APLENZIN (bupropion hydrobromide)

APLENZIN (bupropion hydrobromide)

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APLENZIN (bupropion hydrobromide)

APLENZIN® (bupropion hydrobromide), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-2-(tert-butylamino)-3′- chloropropiophenone hydrobromide. The molecular weight is 320.6. The molecular formula is C13H18ClNO•HBr. Bupropion hydrobromide powder is white or almost white, crystalline, and soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Indications and usage

APLENZIN is an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD) and seasonal affective disorder (SAD). Periodically reevaluate long-term usefulness for the individual patient.

Mechanism of Action

The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

Dosage and administration

Major Depressive Disorder

  • Starting dose: 174 mg once daily (equivalent to 150 mg bupropion HCl). Usual target dose: 348 mg once daily (equivalent to 300 mg bupropion HCl).
  • After 4 days, may increase the dose to 348 mg once daily.

Seasonal Affective Disorder

  • Initiate treatment in the autumn prior to onset of seasonal depressive symptoms.
  • Starting dose: 174 mg once daily (equivalent to 150 mg bupropion HCl). Usual target dose: 348 mg once daily (equivalent to 300 mg bupropion HCl).
  • After one week, may increase the dose to 348 mg once daily.
  • Continue treatment through the winter season.

Hepatic Impairment

  • Moderate to severe hepatic impairment: Maximum dose 174 mg every other day
  • Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing.

Renal Impairment

  • Consider reducing the dose and/or frequency of dosing.

Contraindications

  • Seizure disorder.
  • Current or prior diagnosis of bulimia or anorexia nervosa.
  • Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs.
  • Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with APLENZIN or within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start APLENZIN in a patient who is being treated with linezolid or intravenous methylene blue.
  • Known hypersensitivity to bupropion or other ingredients of APLENZIN

Warnings and 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.
  • Neuropsychiatric Adverse Events During Smoking Cessation: Postmarketing reports of serious or clinically significant neuropsychiatric adverse events have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients attempting to quit smoking with APLENZIN for the occurrence of such symptoms and instruct them to discontinue APLENZIN and contact a healthcare provider if they experience such adverse events.
  • Seizure Risk: The risk is dose-related. Can minimize risk by limiting daily dose to 522 mg and gradually increasing the dose. Discontinue if seizure occurs.
  • Hypertension: APLENZIN can increase blood pressure. Monitor blood pressure before initiating treatment and periodically during treatment.
  • Activation of Mania/Hypomania: Screen patients for bipolar disorder and monitor for these symptoms.
  • Psychosis and Other Neuropsychiatric Reactions: Instruct patients to contact a healthcare professional if such reactions occur.
  • Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.
  • 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 APLENZIN 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.
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Adverse reactions

Most common adverse reactions are (incidence ≥5%; ≥2× placebo rate): dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash.

Drug interactions

Potential for Other Drugs to Affect APLENZIN: Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between APLENZIN and drugs that are inhibitors or inducers of CYP2B6

Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of APLENZIN may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel)

Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of APLENZIN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose

Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). Consider dose reduction when using with bupropion.

Drugs That Lower Seizure Threshold: Use extreme caution when coadministering APLENZIN with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of APLENZIN and increase the dose gradually

Dopaminergic Drugs (Levodopa and Amantadine): Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering APLENZIN concomitantly with these drugs.

Use with Alcohol: In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with APLENZIN. The consumption of alcohol during treatment with APLENZIN should be minimized or avoided.

MAO Inhibitors: Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs.

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.

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

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 APLENZIN is administered to a nursing woman.

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

Overdosage

Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.

Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.

Overdosage Management

There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose.

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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