Wellbutrin XL NDA 21-515

231 (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications

232 that lower seizure threshold

233 ● Clinical situations: Circumstances associated with an increased seizure risk include,

234 among others, excessive use of alcohol or sedatives (including benzodiazepines);

235 addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and

236 anorectics; and diabetes treated with oral hypoglycemics or insulin.

237 ● Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,

238 theophylline, systemic steroids) are known to lower seizure threshold.

239 Recommendations for Reducing the Risk of Seizure: Retrospective analysis of

240 clinical experience gained during the development of bupropion suggests that the risk of

241 seizure may be minimized if

242 ● the total daily dose of WELLBUTRIN XL Tablets does not exceed 450 mg,

243 ● the rate of incrementation of dose is gradual.

244 WELLBUTRIN XL should be administered with extreme caution to patients with a

245 history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients

246 treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic

247 steroids, etc.) that lower seizure threshold.

248 Hepatic Impairment: WELLBUTRIN XL should be used with extreme caution in patients

249 with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,

250 as peak bupropion, as well as AUC, levels are substantially increased and accumulation is

251 likely to occur in such patients to a greater extent than usual. The dose should not exceed

252 150 mg every other day in these patients (see CLINICAL PHARMACOLOGY,

253 PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

254 Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there

255 was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In

256 dogs receiving large doses of bupropion chronically, various histologic changes were seen in the

257 liver, and laboratory tests suggesting mild hepatocellular injury were noted.

258 PRECAUTIONS

259 General: Agitation and Insomnia: Increased restlessness, agitation, anxiety, and insomnia

260 especially shortly after initiation of treatment, have been associated with treatment with

261 bupropion. Patients in placebo-controlled trials with WELLBUTRIN SR, the sustained-release

262 formulation of bupropion, experienced agitation, anxiety, and insomnia as shown in Table 1.