Pharmaceutical Approval Update: Bupropion HCl XL (Wellbutrin XL)
Manufacturer: GlaxoSmithKline, Research Triangle Park, NC
Indication: Generic Bupropion XL extended-release tablets are now approved to prevent major depressive episodes in adult patients with a history of seasonal affective disorder (SAD).
Drug Class: This antidepressant of the amino ketone class is not chemically related to tricyclic and tetracyclic agents, selective serotonin reuptake inhibitors (SSRIs), or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl) amino]-1-propanone HCl.
Uniqueness of Drug: The extended-release form is indicated only for patients who meet strict diagnostic criteria for SAD, including a seasonal pattern of recurrent, clinically significant depressive symptoms with associated impaired functioning.
Boxed Warning:
Suicidality in Children and Adolescents. Anti-depressants increased the risk of suicidal thinking and behavior (sui-cidality) in short-term studies of children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of medication bupropion XL or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be 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.
Bupropion XL is not approved for use in children.
Pooled analyses of short-term (four to 16 weeks) placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepres-sants was 4%, twice the placebo risk of 2%. No suicides occurred in these 24 trials, which involved more than 4,400 patients.
Warnings:
Clinical Worsening and Suicide Risk: Both children and adults with MDD may experience worsening of depression or the emergence of suicidal ideation and behavior or unusual changes in behavior, whether or not they are taking anti-depressant medications. This risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may induce worsening of depression and the emergence of suicidality in some patients. In short-term studies, antidepressants did increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other psychiatric disorders. canadian discount drugs
In trials of the nine antidepressant drugs alluded to in the boxed warning and mentioned above, there was considerable variation in risk among drugs but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (OCD and Social Anxiety Disorder) as well.
No suicides occurred in the trials. It is unknown whether the suicide risk in pediatric patients extends to longer-term use (beyond several months) and whether the risk extends to adults.
All pediatric patients receiving antidepressants for any indication should be observed closely, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Observations include at least weekly face-to-face contact with patients or their family members or caregivers during the first four weeks of treatment, followed by every-other-week visits for the next four weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or comorbid depression in the setting of other psychiatric illness who are taking antidepressants should also be closely observed, especially during the initial few months of a course of drug therapy, or at times of a change in dose, either an increase or decrease.
Patients with a history of suicidal behavior or thoughts, patients exhibiting suicidal ideation before beginning treatment, and young adults are at an increased risk of suicidal thoughts or suicide attempts. All of these patients should receive careful monitoring during treatment.
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Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adults and children using antidepressants for MDD as well as for other psychiatric and nonpsychiatric indications. Although a causal link between the emergence of such symptoms and 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.
Health care providers should consider changing the therapeutic regimen and perhaps 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 if they had not been presenting symptoms.
Families and caregivers of pediatric patients who are using antidepressants for MDD or other psychiatric and non-psychiatric indications should be alerted to the need to watch for agitation, irritability, unusual changes in behavior, and sui-cidality; they should report any of these symptoms immediately to the patient’s health care provider.
To reduce the risk of overdose, health care providers should prescribe bupropion XL tablets in the smallest quantity consistent with good patient management. Families and care-givers of adults being treated for depression should be similarly advised.
Screening for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is believed, although 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 earlier represent such a conversion is unknown. However, before antidepressant treatment begins, patients with depressive symptoms should be screened to determine whether they are at risk for bipolar disorder. Screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and/or depression.
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Bupropion XL is not approved for bipolar depression.
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 the selection of patients for therapy with bupropion XL. Bupropion XL therapy should be discontinued and not restarted in patients who experience a seizure during treatment.
Because bupropion XL is bioequivalent to both the immediate-release (IR) formulation and the sustained-release (SR) formulation, the incidence of seizures with bupropion XL, although not formally evaluated in clinical trials, may be similar to that for the IR and SR forms.
Dose: At doses up to 300 mg/day of the SR formulation, the incidence of seizure was approximately 0.1% (1/1,000). For IR bupropion canadian, the incidence of seizure was approximately 0.4% in patients taking 300 to 450 mg/day; this incidence may exceed that of some other marketed antidepressants. The data on the IR form also suggest that the estimated seizure incidence increased almost 10-fold at doses between 450 and 600 mg/day.
The 600-mg dose is twice the usual adult dose, and 1.33 times the maximum recommended daily dose (450 mg) of bupropion XL tablets. This disproportionate increase in seizure incidence with dose increases calls for caution in dosing.
Patient Factors: Predisposing factors that may increase the risk of seizure with bupropion use include a history of head trauma or prior seizure, central nervous system (CNS) tumors, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold.
Clinical Situations: Circumstances associated with an increased risk of seizures include the excessive use of alcohol or sedatives (e.g., benzodiazepines); an addiction to opiates, cocaine, or stimulants; the use of over-the-counter stimulants and anorectic agents; and the use of oral hypoglycemic agents or insulin for the treatment of diabetes.
Concomitant Medications: Many medications (e.g., anti-psychotic agents, antidepressants, theophylline, and systemic steroids) are known to lower the seizure threshold.
Reducing Seizure Risk: A retrospective analysis of clinical experience gained during the development of bupropion tablet suggests that the risk of seizure may be minimized (1) if the total daily dose of bupropion XL tablets does not exceed 450 mg and (2) if the rate of dose increases is gradual.
Bupropion XL should be administered with extreme caution to patients with a history of seizure, cranial trauma, or a predisposition toward seizures or patients being treated with other agents that lower the seizure threshold.
Hepatic Impairment: Bupropion XL should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, the frequency of the dose should be reduced, because peak bupropion levels as well as area-under-the-curve (AUC) concentrations are substantially increased; accumulation of the drug is likely to occur in such patients to a greater extent than usual. The dose should not exceed 150 mg every other day in hepatically impaired patients.
Drug Interactions: Patients should be made aware that bupropion XL contains the same active ingredient found in Zyban, which is used as an aid to help patients with smoking cessation. Bupropion XL should not be used in combination with Zyban generic or any other medications that contain bupropion (bupropion SR or bupropion IR).
Dosage and Administration: For preventing seasonal major depressive episodes associated with SAD, bupropion XL should generally be initiated in the autumn prior to the onset of depressive symptoms. Treatment should continue through the winter and should be tapered and discontinued in early spring.
The timing of initiation and the duration of treatment should be tailored to each patient based on the historical pattern of seasonal major depressive episodes. Patients whose seasonal depressive episodes are infrequent or not associated with significant impairment should not generally be treated prophy-lactically.
Dosing with bupropion XL should begin at 150 mg/day, given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, the dose should be increased to 300 mg/day after one week. If the 300-mg dose is not adequately tolerated, the dose can be reduced to 150 mg/day.
The usual adult target dose for bupropion XL tablets is 300 mg/day once daily in the morning. If 300 mg/day is taken during autumn or winter, the dose should be tapered to 150 mg/day for two weeks before bupropion is discontinued.
Doses of bupropion XL above 300 mg/day have not been studied for preventing seasonal major depressive episodes.
Contraindications: Bupropion XL is not indicated for children; patients with a seizure disorder; patients using Zyban canadian or SR or IR bupropion or other drugs containing bupropion; patients with a current or prior diagnosis of bulimia or anorexia nervosa (because of a higher incidence of seizures noted when these patients use IR bupropion); patients abruptly discontinuing alcohol or sedatives (including benzodiazepines); patients taking a monoamine oxidase inhibitor; and patients who have shown an allergic response to drug bupropion or the other ingredients that make up the tablets.
Commentary: Bupropion XL is the first medication approved to prevent seasonal major depressive episodes. Seasonal affective disorder (SAD) affects about 6% of American adults. Also known as Major Depressive Disorder with a seasonal pattern, SAD is typically characterized by recurring fall or winter onset of depression, with symptoms subsiding during spring and summer. The exact cause is unknown, but SAD is believed to be related to seasonal variations of light, as well as changes in certain brain chemicals, which may induce feelings of depression. The predominance of SAD is greatest in the northern U.S., where winter daylight hours are shorter and people tend to have less exposure to sunlight.
SAD is a serious and often underdiagnosed form of depression. With the approval of bupropion XL, it may be possible for the first time to prevent the predictable onset of SAD with medication by beginning treatment in the fall, before patients experience depressive symptoms.
