FDA Label for Bupropion Hydrochloride XL

1.1 Major Depressive Disorder

Bupropion hydrochloride extended-release tablets (XL) are 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 (14.1)].

1.2 Seasonal Affective Disorder

Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD).

The efficacy of bupropion hydrochloride extended-release tablets in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined in the DSM [see Clinical Studies (14.2)].

2.1 General Instructions For Use

To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3)].

Bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed.

Bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may be taken with or without food.

2.2 Dosage For Major Depressive Disorder (Mdd)

The recommended starting dose for MDD is 150 mg once daily in the morning. After 4 days of dosing, the dose may be increased to the target dose of 300 mg once daily in the morning.

It is generally agreed that acute episodes of depression require several months or longer of antidepressant treatment beyond the response in the acute episode. It is unknown whether the bupropion hydrochloride extended-release tablets (XL) 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.

2.3 Dosage For Seasonal Affective Disorder (Sad)

The recommended starting dose for SAD is 150 mg once daily. After 7 days of dosing, the dose may be increased to the target dose of 300 mg once daily in the morning. Doses above 300 mg of bupropion HCl extended-release were not assessed in the SAD trials.

For the prevention of seasonal MDD episodes associated with SAD, initiate bupropion hydrochloride extended-release tablets (XL) in the autumn, prior to the onset of depressive symptoms. Continue treatment through the winter season. Taper and discontinue bupropion hydrochloride extended-release tablets (XL) in early spring. For patients treated with 300 mg per day, decrease the dose to 150 mg once daily before discontinuing bupropion hydrochloride extended-release tablets (XL). Individualize the timing of initiation, and duration of treatment should be individualized, based on the patient’s historical pattern of seasonal MDD episodes. 

2.4 Switching Patients From Wellbutrin® Tablets (Bupropion Hydrochloride Tablets) Or From Wellbutrin® Sr (Bupropion Hydrochloride Extended-Release Tablets (Sr))

When switching patients from WELLBUTRIN ^® Tablets (bupropion hydrochloride tablets) to bupropion hydrochloride extended-release tablets (XL) or from WELLBUTRIN ^® SR (bupropion hydrochloride extended-release tablets (SR)) to bupropion hydrochloride extended-release tablets (XL), give the same total daily dose when possible.

2.5 To Discontinue Bupropion Hydrochloride Extended-Release Tablets (Xl), Taper The Dose

When discontinuing treatment in patients treated with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily, decrease the dose to 150 mg once daily prior to discontinuation.

2.6 Dosage Adjustment In Patients With Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.7 Dose Adjustment In Patients With Renal Impairment

Consider reducing the dose and/or frequency of bupropion hydrochloride extended-release tablets in patients with renal impairment (glomerular filtration rate less than 90 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .

2.8 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 bupropion hydrochloride extended-release tablets (XL). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL) before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.6)].

2.9 Use Of Bupropion Hydrochloride Extended-Release Tablets (Xl) With Reversible Maois Such As Linezolid Or Methylene Blue

Do not start bupropion hydrochloride extended-release tablets (XL) in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications (4)].

In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release tablets (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, bupropion hydrochloride extended-release tablets (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 bupropion hydrochloride extended-release tablets (XL) may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg per kg with bupropion hydrochloride extended-release tablets  (XL) are 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)].

3 Dosage Forms And Strengths

Bupropion hydrochloride extended-release tablets (XL), 300 mg of bupropion hydrochloride, are white to off white round tablets printed with “T011” on one side and blank on the other side.

4 Contraindications

• Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with seizure disorder.
• Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with bupropion hydrochloride extended-release tablets (XL) [see Warnings and Precautions (5.3)].
• Bupropion hydrochloride extended-release tablets (XL) are 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 bupropion hydrochloride extended-release tablets (XL) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (XL) is contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are used concomitantly with MAOIs. The use of bupropion hydrochloride extended-release tablets (XL) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride extended-release tablets (XL) in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration (2.9), Warnings and Precautions (5.4) and Drug Interactions (7.6)].
• Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (XL). Anaphylactoid/anaphylactic reactions and Stevens-Johnson Syndrome have been reported [see Warnings and Precautions (5.8)].

5.1 Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults

Patients with major depressive disorder (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 (Selective Serotonin Reuptake Inhibitors [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 major depressive disorder (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 4400 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 1000 patients treated) are provided in Table 1.

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 major depressive disorder 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.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion hydrochloride extended-release tablets (XL) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.2 Neuropsychiatric Adverse Events And Suicide Risk In Smoking Cessation Treatment

Bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports 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 [see Adverse Reactions (6.2)]. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. The healthcare provider should evaluate the severity of the adverse events and the extent to which the patient is benefiting from treatment, and consider options including continued treatment under closer monitoring, or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

5.3 Seizure

Bupropion hydrochloride extended-release tablets (XL) can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue bupropion hydrochloride extended-release tablets (XL) and do not restart treatment if the patient experiences a seizure.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with bupropion hydrochloride extended-release tablets (XL). Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4)]. The following conditions can also increase the risk of seizure: concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), or use of illicit drugs (e.g., cocaine) or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin, use of anorectic drugs, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence of Seizure with Bupropion Use

The incidence of seizure with bupropion hydrochloride extended-release tablets (XL) has not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.

Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the bupropion hydrochloride extended-release tablets (XL) dose does not exceed 450 mg once daily and the titration rate is gradual.

5.4 Hypertension

Treatment with bupropion hydrochloride extended-release tablets (XL) can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride extended-release tablets (XL), and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride extended-release tablets (XL) are used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications (4)].

Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p=0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p=0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days.

In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled studies assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.

5.5 Activation Of Mania/Hypomania

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating bupropion hydrochloride extended-release tablets (XL), screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Bupropion hydrochloride extended-release tablets (XL) are not approved for the treatment of bipolar depression.

5.6 Psychosis And Other Neuropsychiatric Reactions

Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Discontinue bupropion hydrochloride extended-release tablets (XL) if these reactions occur.

5.7 Angle-Closure Glaucoma

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including bupropion hydrochloride extended-release tablets (XL) may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.8 Hypersensitivity Reactions

Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea, requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson Syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion hydrochloride extended-release tablets (XL) and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

There are reports of arthralgia, myalgia, fever with rash and other symptoms of serum sickness suggestive of delayed hypersensitivity.

6 Adverse Reactions

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)]

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 practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bupropion hydrochloride extended-release tablets (XL). 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.

7.1 Potential For Other Drugs To Affect Bupropion Hydrochloride Extended-Release Tablets (Xl)

Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL) and drugs that are inhibitors or inducers of CYP2B6.

Inhibitors of CYP2B6

Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].

Inducers of CYP2B6

Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [see Clinical Pharmacology (12.3)].

Carbamazepine, Phenobarbital, Phenytoin: While not systemically 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 Bupropion Hydrochloride Extended-Release Tablets (Xl) To Affect Other Drugs

Drugs Metabolized by CYP2D6

Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion hydrochloride extended-release tablets (XL) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include 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). When used concomitantly with bupropion hydrochloride extended-release tablets (XL), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen), theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride extended-release tablets (XL) and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].

7.3 Drugs That Lower Seizure Threshold

Use extreme caution when coadministering bupropion hydrochloride extended-release tablets (XL) with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of bupropion hydrochloride extended-release tablets (XL) and increase the dose gradually [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. Use caution when administering bupropion hydrochloride extended-release tablets (XL) concomitantly with these drugs.

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 hydrochloride extended-release tablets (XL). The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (XL) should be minimized or avoided

7.6 Mao Inhibitors

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 intended to treat depression and initiation of treatment with bupropion hydrochloride extended-release tablets (XL). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL) before starting an MAOI antidepressant [see Dosage and Administration (2.8, 2.9) 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. 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.

8.3 Nursing Mothers

Bupropion and its metabolites are present in human milk. In a lactation study of ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when bupropion hydrochloride extended-release tablets (XL) are administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established. When considering the use of bupropion hydrochloride extended-release tablets (XL) in a child or adolescent, balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions (5.1)].

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 old and 47 were ≥75 years old. 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 (2.7), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Consider a reduced dose and/or dosing frequency of bupropion hydrochloride extended-release tablets (XL) in patients with renal impairment (glomerular filtration rate: <90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum bupropion hydrochloride extended-release tablets (XL) dose is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Bupropion is not a controlled substance.

10.1 Human Overdose Experience

Overdoses of up to 30 grams 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, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. 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. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). 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.

11 Description

Bupropion hydrochloride extended-release tablets (XL), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C ₁₃H ₁₈ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is:

Wellbutrin Chemical Structure - bupropion extended release tablets xl 1

Bupropion hydrochloride extended-release tablets (XL) are supplied for oral administration as 300 mg white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: alcohol, ethylcellulose, hydrochloric acid, hydroxypropyl cellulose, hypromellose, methacrylic acid and ethyl acrylate copolymer, polyethylene glycol, povidone, purified water, silicon dioxide, stearic acid and talc. The tablets are printed with edible black ink, which contains ferrosoferric oxide, hypromellose, propylene glycol, and purified water.

The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is eliminated in the feces.

FDA approved dissolution test specifications differ from the USP.

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.

12.3 Pharmacokinetics

Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied.

Following chronic dosing, the mean steady-state plasma concentration of bupropion was reached within 8 days. The mean elimination half-life (±SD) of bupropion is 21 (±9) hours.

In a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day bupropion hydrochloride, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m ² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day of bupropion hydrochloride (approximately 2 to 7 times the MRHD on a mg/m ² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in one Ames bacterial mutagenicity assay, but was negative in another. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.

14.1 Major Depressive Disorder

The efficacy of bupropion in the treatment of major depressive disorder was established with the immediate-release formulation of bupropion hydrochloride in two 4-week, placebo-controlled trials in adult inpatients with MDD and in one 6-week, placebo-controlled trial in adult outpatients with MDD. In the first study, the bupropion dose range was 300 mg to 600 mg per day administered in 3 divided doses; 78% of patients were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of bupropion as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (item 1), and the Clinical Global Impressions-Severity Scale (CGI-S). The second study included 2 fixed doses of bupropion (300 mg and 450 mg per day) and placebo. This trial demonstrated the efficacy of bupropion for only the 450 mg dose. The efficacy results were significant for the HAMD total score and the CGI-S severity score, but not for HAMD item 1. In the third study, outpatients were treated with bupropion 300 mg per day. This study demonstrated the efficacy of bupropion as measured by the HAMD total score, the HAMD item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.

A longer-term, placebo-controlled, randomized withdrawal trial demonstrated the efficacy of bupropion HCl sustained-release in the maintenance treatment of MDD. The trial included adult outpatients meeting DSM-IV criteria for MDD, recurrent type, who had responded during an 8-week open-label trial of bupropion 300 mg per day. Responders were randomized to continuation of bupropion 300 mg per day or placebo for up to 44 weeks of observation for relapse. Response during the open-label phase was defined as a CGI-Improvement Scale score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients in the bupropion group experienced significantly lower relapse rates over the subsequent 44 weeks compared to those in the placebo group.

Although there are no independent trials demonstrating the efficacy of bupropion hydrochloride extended-release tablets (XL) in the acute treatment of MDD, studies have demonstrated similar bioavailability between the immediate-, sustained-, and extended-release formulations of bupropion HCl under steady-state conditions (i.e., the exposures [C _max and AUC] for bupropion and its metabolites are similar among the 3 formulations).

14.2 Seasonal Affective Disorder

The efficacy of bupropion hydrochloride extended-release tablets (XL) in the prevention of seasonal major depressive episodes associated with SAD was established in 3 randomized, double-blind, placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern (as defined by DSM-IV criteria). Bupropion treatment was initiated prior to the onset of symptoms in the autumn (September to November). Treatment was discontinued following a 2-week taper that began during the first week of spring (fourth week of March), resulting in a treatment duration of approximately 4 to 6 months for the majority of patients. Patients were randomized to treatment with bupropion hydrochloride extended-release tablets (XL) or placebo. The initial bupropion dose was 150 mg once daily for 1 week, followed by up-titration to 300 mg once daily. Patients who were deemed by the investigator to be unlikely or unable to tolerate 300 mg once daily were allowed to remain on, or had their dose reduced to, 150 mg once daily. The mean bupropion doses in the 3 trials ranged from 257 mg to 280 mg per day. Approximately 59% of patients continued in the study for 3 to 6 months; 26% continued for <3 months, 15% continued for >6 months.

To enter the trials, patients must have had a low level of depressive symptoms, as demonstrated by a score of <7 on the Hamilton Depression Rating Scale-17 (HAMD17) and a HAMD24 score of <14. The primary efficacy measure was the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders (SIGH-SAD), which is identical to the HAMD24. The SIGH-SAD consists of the HAMD17 plus 7 items specifically assessing core symptoms of seasonal affective disorder: social withdrawal, weight gain, increased appetite, increased eating, carbohydrate craving, hypersomnia, and fatigability. The primary efficacy endpoint was the onset of a seasonal major depressive episode. The criteria for defining an episode included: 1) the investigator’s judgment that a major depressive episode had occurred or that the patient required intervention for depressive symptoms, or 2) a SIGH-SAD score of >20 on 2 consecutive weeks. The primary analysis was a comparison of depression-free rates between the bupropion and placebo groups.

In these 3 trials, the percentage of patients who were depression-free (did not have an episode of MDD) at the end of treatment was significantly higher in the bupropion group than in the placebo group: 81.4% vs. 69.7%, 87.2% vs. 78.7%, and 84.0% vs. 69.0% for Trials 1, 2 and 3, respectively. For the 3 trials combined, the depression-free rate was 84.3% versus 72.0% in the bupropion and placebo group, respectively.

16 How Supplied/Storage And Handling

Bupropion hydrochloride extended-release tablets (XL), 300 mg of bupropion hydrochloride, are white to off-white, round tablets printed with "T011". They are supplied as follows:

Bottles of 30 tablets NDC 71765-002-03

Bottles of  90 tablets NDC 71765-002-09 

Bottles of 500 tablets NDC 71765-002-50.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light.

 Bupropion hydrochloride extended-release tablets (XL) may have an odor.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (XL) and counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (XL)?” is available for bupropion hydrochloride extended-release tablets (XL). Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Advise patients regarding the following issues and to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets (XL).

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 bupropion hydrochloride extended-release tablets (XL) are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN ^® which is approved for this use. 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 bupropion hydrochloride extended-release tablets (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 bupropion hydrochloride extended-release tablets (XL) if they have a severe allergic reaction.

Seizure

Instruct patients to discontinue and not restart bupropion hydrochloride extended-release tablets (XL) if they experience a seizure while on treatment. Advise patients that the excessive use or the abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid the use of alcohol.

Angle-Closure Glaucoma

Patients should be advised that taking bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.7)].

Bupropion-Containing Products

Educate patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) found in ZYBAN ^®, which is used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets should not be used in combination with ZYBAN ^® or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN ^® SR, the sustained-release formulation, WELLBUTRIN ^®, the immediate-release formulation, and APLENZIN ^®, a bupropion hydrobromide formulation). In addition, there are a number of generic bupropion HCl products for the immediate, sustained, and extended-release formulations.

Potential for Cognitive and Motor Impairment

Advise patients that any CNS-active drug like bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that bupropion hydrochloride extended-release tablets (XL) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion hydrochloride extended-release tablets (XL) treatment may lead to decreased alcohol tolerance.

Concomitant Medications

Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs, because bupropion hydrochloride extended-release tablets (XL) and other drugs may affect each other’s metabolism.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.

Precautions for Nursing Mothers

Communicate with the patient and pediatric healthcare provider regarding the infant’s exposure to bupropion through human milk. Instruct patients to immediately contact the infant’s healthcare provider if they note any side effect in the infant that concerns them or is persistent.

Administration Information

Instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole so that the release rate is not altered. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may be taken with or without food.

Manufactured by:
Tulex Pharmaceuticals Inc.
Cranbury, NJ 08512 USA

Manufactured for:

Zhejiang Jutai Pharmaceutical Co., Ltd.
No. 51 Donggang Road, Kecheng District,
Quzhou City, Zhejiang Province,
China 324022

All product/brand names are the trademarks of their respective owners.

PI0010000203 Rev. 08/2019

Principal Display Panel - 300 Mg Tablet Bottle Label

NDC 71765- 002-03

Rx Only

Once-Daily

buPROPion Hydrochloride

Extended-Release Tablets, (XL)

300mg                                 

Warning: Do not use in combination with Zyban® or with any other medicine that contains bupropion hydrochloride.

Pharmacists: Dispense the Medication Guide provided separately to each patient.

30 Tablets

Zhejiang Jutai Pharmaceuticals Co., Ltd

LA0020300202 05/2019

Lot:

Exp:

Bupropion Hydrochloride Extended-Release Tablets (XL), 300 mg, 30 count - bupropion extended release tablets xl 2

NDC 71765- 002-09

Rx Only

Once-Daily

buPROPion Hydrochloride

Extended-Release Tablets, (XL)

300mg                                 

Warning: Do not use in combination with Zyban® or with any other medicine that contains bupropion hydrochloride.

Pharmacists: Dispense the Medication Guide provided separately to each patient.

90 Tablets

Zhejiang Jutai Pharmaceuticals Co., Ltd

LA0020900202 05/2019

Lot:

Exp:

NDC 71765- 002-50

Rx Only

Once-Daily

buPROPion Hydrochloride

Extended-Release Tablets, (XL)

300mg                                 

Warning: Do not use in combination with Zyban® or with any other medicine that contains bupropion hydrochloride.

Pharmacists: Dispense the Medication Guide provided separately to each patient.

500 Tablets

Zhejiang Jutai Pharmaceuticals Co., Ltd

LA0025000202 05/2019

Lot:

Exp: