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
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
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
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
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.
Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine [see
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. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
Human Overdose Experience
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.
Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR). Call 1-800-222-1222 or refer to www.poison.org.
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.
DRUG ABUSE AND DEPENDENCE
Bupropion is not a controlled substance.
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.
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.