Prescription Drug Information: Bupropion Hydrochloride SR (Page 3 of 8)

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment

WELLBUTRIN, bupropion hydrochloride extended-release tablets (SR), and WELLBUTRIN XL are not approved for smoking cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking bupropion who continued to smoke. When symptoms were reported, most were during bupropion treatment, but some were following discontinuation of bupropion therapy.

These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.

Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of ZYBAN.

Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion 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. In many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. It should be noted that bupropion hydrochloride extended-release tablets (SR) is not approved for use in treating bipolar depression.

Bupropion-Containing Products

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in ZYBAN ®, used as an aid to smoking cessation treatment and that bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN ® or any other medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride), the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-release formulation.

Seizures

Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride extended-release tablets (SR). Bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment.

  • Dose: At doses of bupropion hydrochloride extended-release tablets (SR) up to a dose of 300 mg/day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg/day.

    Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300 mg/day to 450 mg/day. The 450 mg/day upper limit of this dose range is close to the currently recommended maximum dose of 400 mg/day for bupropion hydrochloride extended-release tablets (SR). This seizure incidence (0.4%) may exceed that of other marketed antidepressants and bupropion hydrochloride extended-release tablets (SR) up to 300 mg/day by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted.

    Additional data accumulated for the immediate-release formulation of bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 mg/day and 600 mg/day, which is twice the usual adult dose and one and one-half the maximum recommended daily dose (400 mg) of bupropion hydrochloride extended-release tablets (SR). This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.

    Data for bupropion hydrochloride extended-release tablets (SR) revealed a seizure incidence of approximately 0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at doses in a range of 100 mg/day to 300 mg/day. It is not possible to know if the lower seizure incidence observed in this study involving the extended-release formulation of bupropion resulted from the different formulation or the lower dose used. However, as noted above, the immediate-release and extended-release formulations are bioequivalent with regard to both rate and extent of absorption during steady state (the most pertinent condition to estimating seizure incidence), since most observed seizures occur under steady-state conditions.

  • Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis and concomitant medications that lower seizure threshold.
  • Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
  • Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.

Recommendations for Reducing the Risk of Seizure

Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if

  • the total daily dose of bupropion hydrochloride extended-release tablets (SR) does not exceed 400 mg,
  • the daily dose is administered twice daily and
  • the rate of incrementation of dose is gradual.
  • No single dose should exceed 200 mg to avoid high peak concentrations of bupropion and/or its metabolites.

Bupropion hydrochloride extended-release tablets (SR) should be administered with extreme caution to patients with a history of seizure, cranial trauma or other predisposition(s) toward seizure or patients treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.

Hepatic Impairment

Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 100 mg every day or 150 mg every other day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Potential for Hepatotoxicity

In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver and laboratory tests suggesting mild hepatocellular injury were noted.

PRECAUTIONS

General

Agitation and Insomnia

Patients in placebo-controlled trials with bupropion hydrochloride extended-release tablets (SR) experienced agitation, anxiety and insomnia as shown in Table 2.

Table 2: Incidence of Agitation, Anxiety and Insomnia in Placebo-Controlled Trials
Adverse Event Term

Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day

(n=376)

Bupropion Hydrochloride Extended-Release Tablets (SR) 400 mg/day

(n=114)

Placebo

(n=385)

Agitation

Anxiety

3%

5%

9%

6%

2%

3%

In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.

Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 mg/day and 400 mg/day, respectively, of bupropion hydrochloride extended-release tablets (SR) and 0.8% of patients treated with placebo.

Psychosis, Confusion and Other Neuropsychiatric Phenomena

Depressed patients treated with an immediate-release formulation of bupropion or with bupropion hydrochloride extended-release tablets (SR) have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

Activation of Psychosis and/or Mania

Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Bupropion hydrochloride extended-release tablets (SR) are expected to pose similar risks.

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