Wellbutrin XL NDA 21-515

620 Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted

621 in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients

622 showed some increase in motor activity and agitation/excitement.

623 In a population of individuals experienced with drug of abuse, a single dose of 400 mg of

624 bupropion produced a mild amphetamine-like activity as compared to placebo on the

625 Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a

626 Score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These

627 scales measure general feelings of euphoria and drug desirability.

628 Findings in clinical trials, however, are not known to reliably predict the abuse potential of

629 drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily

630 dosage of bupropion when administered in divided doses is not likely to be especially reinforcing

631 to amphetamine or stimulant abusers. However, higher doses that could not be tested because of

632 the risk of seizure might be modestly attractive to those who abuse stimulant drugs.

633 Animals: Studies in rodents and primates have shown that bupropion exhibits some

634 pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase

635 locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of

636 responding in several schedule-controlled behavior paradigms. In primates models to assess the

637 positive reinforcing effects of psychoactive drugs, bupropion self-administered

638 intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative

639 stimulus effects in drug discrimination paradigms used to characterize the subjective effects of

640 psychoactive drugs.

641 OVERDOSAGE

642 Human Overdose Experience: There have been very limited experience with overdosage of

643 the sustained-release formulation of bupropion (WELLBUTRIN SR Tablets); 3 cases were

644 reported during clinical trials. One patient ingested 3,000 mg of the sustained-release formulation

645 of bupropion and vomited quickly after the overdose; the patient experienced blurred vision and

646 lightheadediness. A second patient ingested a “handful” of WELLBUTRIN SR Tablets (the

647 sustained-release formulation) and experienced confusion, lethargy, nausea, jitteriness, and

648 seizure. A third patient ingested 3,600 mg of the sustained-release formulation of bupropion and

649 a bottle of wine; the patient experienced nausea, visual hallucinations, and “grogginess.” None of

650 the patients experienced further sequelae.

651 There had been extensive experience with overdosage of the immediate-release formulation of

652 bupropion. Thirteen overdoses occurred during clinical trials. Twelve patients ingested 850 to

653 4,200 mg and recovered without significant sequelae. Another patient who ingested 9,000 mg of

654 the immediate-release formulation of bupropion and 300 mg of tranylcypromine experienced a

655 grand mal seizure and recovered without further sequelae.

656 Since introduction, overdoses of up to 17,500 mg of the immediate-release formulation of

657 bupropion have been reported. Seizure was reported in approximately one third of all cases.

658 Other serious reactions reported with overdoses of the immediate-release formulation of