Zyntabac

Trouble dépressif majeur

WELLBUTRIN XL® (comprimés à libération prolongée de chlorhydrate de bupropion) est indiqué pour le traitement du trouble dépressif majeur (TDM), tel que défini par le Manuel diagnostique et statistique (DSM).

L'efficacité de la formulation à libération immédiate du bupropion a été établie dans deux essais contrôlés en milieu hospitalier de 4 semaines et un essai en ambulatoire contrôlé de 6 semaines de patients adultes atteints de MDD. L'efficacité de la formulation à libération prolongée du bupropion dans le traitement d'entretien du MDD a été établie à long terme (jusqu'à 44 semaines) essai contrôlé par placebo chez des patients qui avaient répondu au bupropion dans une étude de 8 semaines sur le traitement aigu.

Trouble affectif saisonnier

WELLBUTRIN XL est indiqué pour la prévention des épisodes dépressifs majeurs saisonniers chez les patients avec un diagnostic de trouble affectif saisonnier (TAS).

L'efficacité des comprimés à libération prolongée de chlorhydrate de bupropion dans la prévention des épisodes dépressifs majeurs saisonniers a été établie dans 3 essais contrôlés contre placebo chez des patients externes adultes ayant des antécédents de MDD avec un schéma saisonnier automne-hiver tel que défini dans le DSM

Trouble dépressif majeur

Zyntabac® (comprimés à libération prolongée de chlorhydrate de bupropion) est indiqué pour le traitement du trouble dépressif majeur (TDM), tel que défini par le Manuel de diagnostic et de statistique (DSM).

L'efficacité de la formulation à libération immédiate du bupropion a été établie dans deux essais contrôlés en milieu hospitalier de 4 semaines et un essai en ambulatoire contrôlé de 6 semaines de patients adultes atteints de MDD. L'efficacité de la formulation à libération prolongée du bupropion dans le traitement d'entretien du MDD a été établie à long terme (jusqu'à 44 semaines) essai contrôlé par placebo chez des patients qui avaient répondu au bupropion dans une étude de 8 semaines sur le traitement aigu.

Trouble affectif saisonnier

Zyntabac est indiqué pour la prévention des épisodes dépressifs majeurs saisonniers chez les patients ayant un diagnostic de trouble affectif saisonnier (TAS).

L'efficacité des comprimés à libération prolongée de chlorhydrate de bupropion dans la prévention des épisodes dépressifs majeurs saisonniers a été établie dans 3 essais contrôlés contre placebo chez des patients externes adultes ayant des antécédents de MDD avec un schéma saisonnier automne-hiver tel que défini dans le DSM

Le zyntabac (chlorhydrate de bupropion) est indiqué pour le traitement du trouble dépressif majeur (TDM), tel que défini par le Manuel de diagnostic et de statistique (DSM).

L'efficacité du bupropion dans le traitement d'un épisode dépressif majeur a été établie dans deux essais contrôlés de 4 semaines en milieu hospitalier et un essai de 6 semaines en ambulatoire contrôlé de sujets adultes atteints de MDD

L'efficacité de Zyntabac dans le maintien d'une réponse antidépressive jusqu'à 44 semaines après 8 semaines de traitement aigu a été démontrée dans un essai contrôlé par placebo.

Instructions générales d'utilisation

Pour minimiser le risque de convulsions, augmentez progressivement la dose.

WELLBUTRIN XL doit être avalé entier et non écrasé, divisé ou mâché.

WELLBUTRIN XL doit être administré le matin et peut être pris avec ou sans nourriture.

Posologie du trouble dépressif majeur (TDM)

La dose initiale recommandée pour le MDD est de 150 mg une fois par jour le matin. Après 4 jours d'administration, la dose peut être augmentée à la dose cible de 300 mg une fois par jour le matin.

Il est généralement admis que les épisodes aigus de dépression nécessitent plusieurs mois ou plus de traitement antidépresseur au-delà de la réponse dans l'épisode aigu. On ne sait pas si la dose de WELLBUTRIN XL nécessaire au traitement d'entretien est identique à la dose qui a fourni une réponse initiale. Réévaluer périodiquement la nécessité d'un traitement d'entretien et la dose appropriée pour un tel traitement.

Posologie du trouble affectif saisonnier (TAS)

La dose initiale recommandée pour le TAS est de 150 mg une fois par jour. Après 7 jours d'administration, la dose peut être augmentée à la dose cible de 300 mg une fois par jour le matin. Les doses supérieures à 300 mg de bupropion HCl à libération prolongée n'ont pas été évaluées dans les essais SAD.

Pour la prévention des épisodes saisonniers de MDD associés au DAU, lancez WELLBUTRIN XL à l'automne, avant le début des symptômes dépressifs. Poursuivez le traitement pendant la saison d'hiver. Cône et arrêter WELLBUTRIN XL au début du printemps. Pour les patients traités avec 300 mg par jour, diminuer la dose à 150 mg une fois par jour avant d'arrêter WELLBUTRIN XL. Individualiser le moment de l'initiation et la durée du traitement doit être individualisée, en fonction du schéma historique du patient des épisodes saisonniers de MDD.

Passer des patients à partir de tablettes WELLBUTRIN ou à partir de comprimés à libération prolongée WELLBUTRIN SR

Lorsque vous passez des patients des comprimés WELLBUTRIN à WELLBUTRIN XL ou des comprimés à libération prolongée WELLBUTRIN SR à WELLBUTRIN XL, donnez la même dose quotidienne totale lorsque cela est possible.

Pour arrêter WELLBUTRIN XL, réduisez la dose

Lorsque vous arrêtez le traitement chez les patients traités par WELLBUTRIN XL 300 mg une fois par jour, diminuez la dose à 150 mg une fois par jour avant l'arrêt.

Ajustement posologique chez les patients présentant une insuffisance hépatique

Chez les patients atteints d'insuffisance hépatique modérée à sévère (score de Child-Pugh: 7 à 15), la dose maximale est de 150 mg tous les deux jours. Chez les patients présentant une insuffisance hépatique légère (score de Child-Pugh: 5 à 6), envisagez de réduire la dose et / ou la fréquence de l'administration.

Ajustement de la dose chez les patients présentant une déficience rénale

Envisagez de réduire la dose et / ou la fréquence de WELLBUTRIN chez les patients atteints d'insuffisance rénale (taux de filtration glomérulaire inférieur à 90 ml / min).

Passer un patient à ou à partir d'un antidépresseur à inhibiteur de la monoamine oxydase (IMAO)

Au moins 14 jours doivent s'écouler entre l'arrêt d'un IMAO destiné à traiter la dépression et le début du traitement par WELLBUTRIN XL. Inversement, au moins 14 jours devraient être autorisés après l'arrêt de WELLBUTRIN XL avant de commencer un antidépresseur MAOI.

Utilisation de WELLBUTRIN XL avec des IMAO réversibles tels que Linezolid ou Méthylène Blue

Ne démarrez pas WELLBUTRIN XL chez un patient traité avec un IMAO réversible tel que le linézolide ou le bleu de méthylène intraveineux. Les interactions médicamenteuses peuvent augmenter le risque de réactions hypertensives. Chez un patient qui nécessite un traitement plus urgent d'une affection psychiatrique, des interventions non pharmacologiques, y compris l'hospitalisation, doivent être envisagées.

Dans certains cas, un patient recevant déjà un traitement par WELLBUTRIN XL peut nécessiter un traitement urgent avec du linezolide ou du bleu de méthylène intraveineux. Si des alternatives acceptables au traitement au linézolide ou au bleu de méthylène intraveineux ne sont pas disponibles et que les avantages potentiels du traitement au linézolide ou au bleu de méthylène intraveineux sont jugés supérieurs aux risques de réactions hypertensives chez un patient particulier, WELLBUTRIN XL doit être arrêté rapidement, et du bleu de méthylène linézolide ou intraveineux peut être administré. Le patient doit être surveillé pendant 2 semaines ou jusqu'à 24 heures après la dernière dose de linézolide ou de bleu de méthylène intraveineux, selon la première éventualité. La thérapie avec WELLBUTRIN XL peut être reprise 24 heures après la dernière dose de linézolide ou de bleu de méthylène intraveineux.

Le risque d'administrer du bleu de méthylène par voie non intraveineuse (comme les comprimés oraux ou par injection locale) ou à des doses intraveineuses bien inférieures à 1 mg par kg avec WELLBUTRIN XL n'est pas clair. Le clinicien doit néanmoins être conscient de la possibilité d'une interaction médicamenteuse avec une telle utilisation.

Instructions générales d'utilisation

Pour minimiser le risque de convulsions, augmentez progressivement la dose.

Zyntabac doit être avalé entier et non écrasé, divisé ou mâché.

Zyntabac doit être administré le matin et peut être pris avec ou sans nourriture.

Posologie du trouble dépressif majeur (TDM)

La dose initiale recommandée pour le MDD est de 150 mg une fois par jour le matin. Après 4 jours d'administration, la dose peut être augmentée à la dose cible de 300 mg une fois par jour le matin.

Il est généralement admis que les épisodes aigus de dépression nécessitent plusieurs mois ou plus de traitement antidépresseur au-delà de la réponse dans l'épisode aigu. On ne sait pas si la dose de Zyntabac nécessaire au traitement d'entretien est identique à la dose qui a fourni une réponse initiale. Réévaluer périodiquement la nécessité d'un traitement d'entretien et la dose appropriée pour un tel traitement.

Posologie du trouble affectif saisonnier (TAS)

La dose initiale recommandée pour le TAS est de 150 mg une fois par jour. Après 7 jours d'administration, la dose peut être augmentée à la dose cible de 300 mg une fois par jour le matin. Les doses supérieures à 300 mg de bupropion HCl à libération prolongée n'ont pas été évaluées dans les essais SAD.

Pour la prévention des épisodes saisonniers de MDD associés au TAS, initiez Zyntabac à l'automne, avant l'apparition des symptômes dépressifs. Poursuivez le traitement pendant la saison d'hiver. Cône et arrêter Zyntabac au début du printemps. Pour les patients traités avec 300 mg par jour, diminuer la dose à 150 mg une fois par jour avant d'arrêter Zyntabac. Individualiser le moment de l'initiation et la durée du traitement doit être individualisée, en fonction du schéma historique du patient des épisodes saisonniers de MDD.

Passer des patients à partir de tablettes WELLBUTRIN ou à partir de comprimés à libération prolongée WELLBUTRIN SR

Lorsque vous passez des patients des comprimés WELLBUTRIN à Zyntabac ou des comprimés à libération prolongée WELLBUTRIN SR à Zyntabac, donnez la même dose quotidienne totale lorsque cela est possible.

Pour arrêter Zyntabac, concez la dose

Lorsque vous arrêtez le traitement chez les patients traités par WELLBUTRIN XL 300 mg une fois par jour, diminuez la dose à 150 mg une fois par jour avant l'arrêt.

Ajustement posologique chez les patients présentant une insuffisance hépatique

Chez les patients atteints d'insuffisance hépatique modérée à sévère (score de Child-Pugh: 7 à 15), la dose maximale est de 150 mg tous les deux jours. Chez les patients présentant une insuffisance hépatique légère (score de Child-Pugh: 5 à 6), envisagez de réduire la dose et / ou la fréquence de l'administration.

Ajustement de la dose chez les patients présentant une déficience rénale

Envisagez de réduire la dose et / ou la fréquence de WELLBUTRIN chez les patients atteints d'insuffisance rénale (taux de filtration glomérulaire inférieur à 90 ml / min).

Passer un patient à ou à partir d'un antidépresseur à inhibiteur de la monoamine oxydase (IMAO)

Au moins 14 jours doivent s'écouler entre l'arrêt d'un IMAO destiné à traiter la dépression et le début du traitement par WELLBUTRIN XL. À l'inverse, au moins 14 jours doivent être autorisés après l'arrêt de Zyntabac avant de commencer un antidépresseur IMAO.

Utilisation de Zyntabac avec des IMAO réversibles tels que Linezolid ou Méthylène Blue

Ne démarrez pas Zyntabac chez un patient traité avec un IMAO réversible tel que le linézolide ou le bleu de méthylène intraveineux. Les interactions médicamenteuses peuvent augmenter le risque de réactions hypertensives. Chez un patient qui nécessite un traitement plus urgent d'une affection psychiatrique, des interventions non pharmacologiques, y compris l'hospitalisation, doivent être envisagées.

Dans certains cas, un patient recevant déjà un traitement par Zyntabac peut nécessiter un traitement urgent avec du linézolide ou du bleu de méthylène intraveineux. Si des alternatives acceptables au traitement au linézolide ou au bleu de méthylène intraveineux ne sont pas disponibles et que les avantages potentiels du traitement au linézolide ou au bleu de méthylène intraveineux sont jugés supérieurs aux risques de réactions hypertensives chez un patient particulier, Zyntabac doit être arrêté rapidement, et du bleu de méthylène linézolide ou intraveineux peut être administré. Le patient doit être surveillé pendant 2 semaines ou jusqu'à 24 heures après la dernière dose de linézolide ou de bleu de méthylène intraveineux, selon la première éventualité. Le traitement par Zyntabac peut être repris 24 heures après la dernière dose de linézolide ou de bleu de méthylène intraveineux.

Le risque d'administrer du bleu de méthylène par voie non intraveineuse (comme les comprimés oraux ou par injection locale) ou à des doses intraveineuses bien inférieures à 1 mg par kg avec Zyntabac n'est pas clair. Le clinicien doit néanmoins être conscient de la possibilité d'une interaction médicamenteuse avec une telle utilisation.

Instructions générales d'utilisation

Pour minimiser le risque de convulsions, augmentez progressivement la dose. Les comprimés de Zyntabac doivent être avalés entiers et non écrasés, divisés ou mâchés. Zyntabac peut être pris avec ou sans nourriture.

La dose cible habituelle pour les adultes de Zyntabac est de 300 mg par jour, administrée en 150 mg deux fois par jour. Lancer l'administration de 150 mg par jour, administré en une seule dose quotidienne le matin. Après 3 jours d'administration, la dose peut être augmentée à la dose cible de 300 mg par jour, administrée sous forme de 150 mg deux fois par jour. Il doit y avoir un intervalle d'au moins 8 heures entre les doses successives. Un maximum de 400 mg par jour, administré en 200 mg deux fois par jour, peut être envisagé pour les patients chez lesquels aucune amélioration clinique n'est notée après plusieurs semaines de traitement à 300 mg par jour. Pour éviter des concentrations maximales élevées de bupropion et / ou de ses métabolites, ne dépassez pas 200 mg en une seule dose.

Il est généralement admis que les épisodes aigus de dépression nécessitent plusieurs mois ou plus de traitement antidépresseur au-delà de la réponse dans l'épisode aigu. On ne sait pas si la dose de Zyntabac nécessaire au traitement d'entretien est identique à la dose qui a fourni une réponse initiale. Réévaluer périodiquement la nécessité d'un traitement d'entretien et la dose appropriée pour un tel traitement.

Ajustement de la dose chez les patients présentant une insuffisance hépatique

Chez les patients atteints d'insuffisance hépatique modérée à sévère (score de Child-Pugh: 7 à 15), la dose maximale de Zyntabac est de 100 mg par jour ou 150 mg tous les deux jours. Chez les patients présentant une insuffisance hépatique légère (score de Child-Pugh: 5 à 6), envisagez de réduire la dose et / ou la fréquence de l'administration.

Ajustement de la dose chez les patients présentant une déficience rénale

Envisagez de réduire la dose et / ou la fréquence de WELLBUTRIN SR chez les patients atteints d'insuffisance rénale (taux de filtration glomérulaire inférieur à 90 ml par minute).

Passer un patient à ou à partir d'un antidépresseur à inhibiteur de la monoamine oxydase (IMAO)

Au moins 14 jours doivent s'écouler entre l'arrêt d'un IMAO destiné à traiter la dépression et le début du traitement par WELLBUTRIN SR. À l'inverse, au moins 14 jours doivent être autorisés après l'arrêt de Zyntabac avant de commencer un antidépresseur IMAO.

Utilisation de Zyntabac avec des IMAO réversibles tels que Linezolid ou Méthylène Blue

Ne démarrez pas Zyntabac chez un patient traité avec un IMAO réversible tel que le linézolide ou le bleu de méthylène intraveineux. Les interactions médicamenteuses peuvent augmenter le risque de réactions hypertensives. Chez un patient qui nécessite un traitement plus urgent d'une affection psychiatrique, des interventions non pharmacologiques, y compris l'hospitalisation, doivent être envisagées.

Dans certains cas, un patient recevant déjà un traitement par WELLBUTRIN SR peut nécessiter un traitement urgent avec du bleu de méthylène linézolide ou intraveineux. Si des alternatives acceptables au traitement au linézolide ou au bleu de méthylène intraveineux ne sont pas disponibles et que les avantages potentiels du traitement au linézolide ou au bleu de méthylène intraveineux sont jugés supérieurs aux risques de réactions hypertensives chez un patient particulier, Zyntabac doit être arrêté rapidement, et du bleu de méthylène linézolide ou intraveineux peut être administré. Le patient doit être surveillé pendant 2 semaines ou jusqu'à 24 heures après la dernière dose de linézolide ou de bleu de méthylène intraveineux, selon la première éventualité. Le traitement par Zyntabac peut être repris 24 heures après la dernière dose de linézolide ou de bleu de méthylène intraveineux.

Le risque d'administrer du bleu de méthylène par voie non intraveineuse (comme les comprimés oraux ou par injection locale) ou à des doses intraveineuses bien inférieures à 1 mg par kg avec Zyntabac n'est pas clair. Le clinicien doit néanmoins être conscient de la possibilité d'une interaction médicamenteuse avec une telle utilisation.

• WELLBUTRIN XL est contre-indiqué chez les patients atteints de trouble convulsif.
• WELLBUTRIN XL est contre-indiqué chez les patients présentant un diagnostic actuel ou antérieur de boulimie ou d'anorexie nerveuse car une incidence plus élevée de crises a été observée chez ces patients traités par WELLBUTRIN XL
• WELLBUTRIN XL est contre-indiqué chez les patients subissant un arrêt brutal de l'alcool, des benzodiazépines, des barbituriques et des antiépileptiques.
• L'utilisation d'IMAO (destinés à traiter des troubles psychiatriques) en concomitance avec WELLBUTRIN XL ou dans les 14 jours suivant l'arrêt du traitement par WELLBUTRIN XL est contre-indiquée. Il y a un risque accru de réactions hypertendues lorsque WELLBUTRIN XL est utilisé en concomitance avec les IMAO. L'utilisation de WELLBUTRIN XL dans les 14 jours suivant l'arrêt du traitement par un IMAO est également contre-indiquée. Le démarrage de WELLBUTRIN XL chez un patient traité avec des IMAO réversibles tels que le linézolide ou le bleu de méthylène intraveineux est contre-indiqué.
• WELLBUTRIN XL est contre-indiqué chez les patients présentant une hypersensibilité connue au bupropion ou à d'autres ingrédients de WELLBUTRIN XL. Des réactions anaphylactoïdes / anaphylactiques et le syndrome de Stevens-Johnson ont été rapportés.

• Zyntabac est contre-indiqué chez les patients atteints de trouble convulsif.
• Zyntabac est contre-indiqué chez les patients présentant un diagnostic actuel ou antérieur de boulimie ou d'anorexie nerveuse car une incidence plus élevée de convulsions a été observée chez ces patients traités par Zyntabac.
• Zyntabac est contre-indiqué chez les patients subissant un arrêt brutal de l'alcool, des benzodiazépines, des barbituriques et des antiépileptiques.
• L'utilisation d'IMAO (destinés à traiter des troubles psychiatriques) en concomitance avec Zyntabac ou dans les 14 jours suivant l'arrêt du traitement par Zyntabac est contre-indiquée. Il y a un risque accru de réactions hypertendues lorsque Zyntabac est utilisé en concomitance avec des IMAO. L'utilisation de Zyntabac dans les 14 jours suivant l'arrêt du traitement par un IMAO est également contre-indiquée. Le démarrage de Zyntabac chez un patient traité avec des IMAO réversibles tels que le linézolide ou le bleu de méthylène intraveineux est contre-indiqué.
• Zyntabac est contre-indiqué chez les patients présentant une hypersensibilité connue au bupropion ou à d'autres ingrédients du Zyntabac. Des réactions anaphylactoïdes / anaphylactiques et le syndrome de Stevens-Johnson ont été rapportés.

• Zyntabac est contre-indiqué chez les patients atteints d'un trouble convulsif.
• Zyntabac est contre-indiqué chez les patients présentant un diagnostic actuel ou antérieur de boulimie ou d'anorexie nerveuse car une incidence plus élevée de crises a été observée chez ces patients traités par la formulation à libération immédiate de bupropion.
• Zyntabac est contre-indiqué chez les patients subissant un arrêt brutal de l'alcool, des benzodiazépines, des barbituriques et des antiépileptiques.
• L'utilisation d'IMAO (destinés à traiter des troubles psychiatriques) en concomitance avec Zyntabac ou dans les 14 jours suivant l'arrêt du traitement par Zyntabac est contre-indiquée. Il y a un risque accru de réactions hypertendues lorsque Zyntabac est utilisé en concomitance avec des IMAO. L'utilisation de Zyntabac dans les 14 jours suivant l'arrêt du traitement par un IMAO est également contre-indiquée. Le démarrage de Zyntabac chez un patient traité avec des IMAO réversibles tels que le linézolide ou le bleu de méthylène intraveineux est contre-indiqué.
• Zyntabac est contre-indiqué chez les patients présentant une hypersensibilité connue au bupropion ou à d'autres ingrédients du Zyntabac. Des réactions anaphylactoïdes / anaphylactiques et le syndrome de Stevens-Johnson ont été rapportés.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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

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 (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 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 4400 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 1000 patients 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 Patients

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.

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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN 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

WELLBUTRIN XL is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion 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. 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 bupropion who continued to smoke.

Seizure

WELLBUTRIN XL can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue WELLBUTRIN XL 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 WELLBUTRIN XL. WELLBUTRIN XL is contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The following conditions can also increase the risk of seizure: 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), or 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, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence Of Seizure With Bupropion Use

The incidence of seizure with WELLBUTRIN XL has not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.

Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the WELLBUTRIN XL dose does not exceed 450 mg once daily and the titration rate is gradual.

Hypertension

Treatment with WELLBUTRIN XL can result in elevated blood pressure and hypertension.

Assess blood pressure before initiating treatment with WELLBUTRIN XL, and monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN XL is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity.

Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion 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 and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion 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 sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p=0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p=0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days.

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 studies 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 manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating WELLBUTRIN XL, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). WELLBUTRIN XL is not approved for the treatment of bipolar depression.

Psychosis And Other Neuropsychiatric Reactions

Depressed patients treated with bupropion 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. Discontinue WELLBUTRIN XL if these reactions occur.

Angle-Closure Glaucoma

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including WELLBUTRIN XL 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 WELLBUTRIN XL 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 symptoms of serum sickness suggestive of delayed hypersensitivity.

Patient Counseling Information

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

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with WELLBUTRIN XL and 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 Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About WELLBUTRIN XL?” is available for WELLBUTRIN XL. 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 WELLBUTRIN XL.

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 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 WELLBUTRIN XL is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN® which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation) or worsen pre-existing psychiatric illness. 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.

Severe Allergic Reactions

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

Seizure

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

Angle-Closure Glaucoma

Patients should be advised that taking WELLBUTRIN 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-angleglaucoma 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.

Bupropion-Containing Products

Educate patients that WELLBUTRIN XL contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that WELLBUTRIN XL should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation, and APLENZIN, a bupropion hydrobromide formulation). 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 WELLBUTRIN XL Tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN XL Tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. WELLBUTRIN XL treatment 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 WELLBUTRIN XL Tablets and other drugs may affect each other's metabolism.

Pregnancy

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

Precautions For Nursing Mothers

Communicate with the patient and pediatric healthcare provider regarding the infant's exposure to bupropion through human milk. Instruct patients to immediately contact the infant's healthcare provider if they note any side effect in the infant that concerns them or is persistent.

Administration Information

Instruct patients to swallow WELLBUTRIN XL Tablets whole so that the release rate is not altered. 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. Instruct patients that WELLBUTRIN XL tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN XL should be administered in the morning and may be taken with or without food.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Pregnancy

Pregnancy Category C

Risk Summary

Data from epidemiological studies including 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 equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. WELLBUTRIN XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Human Data

Data from an 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-controlled study (6,853 infants with cardiovascular malformations and 5,753 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 left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding 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 an 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 at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the 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 observed at 50 mg/kg and greater. When rats were administered bupropion 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.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. When considering the use of WELLBUTRIN XL in a child or adolescent, balance the potential risks with the clinical need.

Geriatric Use

Of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥ 65 years old and 47 were ≥ 75 years old. In addition, several hundred patients ≥ 65 years of age 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.

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.

Renal Impairment

Consider a reduced dose and/or dosing frequency of WELLBUTRIN XL in patients with renal impairment (Glomerular Filtration Rate: < 90 mL/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.

Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum WELLBUTRIN XL dose 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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

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 (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 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 4400 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 1000 patients 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 Patients

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.

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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Zyntabac 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

Zyntabac is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion 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. 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 bupropion who continued to smoke.

Seizure

Zyntabac can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue Zyntabac 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 Zyntabac. Zyntabac is contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The following conditions can also increase the risk of seizure: 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), or 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, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence Of Seizure With Bupropion Use

The incidence of seizure with Zyntabac has not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.

Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the Zyntabac dose does not exceed 450 mg once daily and the titration rate is gradual.

Hypertension

Treatment with Zyntabac can result in elevated blood pressure and hypertension.

Assess blood pressure before initiating treatment with Zyntabac, and monitor periodically during treatment. The risk of hypertension is increased if Zyntabac is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity.

Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion 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 and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion 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 sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p=0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p=0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days.

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 studies 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 manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating Zyntabac, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Zyntabac is not approved for the treatment of bipolar depression.

Psychosis And Other Neuropsychiatric Reactions

Depressed patients treated with bupropion 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. Discontinue Zyntabac if these reactions occur.

Angle-Closure Glaucoma

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

Hypersensitivity Reactions

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

Patient Counseling Information

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

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Zyntabac and 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 Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Zyntabac?” is available for Zyntabac. 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 Zyntabac.

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 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 Zyntabac is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN® which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation) or worsen pre-existing psychiatric illness. 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.

Severe Allergic Reactions

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

Seizure

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

Angle-Closure Glaucoma

Patients should be advised that taking Zyntabac 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-angleglaucoma 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.

Bupropion-Containing Products

Educate patients that Zyntabac contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that Zyntabac should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation, and APLENZIN, a bupropion hydrobromide formulation). 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 WELLBUTRIN XL Tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that Zyntabac Tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Zyntabac treatment 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 Zyntabac Tablets and other drugs may affect each other's metabolism.

Pregnancy

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

Precautions For Nursing Mothers

Communicate with the patient and pediatric healthcare provider regarding the infant's exposure to bupropion through human milk. Instruct patients to immediately contact the infant's healthcare provider if they note any side effect in the infant that concerns them or is persistent.

Administration Information

Instruct patients to swallow Zyntabac Tablets whole so that the release rate is not altered. 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. Instruct patients that Zyntabac tablets should be swallowed whole and not crushed, divided, or chewed. Zyntabac should be administered in the morning and may be taken with or without food.

Nonclinical Toxicology

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

Pregnancy

Pregnancy Category C

Risk Summary

Data from epidemiological studies including 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 equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Zyntabac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Human Data

Data from an 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-controlled study (6,853 infants with cardiovascular malformations and 5,753 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 left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding 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 an 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 at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the 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 observed at 50 mg/kg and greater. When rats were administered bupropion 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.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. When considering the use of Zyntabac in a child or adolescent, balance the potential risks with the clinical need.

Geriatric Use

Of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥ 65 years old and 47 were ≥ 75 years old. In addition, several hundred patients ≥ 65 years of age 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.

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.

Renal Impairment

Consider a reduced dose and/or dosing frequency of Zyntabac in patients with renal impairment (Glomerular Filtration Rate: < 90 mL/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.

Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum Zyntabac dose 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicidal Thoughts And Behaviors In Children, Adoles cents , 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

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.

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 Zyntabac should be written for the smallest quantity of tablets cons is tent with good patient management, in order to reduce the risk of overdose.

Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment

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 bupropion who continued to smoke.

Seizure

Zyntabac can cause seizure. The risk of seizure is dose-related. The dose should not exceed 400 mg per day. Increase the dose gradually. Discontinue Zyntabac 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 Zyntabac. WELLBUTRIN SR 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. 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

When Zyntabac is dosed up to 300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.

The risk of seizure can be reduced if the dose of Zyntabac does not exceed 400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.

Hypertension

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

Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal