Bupropion Hydrochloride SR (Page 3 of 10)

5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

Serious neuropsychiatric adverse events have been reported in patients taking bupropion hydrochloride extended-release tablets (SR) for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Adverse Reactions (6.2)]. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion hydrochloride extended-release tablets (SR) who continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illness. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking bupropion hydrochloride extended-release tablets (SR) and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. The healthcare provider should evaluate the severity of the adverse events and the extent to which the patient is benefiting from treatment, and consider options including continued treatment under closer monitoring or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion hydrochloride extended-release tablets (SR) was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

The neuropsychiatric safety of bupropion hydrochloride extended-release tablets (SR) was evaluated in a randomized, double-blind, active- and placebo-controlled study that included patients without a history of psychiatric disorder (non-psychiatric cohort, n = 3,912) and patients with a history of psychiatric disorder (psychiatric cohort n = 4,003). In the non-psychiatric cohort, bupropion hydrochloride extended-release tablets (SR) were not associated with an increase composite of the following neuropsychiatric (NPS) adverse events: severe events of anxiety, depression, feeling abnormal, or hostility, and moderate or severe events of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability. In the psychiatric cohort, there were more events reported in each treatment group compared with the non-psychiatric cohort and the incidence of events in the composite endpoint was higher for bupropion hydrochloride extended-release tablets (SR) compared with placebo: Risk Difference (95% CI) vs. placebo was 2.2% (-0.5, 4.9) for bupropion hydrochloride extended-release tablets (SR).

In the non-psychiatric cohort, neuropsychiatric adverse events of a serious nature were reported in 0.5% of patients treated with bupropion hydrochloride extended-release tablets (SR) and 0.4% of placebo-treated patients. In the psychiatric cohort, neuropsychiatric events of a serious nature were reported in 0.8% of patients treated with bupropion hydrochloride extended-release tablets (SR), all involving psychiatric hospitalization. In placebo-treated patients, serious neuropsychiatric events occurred in 0.6%, with 0.2% requiring psychiatric hospitalization [see Clinical Studies (14)].

5.3 Seizure

Bupropion hydrochloride extended-release tablets (SR) can cause seizure. The risk of seizure is dose-related. The dose of bupropion hydrochloride extended-release tablets (SR) should not exceed 300 mg per day [see Dosage and Administration (2.1)]. Discontinue bupropion hydrochloride extended-release tablets (SR) and do not restart treatment if the patient experiences a seizure.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with bupropion hydrochloride extended-release tablets (SR). Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4), Drug Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), use of illicit drugs (e.g., cocaine), or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence of Seizure with Bupropion Use

Doses for smoking cessation should not exceed 300 mg per day. The seizure rate associated with doses of sustained-release bupropion in depressed patients up to 300 mg per day is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1000) at doses up to 400 mg per day.

The risk of seizure can be reduced if the dose of bupropion hydrochloride extended-release tablets (SR) for smoking cessation does not exceed 300 mg per day, given as 150 mg twice daily, and titration rate is gradual.

5.4 Hypertension

Treatment with bupropion hydrochloride extended-release tablets (SR) can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride extended-release tablets (SR), and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride extended-release tablets (SR) are used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications (4)].

Data from a comparative trial of bupropion hydrochloride extended-release tablets (SR), NTS, the combination of bupropion hydrochloride extended-release tablets (SR) plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of bupropion hydrochloride extended-release tablets (SR) and NTS. In this trial, 6.1% of subjects treated with the combination of bupropion hydrochloride extended-release tablets (SR) and NTS had treatment-emergent hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with bupropion hydrochloride extended-release tablets (SR), NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of bupropion hydrochloride extended-release tablets (SR) and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with bupropion hydrochloride extended-release tablets (SR) or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.

5.5 Activation of Mania/Hypomania

Antidepressant treatment can precipitate a manic, mixed, or hypomanic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. There were no reports of activation of psychosis or mania in premarketing clinical trials with bupropion hydrochloride extended-release tablets (SR) conducted in nondepressed smokers. However, events of this nature were seen in patients with pre-existing psychiatric diagnoses in a smoking cessation trial [see Warnings and Precautions (5.2)]. Bupropion is not approved for use in treating bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion in depression trials have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur.

In premarketing clinical trials with bupropion hydrochloride extended-release tablets (SR) conducted in non-depressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. However, in the postmarketing experience, patients taking bupropion hydrochloride extended-release tablets (SR) to quit smoking have reported similar types of neuropsychiatric symptoms to those reported by patients in the clinical trials of bupropion for depression [see Warnings and Precautions (5.2)].

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