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Zyban

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Zyban

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment

Serious neuropsychiatric symptoms have been reported in patients taking ZYBAN for smoking cessation. 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 BOXED WARNING, ADVERSE REACTIONS]. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur.

In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking ZYBAN who continued to smoke.

The risks of ZYBAN 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 6 months compared with treatment with placebo. The health benefits of quitting smoking are immediate and substantial.

Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults

Patients with 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 (selective serotonin reuptake inhibitors [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 MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with 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 subjects. 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 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects 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 subjects treated) are provided in Table 1.

Table 1: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-controlled Trials of Antidepressants in Pediatric and Adult Subjects

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Subjects Treated
Increases Compared with Placebo
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared with 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].

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 MDD 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ZYBAN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Seizure

ZYBAN can cause seizure. The risk of seizure is dose-related. The dose of ZYBAN should not exceed 300 mg per day [see DOSAGE AND ADMINISTRATION]. Discontinue ZYBAN 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 ZYBAN. ZYBAN is 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, DRUG INTERACTIONS]. 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 ZYBAN for smoking cessation does not exceed 300 mg per day, given as 150 mg twice daily, and titration rate is gradual.

Hypertension

Treatment with ZYBAN can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with ZYBAN, and monitor periodically during treatment. The risk of hypertension is increased if ZYBAN is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see CONTRAINDICATIONS].

Data from a comparative trial of ZYBAN, nicotine transdermal system (NTS), the combination of ZYBAN 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 ZYBAN and NTS. In this trial, 6.1% of subjects treated with the combination of ZYBAN and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with ZYBAN, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of ZYBAN 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 ZYBAN 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.

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 clinical trials with ZYBAN conducted in nondepressed smokers. Bupropion is not approved for use in treating bipolar depression.

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 clinical trials with ZYBAN conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. However, in the postmarketing experience, patients taking ZYBAN to quit smoking have reported similar types of neuropsychiatric symptoms to those reported by patients in the clinical trials of bupropion for depression.

Angle-closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including bupropion may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Hypersensitivity Reactions

Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue ZYBAN and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Although ZYBAN is not indicated for treatment of depression, it contains the same active ingredient as the antidepressant medications WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL. Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with ZYBAN and counsel them in its appropriate use.

A patient Medication Guide about “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About ZYBAN?” is available for ZYBAN. Instruct patients, their families, and their caregivers to read the Medication Guide and 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.

Advise patients regarding the following issues and to alert their prescriber if these occur while taking ZYBAN.

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment

Inform patients 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, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.

Suicidal Thoughts and Behaviors

Instruct patients, their families, and/or their caregivers 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. Advise families and caregivers of patients 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 healthcare 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.

Severe Allergic Reactions

Educate patients on the symptoms of hypersensitivity and to discontinue ZYBAN if they have a severe allergic reaction to ZYBAN.

Seizure

Instruct patients to discontinue ZYBAN and not restart it if they experience a seizure while on treatment. Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.

Angle-closure Glaucoma

Patients should be advised that taking ZYBAN 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].

Bupropion-containing Products

Educate patients that ZYBAN contains the same active ingredient (bupropion hydrochloride) found in WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL, which are used to treat depression and that ZYBAN should not be used in conjunction with any other medications that contain bupropion (such as WELLBUTRIN, the immediate-release formulation; WELLBUTRIN SR, the sustained-release formulation; WELLBUTRIN XL or FORFIVO XL™, the extended-release formulations; and APLENZIN®, the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.

Potential for Cognitive and Motor Impairment

Advise patients that any CNS-active drug like ZYBAN may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that ZYBAN does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. ZYBAN may lead to decreased alcohol tolerance.

Concomitant Medications

Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because ZYBAN and other drugs may affect each others' metabolisms.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.

Precautions for Nursing Mothers

Advise patients that ZYBAN is present in human milk in small amounts.

Storage Information

Instruct patients to store ZYBAN at room temperature, between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.

Administration Information

Instruct patients to swallow ZYBAN Tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are designed to slowly release drug in the body. When patients take more than 150 mg per day, instruct them to take ZYBAN in 2 doses at least 8 hours apart, to minimize the risk of seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. ZYBAN can be taken with or without food. Advise patients that ZYBAN Tablets may have an odor.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg per kg per day, respectively. These doses are approximately 10 and 2 times the MRHD, respectively, on a mg per m basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg per kg per day (approximately 3 to 10 times the MRHD on a mg per m 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 the Ames bacterial mutagenicity assay. 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 per kg per day revealed no evidence of impaired fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately 2 times the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses three times the MRHD and greater. ZYBAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before pharmacological approaches are used.

Human Data

Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.

No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.

Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.

Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.

For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.

Animal Data

In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 15 and 10 times the MRHD respectively, on a mg per m basis). 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 per kg per day, approximately 2 times the MRHD on a mg per m basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater.

When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 10 times the MRHD on a mg per m basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

Nursing Mothers

Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when ZYBAN is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established [see BOXED WARNING, WARNINGS AND PRECAUTIONS].

Geriatric Use

Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥ 65 years and 47 were aged ≥ 75 years. In addition, several hundred subjects aged ≥ 65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). 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.

Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see DOSAGE AND ADMINISTRATION, Use in Specific Populations, CLINICAL PHARMACOLOGY].

Renal Impairment

Consider a reduced dose and/or dosing frequency of ZYBAN in patients with renal impairment (Glomerular Filtration Rate: less than 90 mL per min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of ZYBAN is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 8/28/2014
This monograph has been modified to include the generic and brand name in many instances.

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