Wellbutrin XL NDA 21-515

411 should be approached with caution and should be initiated at the lower end of the dose range of

412 the concomitant medication. If bupropion is added to the treatment regimen of a patient already

413 receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original

414 medication should be considered, particularly for those concomitant medications with a narrow

415 therapeutic index.

416 MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is

417 enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).

418 Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse

419 experiences inpatients receiving bupropion concurrently with either levodopa or amantadine.

420 Administration of WELLBUTRIN XL Tablets to patients receiving either levodopa or

421 amantadine concurrently should be undertaken with caution, using small initial doses and

422 gradual dose increases.

423 Drugs That Lower Seizure Threshold: Concurrent administration of

424 WELLBUTRIN XL Tablets and agents (e.g., antipsychotics, other antidepressants, thephylline,

425 systemic steroids, etc.) that lower seizure threshold should be taken only with extreme

426 caution (see WARNINGS). Low initial dosing and gradual dose increases should be employed.

427 Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).

428 Alcohol: In postmarketing experience, there have been rare reports of adverse

429 neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol

430 during treatment with bupropion. The consumption of alcohol during treatment with

431 WELLBUTRIN XL should be minimized or avoided (also see CONTRAINDICATIONS).

432 Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies

433 were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These

434 doses are approximately 7 and 2 times the maximum recommended human dose (MRHD),

435 respectively, on a mg/m² basis. In the rat study there was an increase in nodular proliferative

436 lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a

437 mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be

438 precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not see

439 in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in

440 either study.

441 Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in

442 the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in

443 vivo rat bone marrow cytogenetic studies.

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

445 fertility.

446 Pregnancy: Teratogenic Effects: Pregnancy Category B. Teratology studies have been

447 performed with bupropion immediate-release formulation at dosages up to 450 mg/kg in rats, and

448 at doses up to 150 mg/kg in rabbits (approximately 7 to 11 and 7 times the MRHD, respectively,

449 on a mg/m² basis), and have revealed no evidence of harm to fetus due to bupropion. There

450 are no adequate and well-controlled studies in pregnant women. Because animal reproduction