Side Effects of Forfivo XL (bupropion hydrochloride)

Forfivo XL (bupropion hydrochloride) is an antidepressant that affects chemicals within the brain that nerves use to send messages to each other. Forfivo XL is an extended-release form of bupropion hydrochloride.

Many experts believe depression is caused by an imbalance among the amounts of neurotransmitters that are released. Nerves may recycle neurotransmitters by a process referred to as reuptake in which the released neurotransmitters are taken up and reused (released again) by the nerves. 

Forfivo XL works by inhibiting the reuptake of dopamine, serotonin, and norepinephrine by the nerves after they have been released, an action that results in more dopamine, serotonin, and norepinephrine to transmit messages to other nerves. 

Bupropion is unique and unlike other antidepressants in that its major effect is on dopamine, an effect that is not shared by the related selective serotonin reuptake inhibitors (SSRIs). 

Common side effects of Forfivo XL include agitation, dry mouth, insomnia, headache, nausea, constipation, tremor, and weight loss.

Serious side effects of Forfivo XL include manic episodes, hallucinations, and increased risk of suicidal thinking and behavior (suicidality) in children and adolescents with depression and other psychiatric disorders.

Drug interactions of Forfivo XL include drugs that reduce the threshold for seizures, such as include prochlorperazine, chlorpromazine, and other antipsychotic medications of the phenothiazine class.

Additionally, persons who are withdrawing from benzodiazepines are at increased risk for seizures. Carbamazepine may reduce the effect of Forfivo XL by reducing its blood concentration. Monoamine oxidase inhibitors (MAOIs) should not be combined with Forfivo XL because of the risk of severe reactions.

At least 14 days should elapse between discontinuation of a monoamine oxidase inhibitor and initiation of Forfivo XL. Forfivo XL may affect the action of warfarin. Ritonavir may increase the breakdown and elimination of Forfivo XL. 

There are no adequate studies of Forfivo XL in pregnant women. In one study, there was no difference between Forfivo XL and other antidepressants in the occurrence of birth defects. Forfivo XL should only be used in pregnancy if the benefit outweighs the potential risk. 

Forfivo XL is secreted in breast milk. Consult your doctor before breastfeeding.

What are the common side effects of Forfivo XL?

The most common side effects associated with bupropion are:

• agitation,
• dry mouth,
• insomnia,
• headache,
• nausea,
• constipation, and
• tremor.

In some people, the agitation or insomnia is most marked shortly after starting therapy. Some patients may experience weight loss. Uncommonly, patients may experience manic episodes or hallucinations.

Four of every 1000 persons who receive bupropion in doses less than 450 mg/day experience seizures. When doses exceed 450 mg/day, the risk increases ten-fold. Other risk factors for seizures include past injury to the head and medications which can lower the threshold for seizures. (See drug interactions.)

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with depression and other psychiatric disorders. Anyone considering the use of Forfivo or any other antidepressant in a child or adolescent must balance this risk with the clinical need.

Patients who are started on therapy should be closely observed for clinical worsening, suicidality, or unusual changes in behavior.

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.

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.
• Carbamazepine, Phenobarbital, and Phenytoin: Although not systematically studied, these drugs may induce metabolism of bupropion and may decrease bupropion exposure.
• 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 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 (eg, venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (eg, haloperidol, risperidone, and thioridazine), beta-blockers (eg, metoprolol), and Type 1C antiarrhythmics (eg, 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 (eg, 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.

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 (eg, other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids) should be undertaken only with extreme caution.

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.

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 ForfivoXL in vitro. The consumption of alcohol during treatment with Forfivo XL should be avoided.

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.

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

Controlled Substance

Bupropion is not a controlled substance.

Abuse

Humans

• 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 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 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 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.
• Bupropion hydrochloride extended-release tablets are 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.

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.

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 
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment 
• Seizure 
• Hypertension 
• Activation of mania or hypomania 
• Psychosis and other neuropsychiatric events 
• Angle-closure Glaucoma 
• Hypersensitivity reactions

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 sustainedrelease 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

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

The following additional adverse reactions occurred in controlled trials of bupropion hydrochloride immediate-release (300 to 600 mg/day) at an incidence of at least 1% more frequently than in the placebo group:

• 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%).

Changes In Body Weight

Table 4 presents the incidence of body weight changes ( ≥ 5 lbs) in the short-term MDD trials using bupropion hydrochloride sustained-release. There was a dose-related decrease in body weight.

Table 4: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in Placebo-controlled Trials of Bupropion Hydrochloride Sustained-release Tablets for Major Depressive Disorder

Postmarketing Experience

The following adverse reactions have been identified during postapproval 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.

• 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.