WELLBUTRIN- bupropion hydrochloride tablet, film coated
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC REACTIONS
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 over age 24; there was a reduction in risk 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)].
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR SMOKING CESSATION
Serious neuropsychiatric reactions have occurred in patients taking bupropion for smoking cessation [see Warnings and Precautions (5.2)]. The majority of these reactions occurred during bupropion treatment, but some occurred in the context of discontinuing treatment. In many cases, a causal relationship to bupropion treatment is not certain, because depressed mood may be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke. Although WELLBUTRIN® is not approved for smoking cessation, observe all patients for neuropsychiatric reactions. Instruct the patient to contact a healthcare provider if such reactions occur [see Warnings and Precautions (5.2)].
1 INDICATIONS AND USAGE
WELLBUTRIN (bupropion hydrochloride) is indicated for the treatment of major depressive disorder(MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of WELLBUTRIN in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD [see Clinical Studies (14)].
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)]. Increases in dose should not exceed 100 mg per day in a 3?day period. WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN may be taken with or without food.
The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg per day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg per day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg per day. Administer the 100?mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of WELLBUTRIN 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.
2.2 Dose Adjustment in Patients with Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN is 75 mg per 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), Clinical Pharmacology (12.3)].
2.3 Dose Adjustment in Patients with Renal Impairment
Consider reducing the dose and/or frequency of WELLBUTRIN in patients with renal impairment (Glomerular Filtration Rate less than 90 mL per min) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
2.4 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 WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN before starting an MAOI antidepressant [see Contraindications (4), Drug Interactions (7.6)].
2.5 Use of WELLBUTRIN with Reversible MAOIs Such as Linezolid or Methylene Blue
Do not start WELLBUTRIN 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, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications (4), Drug Interactions (7.6)].
In some cases, a patient already receiving therapy with WELLBUTRIN 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, WELLBUTRIN 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 WELLBUTRIN 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 WELLBUTRIN is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications (4), Drug Interactions (7.6)].
3 DOSAGE FORMS AND STRENGTHS
75 mg – yellow?gold, round, biconvex tablets printed with “WELLBUTRIN 75”.
100 mg – red, round, biconvex tablets printed with “WELLBUTRIN 100”.
WELLBUTRIN is contraindicated in patients with a seizure disorder.
WELLBUTRIN is 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 WELLBUTRIN [see Warnings and Precautions (5.3)].
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3), Drug Interactions (7.3)].
The use of MAOIs (intended to treat psychiatric disorders) concomitantly with WELLBUTRIN or within 14 days of discontinuing treatment with WELLBUTRIN is contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN is used concomitantly with MAOIs. The use of WELLBUTRIN within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4), Drug Interactions (7.6)].
WELLBUTRIN is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of WELLBUTRIN. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported.
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 (including QRS prolongation) 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 Physician’s 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. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.
WELLBUTRIN (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 (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13 H18 ClNO•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.
WELLBUTRIN is supplied for oral administration as 75?mg (yellow?gold) and 100?mg (red) film?coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: 75?mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100?mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.