"Jan. 1, 2013 -- Antidepressant use during pregnancy, long debated for its safety, is linked with a higher overall risk of stillbirth and newborn death. Now, a new study shows that risk may not be warranted.
"After taking maternal char"...
Clinical Worsening And Suicide Risk In Treating Psychiatric Disorder
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 18-24) 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].
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 PATIENT INFORMATION]. Prescription for FORFIVO XL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
FORFIVO XL 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 ]. 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 [see PATIENT INFORMATION].
Activation Of Mania/Hypomania
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. 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 FORFIVO XL is not approved for use in treating bipolar depression.
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 FORFIVO XL. FORFIVO XL should be discontinued and not restarted in patients who experience a seizure while on treatment.
At doses up to 300 mg/day 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. 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. The 600 mg dose is twice the usual adult dose and one and one-third the maximum recommended daily dose (450 mg) of FORFIVO XL. This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
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.
Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
Many medications (e.g., antipsychotics, antidepressants, theophylline, and 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 does not exceed 450 mg,
- the rate of incrementation of the bupropion dose is gradual.
Psychosis And Other Neuropsychiatric Events
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. It is recommended stopping bupropion when the symptoms occurred.
Angle Closure Glaucoma
Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including FORFIVO XL may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
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. 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 FORFIVO XL 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.
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 sustained-release formulation of bupropion hydrochloride, experienced agitation, anxiety, and insomnia as shown in Table 2.
Table 2: Incidence of Agitation, Anxiety, and Insomnia
in Placebo-Controlled Trials of Bupropion HCl Sustained-release Tablets for
Major Depressive Disorder
|Adverse Reactions Term||Bupropion HCl 300 mg/day
(n = 376)
|Bupropion HCl 400 mg/day
(n = 385)
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.
Altered Appetite And Weight
In placebo-controlled short-term studies of major depressive disorder using the sustained-release formulation of bupropion hydrochloride, patients experienced weight gain or weight loss as shown in Table 3.
Table 3: Incidence of Weight Gain and Weight Loss in
Placebo-Controlled Trials of Bupropion Hydrochloride Sustained-release tablets
for Major Depressive Disorder
|Weight Change||Bupropion HCl) 300 mg/day
(n = 339)
|Bupropion HCl 400 mg/day
(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 FORFIVO XL tablets should be considered.
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 FORFIVO XL 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 [see CONTRAINDICATIONS].
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Information For Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with FORFIVO XL and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions”, “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions” and “What Other Important Information Should I Know about FORFIVO XL” is available for FORFIVO XL. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking FORFIVO XL.
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
Although FORFIVO XL is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN which is approved for this use. Patients should be informed that quitting smoking, with or without ZYBAN, may be associated with nicotine withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing psychiatric illness. Furthermore, some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation and completed suicide when attempting to quit smoking while taking ZYBAN.
Bupropion-Containing Products: Patients should be made aware that FORFIVO XL contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that FORFIVO XL should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN XL®, the extended-release formulation, WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation) or APLENZIN, Extended Release tablet.
Patients should be told that FORFIVO XL should be discontinued and not restarted if they experience a seizure while on treatment.
Patients should be told that any CNS-active drug like FORFIVO XL tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that FORFIVO XL tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with bupropion. Patients should be advised that the consumption of alcohol should be minimized or avoided.
Patients should be advised that taking FORFIVO XL can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see WARNINGS AND PRECAUTIONS].
Patients should be advised to notify their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because FORFIVO XL tablets and other drugs may affect each other's metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to swallow FORFIVO XL tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets, as this may lead to an increased risk of adverse effects, including seizures.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day bupropion hydrochloride, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day of bupropion hydrochloride (approximately 2 to 7 times the MRHD on a mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in one Ames bacterial mutagenicity assay, but was negative in another. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
In studies conducted in rats and rabbits, bupropion hydrochloride was administered orally at doses up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively, on a mg/m² basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion hydrochloride at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care database study assessed the risk of congenital malformations overall, and cardiovascular malformations specifically, following exposure to bupropion in the first trimester compared to the risk of these malformations following exposure to other antidepressants in the first trimester and bupropion outside of the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study showed no greater risk for congenital malformations overall, or cardiovascular malformations specifically, following first trimester bupropion exposure compared to exposure to all other antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this study have not been corroborated. FORFIVO XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Like many other drugs, bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from FORFIVO XL tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established. Anyone considering the use of FORFIVO XL in a child or adolescent must balance the potential risks with the clinical need.
Of the approximately 6,000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were 65 years old and over and 47 were 75 years old and over. In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see CLINICAL PHARMACOLOGY].
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
Since there is no lower dose strength for FORFIVO XL, FORFIVO XL is not recommended in patients with renal impairment [see CLINICAL PHARMACOLOGY].
Since there is no lower dose strength for FORFIVO XL, FORFIVO XL is not recommended in patients with hepatic impairment [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 7/31/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Forfivo XL Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get tips on therapy and treatment.