use of FORFIVO XL in a child or adolescent, balance the potential risks with the clinical need [see Boxed Warning , and Warnings and Precautions ( 5.1 )] .
Geriatric use
8.5 Geriatric Use Of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥ 65 years of age and 47 were ≥ 75 years of age. In addition, several hundred patients ≥ 65 years of age participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration ( 2.6 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] .
Overdosage
10.1 Human Overdose Experience Overdoses of up to 30 g or more of bupropion have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes such as conduction disturbances or arrhythmias, clonus, myoclonus, and hyperreflexia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. 10.2 Overdosage Management Consult a Certified Poison Control Center for up-to-date guidance and advice. Call 1-800-222-1222 or refer to www.poison.org. There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose.
Description
(bupropion hydrochloride), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-2-(tert-Butylamino)-3'-chloropropiophenone hydrochloride. The molecular weight is 276.2. The empirical formula is C 13 H 18 ClNO·HCl. Bupropion hydrochloride powder is white or almost white, crystalline, and soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: FORFIVO XL tablets are supplied for oral administration of 450 mg of bupropion hydrochloride as white to off-white extended-release tablets. Each film-coated tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: carboxymethyl cellulose sodium, colloidal silicon dioxide, hydrochloric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 8000, polyethylene oxide, polyvinyl pyrrolidone and polyvinyl acetate blend, stearic acid, talc, titanium dioxide and triacetin. The logo “Forfivo” is printed on one side of the tablet with edible black ink. Structural Formula
Mechanism of action
12.1 Mechanism of Action The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the reuptake of serotonin.
How supplied
Extended-Release Tablets, 450 mg of bupropion hydrochloride, are white to off-white, oblong-shaped tablets printed with the “Forfivo” logo on one side supplied in bottles of 30 tablets (NDC 24979-247-06). Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). 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 Adverse Events and Suicide Risk in Smoking Cessation Treatment Although FORFIVO XL is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN ® which is approved for this use. Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking bupropion. Instruct patients to discontinue FORFIVO XL and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )] . Severe Allergic Reactions Educate patients on the symptoms of hypersensitivity and to discontinue FORFIVO XL if they have a severe allergic reaction. Seizure Instruct patients to discontinue and not restart FORFIVO 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 avoid the use of alcohol. Angle-closure Glaucoma Patients should be advised that taking FORFIVO 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 FORFIVO XL contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that FORFIVO XL should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN XL, the extended-release formulation; 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 hydrochloride products for the immediate-, sustained-, and extended-release formulations. Potential for Cognitive and Motor Impairment Advise patients that any CNS-active drug like FORFIVO XL tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that FORFIVO XL tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. FORFIVO 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 FORFIVO XL tablets 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 with FORFIVO XL. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FORFIVO XL during pregnancy [see Use in Specific Populations ( 8.1 )] . Administration Information Instruct patients to swallow FORFIVO XL tablets whole so that the release rate is not altered. Instruct patients that FORFIVO XL tablets should not be chewed, divided, or crushed. FORFIVO XL may be taken with or without food. FORFIVO XL is a registered trademark of TWi Pharmaceuticals, Inc. All other products/brand names are trademarks of their respective owners.
Label text from the FDA structured product label by Upsher-Smith Laboratories, LLC (revised Nov 6, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Bupropion Hydrochloride in 1 product
Forfivo NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 24979-247 | Bupropion Hydrochloride 450 mg/1 Tablet, Film Coated, Extended Release | Upsher-Smith Laboratories, LLC | NDA |
Frequently asked questions
What is Forfivo used for?
(bupropion hydrochloride extended-release tablets) is indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The efficacy of the…
What are the side effects of Forfivo?
The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal thoughts and behaviors in children, adolescents, and young adults [see Warnings and Precautions ( 5.1 )] • Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see Warnings and Precautions ( 5.2 )] • Seizure [see Warnings and Precautions ( 5.3 )] • Hypertension… See the full label for the complete list.
Who makes Forfivo?
Forfivo is listed by 1 labeler in the FDA NDC directory, including Upsher-Smith Laboratories, LLC.