sustained-release formulation is substantially less than that of the immediate-release formulation, and comparable to that of other commercially-marketed antidepressants.

 

The proposed labeling states that limited clinical data suggests a higher incidence of adverse experiences in patient receiving concurrent administration of immediate-release bupropion and levodopa and advises caution in prescribing the sustained-release formulation along with levodopa.  Physicians are also advised exercise caution when co-administering drugs that affect hepatic drug-metabolizing enzyme systems (e.g., carbamazepine, cimetidine, phenobarital, and phenytoin).

 

Caution is urged patients with known cardiovascular, hepatic, or renal disease.

 

The drug is classified as belonging to Pregnancy Category B.  Because of the potential for serious adverse reactions in infants who might receive bupropion through mother’s milk, the physician is advised to use clinical judgment in deciding whether to recommend that a mother discontinue breast feeding, or alternatively, discontinue bupropion.

 

Regarding special populations, it is stated that safety and effectiveness in children has not been established.  For geriatric use, the sponsor notes that exposure of elderly patients to sustained-release bupropion is limited, but that one study has demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects.

 

Although the sponsor has limited experience with sustained-release bupropion in overdose, the proposed labeling does address overdoses with the immediate release formulation of the substance.  The manufacturer recommends hospitalization and general supportive measures along with EKG and EEG monitoring for 48 hours after suspected overdoses.

 

The recommended initial dosage is 150 mg daily, titrated up to a maximum daily dose of 300 mg, with dose increases occurring at intervals of at least one week.  The sponsor recommends administering individual doses of no greater than 150 mg, with daily doses greater than 150 mg being given b.i.d. with at least eight hours between successive doses.

 

2.5                            Foreign Marketing

 

Neither bupropion immediate-release nor bupropion sustained-release has ever been marketed outside the U.S.A.  Applications to market the immediate-release form of bupropion in the United Kingdom and Canada were withdrawn in 1984 and 1986, respectively, following deficiency that each country’s regulatory agency found in the applications.  No applications for the marketing of bupropion sustained-release have been made outside of the U.S.A.

 

3.0                            Chemistry

 

The chemistry has been reviewed separately.  An environmental assessment is still pending.  the stability of the sustained-release formulation has not yet been adequately reported to the satisfaction of the agency.  There are no other outstanding chemistry concerns of clinical relevance.

 

4.0                            Animal Pharmacology

 

The animal pharmacology is reviewed separately, and only a brief summary is presented here.

 

Nonclinical pharmacology studies suggest that bupropion may inhibit the reuptake of both norepinephrine and dopamine.  It spares central and peripheral α₁ and α₂ adrenergic receptors, H₁ histamine receptors, muscarinic (cholingergic) receptors, and D₂ dopaminergic receptors.

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