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Aplenzin

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride

Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustainedrelease (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below.

300 mg/day of bupropion HCl sustained-release (equivalent to APLENZIN 348 mg/day): anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

400 mg/day of bupropion HCl sustained-release (equivalent to APLENZIN 464 mg/day): abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

APLENZIN is bioequivalent to bupropion HCl extended-release, which has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion. The information included under this subsection and under the subsections 6.2 and 6.3 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride.

Major Depressive Disorder

Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended- Release in Major Depressive Disorder Trials

In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 3.

Table 3: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD

Adverse Reaction Term Placebo
(n=385)
Bupropion HCl Sustained-Release 300 mg/day*
(n=376)
Bupropion HCl Sustained-Release 400 mg/day**
(n=114)
Rash 0.0% 2.4% 0.9%
Nausea 0.3% 0.8% 1.8%
Agitation 0.3% 0.3% 1.8%
Migraine 0.3% 0.0% 1.8%
* Equivalent to 348 mg/day bupropion HBr
** Equivalent to 464 mg/day bupropion HBr

In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation, (in addition to those listed above for the sustained-release formulation), included vomiting, seizures, and sleep disturbances.

Adverse Reactions Occurring at an Incidence of > 1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD

Table 4 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group are included.

Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD

Body System/Adverse Reaction Placebo
(n=385)
Bupropion HCl Sustained-Release 300 mg/day*
(n=376)
Bupropion HCl Sustained-Release 400 mg/day**
(n=114)
Body (General)
  Headache 23% 26% 25%
  Infection 6% 8% 9%
  Abdominal pain 2% 3% 9%
  Asthenia 2% 2% 4%
  Chest pain 1% 3% 4%
  Pain 2% 2% 3%
  Fever 1% 2%
Cardiovascular
  Palpitation 2% 2% 6%
  Flushing 1% 4%
  Migraine 1% 1% 4%
  Hot flashes 1% 1% 3%
Digestive
  Dry mouth 7% 17% 24%
  Nausea 8% 13% 18%
  Constipation 7% 10% 5%
  Diarrhea 6% 5% 7%
  Anorexia 2% 5% 3%
  Vomiting 2% 4% 2%
  Dysphagia 0% 0% 2%
Musculoskeletal
  Myalgia 3% 2% 6%
  Arthralgia 1% 1% 4%
  Arthritis 0% 0% 2%
  Twitch 1% 2%
Nervous System
  Insomnia 6% 11% 16%
  Dizziness 5% 7% 11%
  Agitation 2% 3% 9%
  Anxiety 3% 5% 6%
  Tremor 1% 6% 3%
  Nervousness 3% 5% 3%
  Somnolence 2% 2% 3%
  Irritability 2% 3% 2%
  Memory decreased 1% 3%
  Paresthesia 1% 1% 2%
  Central nervous system stimulation 1% 2% 1%
Respiratory
  Pharyngitis 2% 3% 11%
  Sinusitis 2% 3% 1%
  Increased cough 1% 1% 2%
Skin
  Sweating 2% 6% 5%
  Rash 1% 5% 4%
  Pruritus 2% 2% 4%
  Urticaria 0% 2% 1%
Special Senses
  Tinnitus 2% 6% 6%
  Taste perversion 2% 4%
  Blurred vision or diplopia 2% 3% 2%
Urogenital
  Urinary frequency 2% 2% 5%
  Urinary urgency 0% 2%
   Vaginal hemorrhage&dagger 0% 2%
  Urinary tract infection 1% 0%
* Equivalent to 348 mg/day bupropion HBr
** Equivalent to 464 mg/day bupropion HBr
† Incidence based on the number of female patients.
— Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.

The following additional adverse reactions occurred in controlled trials of bupropion HC1 immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), tachycardia (11% vs. 9%), appetite increased (4% vs. 2%), dyspepsia (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%).

Seasonal Affective Disorder

In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion HCl extended-release and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. < 1%) and headache (1% vs. < 1%).

Table 5 summarizes the adverse reactions that occurred in patients treated with bupropion HCl extended-release for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group.

Table 5: Adverse Reactions in Placebo-Controlled Trial in Patients with SAD

System Organ Class/ Preferred Term Placebo
(n=511)
Bupropion HCl Extended-Release
(n=537)
Gastrointestinal Disorder
  Dry mouth 15% 26%
  Nausea 8% 13%
  Constipation 2% 9%
  Flatulence 3% 6%
  Abdominal pain < 1% 2%
Nervous System Disorders
  Headache 26% 34%
  Dizziness 5% 6%
  Tremor < 1% 3%
Infections and Infestations
  Nasopharyngitis 12% 13%
  Upper respiratory tract infection 8% 9%
  Sinusitis 4% 5%
Psychiatric Disorders
  Insomnia 13% 20%
  Anxiety 5% 7%
  Abnormal dreams 2% 3%
  Agitation < 1% 2%
Musculoskeletal and Connective Tissue Disorders
  Myalgia 2% 3%
  Pain in extremity 2% 3%
Respiratory, Thoracic, and Mediastinal Disorders
  Cough 3% 4%
General Disorders and Administration Site Conditions
  Feeling jittery 2% 3%
Skin and Subcutaneous Tissue Disorders 
  Rash 2% 3%
Metabolism and Nutrition Disorders
  Decreased appetite 1% 4%
Reproductive System and Breast Disorders
  Dysmenorrhea < 1% 2%
Ear and Labyrinth Disorders
  Tinnitus < 1% 3%
Vascular Disorders
  Hypertension 0% 2%

Changes In Body Weight

Table 6 presents the incidence of body weight changes ( ≥ 5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight.

Table 6: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs.) in MDD Trials Using Bupropion HCl Sustained-Release

Weight Change Bupropion HCl Sustained-Release 300 mg/day*
(n=339)
Bupropion HCl Sustained-Release 400 mg/day**
(n=112)
Placebo
(n=347)
Gained > 5 lbs 3% 2% 4%
Lost > 5 lbs 14% 19% 6%
* Equivalent to 348 mg/day bupropion HBr
** Equivalent to 464 mg/day bupropion HBr

Table 7 presents the incidence of body weight changes ( ≥ 5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥ 5 lbs., compared to the placebo group (11%). These were relatively long-term trials (up to 6 months).

Table 7: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in SAD Trials Using Bupropion HCl Extended-Release

Weight Change Bupropion HCl Extended-Release 150 to 300 mg/day
(n=537)
Placebo
(n=511)
Gained > 5 lbs 11% 21%
Lost > 5 lbs 23% 11%

Postmarketing Experience

The following adverse reactions have been identified during post approval use of APLENZIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body (General)

Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.

Cardiovascular

Postural hypotension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive

Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.

Endocrine

Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and Lymphatic

Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Metabolic and Nutritional

Glycosuria.

Musculoskeletal

Leg cramps, fever/rhabdomyolysis, and muscle weakness.

Nervous System

Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory

Bronchospasm and pneumonia.

Skin

Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism.

Special Senses

Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.

Urogenital

Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

Read the Aplenzin (bupropion hydrobromide tablet) Side Effects Center for a complete guide to possible side effects

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. Dosage reduction of APLENZIN may be necessary when coadministered with ticlopidine or clopidogrel [see CLINICAL PHARMACOLOGY].

Inducers of CYP2B6

Ritonavir, Lopinavir, and Efavirenz. Concomitant treatment with these drugs can decrease bupropion exposure. Dosage increase of APLENZIN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see CLINICAL PHARMACOLOGY].

Other CYP Inducers

Carbamazepine, Phenobarbital, Phenytoin: Concomitant treatment with these drugs can decrease bupropion exposure. It may be necessary to increase the dose of APLENZIN when coadministered with carbamazepine, phenobarbital, or phenytoin [see CLINICAL PHARMACOLOGY].

In addition, studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion and may increase bupropion exposure.

Potential For APLENZIN To Affect Other Drugs

Drugs Metabolized by CYP2D6

Bupropion and hydroxybupropion are CYP2D6 inhibitors. Therefore, coadministration of APLENZIN with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, and flecainide). When used concomitantly with APLENZIN, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen), theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with APLENZIN and such drugs may require increased doses of the drug [see CLINICAL PHARMACOLOGY].

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 [see WARNINGS AND PRECAUTIONS].

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.

MAO Inhibitors

Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine [see CONTRAINDICATIONS].

Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. Falsepositive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

Drug Abuse And Dependence

Controlled Substance

Bupropion is not a controlled substance.

Abuse

Humans

Controlled clinical studies of bupropion HCl immediate-release conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients demonstrated an increase in motor activity and agitation/excitement.

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg bupropion produced mild amphetamine-like activity as compared to placebo on the Morphine- Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.

Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.

Animals

Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

Read the Aplenzin Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 7/24/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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