bupropion hydrobromide
Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION
Aplenzin® (bupropion hydrobromide) Extended-Release Tablets
Use in treating Psychiatric Disorders: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Aplenzin™ or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Aplenzin is not approved for use in pediatric patients [See WARNINGS AND PRECAUTIONS, Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders (5.1) and USE IN SPECIFIC POPULATIONS, Pediatric Use (8.4)].
Use in Smoking Cessation Treatment: Aplenzin is not approved for smoking cessation treatment, but bupropion under the name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking bupropion for smoking cessation. Some 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.
All patients being treated with bupropion for smoking cessation treatment should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking ZYBAN in the post-marketing experience. When symptoms were reported, most were during treatment with ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. 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, hostility, depressed mood, or changes in thinking or behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing 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 [See WARNINGS AND PRECAUTIONS: Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment (5.2) and PATIENT COUNSELING INFORMATION (17)]
Indications and Usage for Aplenzin
Aplenzin® (bupropion hydrobromide extended-release tablets) is indicated for the treatment of major depressive disorder.
The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of inpatients and in one 6-week controlled trial of outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) [see CLINICAL STUDIES (14)].
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation.
The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial with the sustained-release formulation of bupropion [see CLINICAL STUDIES (14)]. Nevertheless, the physician who elects to use Aplenzin for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Aplenzin Dosage and Administration
General Dosing Considerations
It is particularly important to administer Aplenzin Tablets in a manner most likely to minimize the risk of seizure [see WARNINGS AND PRECAUTIONS: Seizures (5.5)]. Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. Aplenzin should be swallowed whole and not crushed, divided, or chewed. Aplenzin may be taken without regard to meals.
Initial Treatment
The usual adult target dose for Aplenzin Tablets is 348 mg/day (equivalent to 300 mg/day bupropion HCl), given once daily in the morning. Dosing with Aplenzin Tablets should begin at 174 mg/day (equivalent to 150 mg/day bupropion HCl) given as a single daily dose in the morning. If the 174 mg initial dose is adequately tolerated, an increase to the 348 mg/day target dose, given as once daily, may be made as early as day 4 of dosing. There should be an interval of at least 24 hours between successive doses.
Increasing the Dosage Above 348 mg/day: As with other antidepressants, the full antidepressant effect of Aplenzin Tablets may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 522 mg/day, given as a single dose, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 348 mg/day.
Maintenance Treatment
It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. It is unknown whether or not the dose of Aplenzin needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Switching Patients from WELLBUTRIN, WELLBUTRIN SR or WELLBUTRIN XL
When switching patients from WELLBUTRIN®, WELLBUTRIN® SR or WELLBUTRIN XL® Tablets to Aplenzin, give the equivalent total daily dose when possible (522 mg bupropion HBr are equivalent to 450 mg bupropion HCl; 348 mg bupropion HBr are equivalent to 300 mg bupropion HCl; 174 mg bupropion HBr are equivalent to 150 mg bupropion HCl). Patients who are currently being treated with WELLBUTRIN Tablets at 300 mg/day (for example, 100 mg 3 times a day) may be switched to Aplenzin 348 mg once daily. Patients who are currently being treated with WELLBUTRIN SR Sustained-Release Tablets at 300 mg/day (for example, 150 mg twice daily) may be switched to Aplenzin 348 mg once daily.
Dosage Adjustment for Patients with Impaired Hepatic Function
Aplenzin should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 174 mg every other day in these patients. Aplenzin should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis [see WARNINGS AND PRECAUTIONS: Hepatic Impairment (5.6), USE IN SPECIFIC POPULATION: Hepatic Impairment (8.7), and CLINICAL PHARMACOLOGY: Pharmacokinetics (12.3)].
Dosage Adjustment for Patients with Impaired Renal Function
Aplenzin should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see USE IN SPECIFIC POPULATIONS: Renal Impairment (8.6) and CLINICAL PHARMACOLOGY, Pharmacokinetics (12.3)].
Dosage Forms and Strengths
Aplenzin Extended-Release Tablets, 174 mg of bupropion hydrobromide, are white to off white, round tablets printed with "BR" over "174" in bottles of 30 tablets.
Aplenzin Extended-Release Tablets, 348 mg of bupropion hydrobromide, are white to off white, round tablets printed with "BR" over "348" in bottles of 30 tablets .
Aplenzin Extended-Release Tablets, 522 mg of bupropion hydrobromide, are white to off white, round tablets printed with "BR" over "522" in bottles of 30 tablets .
Contraindications
Aplenzin is contraindicated in patients with a seizure disorder.
Aplenzin is contraindicated in patients treated with ZYBAN® (bupropion hydrochloride) Sustained-Release Tablets; WELLBUTRIN® (bupropion hydrochloride immediate-release formulation); WELLBUTRIN® SR (bupropion hydrochloride sustained-release formulation); WELLBUTRIN XL® (bupropion hydrochloride extended-release formulation); or any other medications that contain bupropion because the incidence of seizure is dose dependent.
Aplenzin is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia with the immediate-release formulation of bupropion.
Aplenzin is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).
The concurrent administration of Aplenzin Tablets and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with Aplenzin Tablets.
Aplenzin is contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up Aplenzin Tablets.
Warnings and Precautions
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
|---|---|
| Increases Compared to Placebo | |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25-64 | 1 fewer case |
| ≥65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases [see BOXED WARNING and USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4)].
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.[See also PATIENT COUNSELING INFORMATION (17)] Prescriptions for Aplenzin should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
Aplenzin is 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 and ADVERSE REACTIONS (6)]. 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 post-marketing cases, resolution of symptoms after discontinuation of ZYBAN was reported, and some 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.
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. Aplenzin is expected to pose similar risks.
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 Aplenzin is not approved for use in treating bipolar depression.
Patients should be made aware that Aplenzin contains bupropion, the same active ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that Aplenzin should not be used in combination with ZYBAN, or any other medications that contain bupropion, such as WELLBUTRIN XL (bupropion hydrochloride extended-release formulation), WELLBUTRIN SR (bupropion hydrochloride sustained-release formulation), or WELLBUTRIN (bupropion hydrochloride immediate-release formulation). [See also PATIENT COUNSELING INFORMATION (17) ].
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 Aplenzin. Aplenzin should be discontinued and not restarted in patients who experience a seizure while on treatment.
The seizure incidence with Aplenzin has not been formally evaluated in clinical trials. Studies in mice suggest the potential for a significant reduction in the risk of seizure with bupropion HBr as compared to bupropion HCl. The seizure incidence is not expected to be worse than presented below for comparable doses of the immediate-release and sustained-release formulations of bupropion HCl.
- Dose
At doses up to 300 mg/day (equivalent to 348 mg/day of bupropion HBr) of the sustained-release formulation of bupropion hydrochloride (WELLBUTRIN SR), the incidence of seizure is approximately 0.1% (1/1,000).
Data for the immediate-release formulation of bupropion hydrochloride 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 to 450 mg/day (equivalent to a range of 348 to 522 mg/day of bupropion HBr). This seizure incidence (0.4%) may exceed that of some other marketed antidepressants.
Additional data accumulated for the immediate-release formulation of bupropion hydrochloride suggested that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day (equivalent to 522 and 696 mg/day bupropion HBr). The 600 mg dose is twice the usual adult dose and one and one-third the maximum recommended daily dose (450 mg) of WELLBUTRIN XL (equivalent to 522 mg Aplenzin) Tablets. This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
- 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 Aplenzin Tablets does not exceed 522 mg,
- the rate of incrementation of dose is gradual.
Aplenzin 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
Aplenzin 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 174 mg every other day in these patients.
Aplenzin should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels.
See DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Hepatic Function (2.5), USE IN SPECIFIC POPULATIONS: Hepatic Impairment (8.7), and CLINICAL PHARMACOLOGY: Pharmacokinetics (12.3).
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.
Agitation and Insomnia
Increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment, have been associated with treatment with bupropion.
Patients in placebo-controlled trials of major depressive disorder with WELLBUTRIN SR, the sustained-release formulation of bupropion hydrochloride, experienced agitation, anxiety, and insomnia as shown in Table 2.
| Adverse Reaction Term | WELLBUTRIN® SR (Bupropion HCl) 300 mg/day* (n = 376) | WELLBUTRIN® SR (Bupropion HCl) 400 mg/day† (n = 114) | Placebo (n = 385) |
|---|---|---|---|
| |||
| Agitation | 3% | 9% | 2% |
| Anxiety | 5% | 6% | 3% |
| Insomnia | 11% | 16% | 6% |
In clinical studies of major depressive disorder, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.
Symptoms in these studies were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion hydrochloride sustained-release tablets and 0.8% of patients treated with placebo.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena
Depressed patients treated with bupropion 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.
Altered Appetite and Weight
In placebo-controlled studies of major depressive disorder using WELLBUTRIN SR®, the sustained-release formulation of bupropion hydrochloride, patients experienced weight gain or weight loss as shown in Table 3.
| Weight Change | WELLBUTRIN® SR (Bupropion HCl) 300 mg/day* (n = 339) | WELLBUTRIN® SR (Bupropion HCl) 400 mg/day† (n = 112) | Placebo (n = 347) |
|---|---|---|---|
| |||
| Gained >5 lbs | 3% | 2% | 4% |
| Lost >5 lbs | 14% | 19% | 6% |
In studies conducted with the immediate-release formulation of bupropion hydrochloride, 35% of patients receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the immediate-release formulation of bupropion hydrochloride. If weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight-reducing potential of Aplenzin Tablets should be considered.
Allergic Reactions
Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking Aplenzin and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.
Cardiovascular Effects
In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These reactions have been observed in both patients with and without evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion hydrochloride (ZYBAN® Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion hydrochloride 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 sustained-release bupropion hydrochloride and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion hydrochloride and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion hydrochloride, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and 1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of Aplenzin Tablets in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups.
Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.
Laboratory Tests
There are no specific laboratory tests recommended.
Adverse Reactions
The following risks are discussed in greater detail in other sections of the labeling:
- Clinical worsening and suicide risk [see WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders (5.1)]
- Activation of Psychosis and/or Mania [see WARNINGS AND PRECAUTIONS: Activation of Psychosis and/or Mania (5.3) and WARNINGS AND PRECAUTIONS: Screening Patients for Bipolar Disorder (5.4)]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS: Potential for Hepatotoxicity(5.7)]
- Agitation and Insomnia [see WARNINGS AND PRECAUTIONS: Agitation and Insomnia (5.8)]
- Psychosis, confusion and other neuropsychiatric phenomena [see WARNINGS AND PRECAUTIONS: Psychosis, Confusion, and Other Neuropsychiatric Phenomena (5.9)]
- Altered appetite [see WARNINGS AND PRECAUTIONS: Altered Appetite and Weight (5.10)]
- Allergic reactions, including anaphylactoid/anaphylactic reactions, erythema multiforme, Stevens-Johnson syndrome and other symptoms suggestive of delayed hypersensitivity [see WARNINGS AND PRECAUTIONS: Allergic Reactions (5.11)]
- Hypertension [see WARNINGS AND PRECAUTIONS: Cardiovascular Effects (5.12)]
Commonly Observed Adverse Reactions in Controlled Clinical Trials
Adverse reactions from Table 5 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion hydrochloride and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day dose groups.
300 mg/day of WELLBUTRIN SR (equivalent to 348 mg/day bupropion HBr): Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
400 mg/day of WELLBUTRIN SR (equivalent to 464 mg/day bupropion HBr): Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
Aplenzin is bioequivalent to WELLBUTRIN XL, which has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion. The information included under this subsection and under the subsections 6.2 and 6.3 is based primarily on data from controlled clinical trials with WELLBUTRIN SR Tablets, the sustained-release formulation of bupropion hydrochloride.
Adverse Reactions Leading to Discontinuation of Treatment With WELLBUTRIN or WELLBUTRIN SR
In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion hydrochloride and 4% of patients treated with placebo discontinued treatment due to adverse reactions. The specific adverse reactions in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of WELLBUTRIN SR, the sustained-release formulation of bupropion hydrochloride, and at a rate at least twice the placebo rate are listed in Table 4.
| Adverse Reaction Term | WELLBUTRIN® SR (Bupropion HCl) 300 mg/day * (n = 376) | WELLBUTRIN® SR (Bupropion HCl) 400 mg/day† (n = 114) | Placebo (n = 385) |
|---|---|---|---|
| |||
| Rash | 2.4% | 0.9% | 0.0% |
| Nausea | 0.8% | 1.8% | 0.3% |
| Agitation | 0.3% | 1.8% | 0.3% |
| Migraine | 0.0% | 1.8% | 0.3% |
In clinical trials with the immediate-release formulation of bupropion, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation, in addition to those listed above for the sustained-release formulation of bupropion hydrochloride, include vomiting, seizures, and sleep disturbances.
Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated With WELLBUTRIN or WELLBUTRIN SR
Table 5 enumerates treatment-emergent adverse reactions that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion hydrochloride and with placebo in controlled trials. Reactions that occurred in either the 300- or 400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo group are included. Reported adverse reactions were classified using a COSTART-based Dictionary.
Accurate estimates of the incidence of adverse reactions associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward reactions in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the reactions. A better perspective on the serious adverse reactions associated with the use of bupropion is provided in WARNINGS AND PRECAUTIONS section (5).
| Body System/Adverse Reaction | WELLBUTRIN® SR (Bupropion HCl) 300 mg/day† (n = 376) | WELLBUTRIN® SR (Bupropion HCl) 400 mg/day‡ (n = 114) | Placebo (n = 385) |
|---|---|---|---|
| — Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients. | |||
| |||
| Body (General) | |||
| Headache | 26% | 25% | 23% |
| Infection | 8% | 9% | 6% |
| Abdominal pain | 3% | 9% | 2% |
| Asthenia | 2% | 4% | 2% |
| Chest pain | 3% | 4% | 1% |
| Pain | 2% | 3% | 2% |
| Fever | 1% | 2% | — |
| Cardiovascular | |||
| Palpitation | 2% | 6% | 2% |
| Flushing | 1% | 4% | — |
| Migraine | 1% | 4% | 1% |
| Hot flashes | 1% | 3% | 1% |
| Digestive | |||
| Dry mouth | 17% | 24% | 7% |
| Nausea | 13% | 18% | 8% |
| Constipation | 10% | 5% | 7% |
| Diarrhea | 5% | 7% | 6% |
| Anorexia | 5% | 3% | 2% |
| Vomiting | 4% | 2% | 2% |
| Dysphagia | 0% | 2% | |
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