Bupropion Hydrochloride XL: Package Insert and Label Information

BUPROPION HYDROCHLORIDE XL- bupropion hydrochloride tablet, extended release
Slate Run Pharmaceuticals, LLC

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in subjects aged 65 and older [ see Warnings and Precautions ( 5.1)] .

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions ( 5.1)] .

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder (MDD)

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 Disorde (SAD)

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 DOSAGE AND ADMINISTRATION

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 hydrochloride 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 (Bupropion Hydrochloride Tablets) or from WELLBUTRIN SR (Bupropion Hydrochloride Extended-Release Tablets (SR))

When switching patients from WELLBUTRIN (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 (XL) 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) 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)].

3 DOSAGE FORMS AND STRENGTHS

Bupropion Hydrochloride Extended-Release Tablets USP (XL), 150 mg of bupropion hydrochloride, are white to pale yellow, round biconvex tablet with imprinting “YH 102” on one side and plain on the other side.

Bupropion Hydrochloride Extended-Release Tablets USP (XL), 300 mg of bupropion hydrochloride, are white to pale yellow, round biconvex tablet with imprinting “YH 101” on one side and plain 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 WARNINGS AND PRECAUTIONS

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 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 Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18 years 14 additional cases
18-24 years 5 additional cases
Decreases Compared to Placebo
25-64 years 1 fewer case
≥65 years 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 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.

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