4.4.3.8  Is there a known mechanism basis for pharmacodynamic drug-drug interactions, if any?

 

Bupropion is associated with a dose-related risk of seizures and this risk may be increased if given with other medications that lower the seizure threshold.

 

Other potential pharmacodynamic drug interactions are listed in the label and include a contraindication for use with MAO inhibitors due to potential for enhanced toxicity of bupropion, caution with levodopa or amantadine administration due to higher incidence of adverse effects, precautions regarding the potential for hypertension in patients receiving nicotine transdermal systems, and adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during treatment with bupropion.

 

4.4.3.9  Are there any unresolved questions related to metabolism, active metabolites, metabolic drug interactions or protein binding?

 

In light of the in vitro studies suggesting inhibition of bupropion metabolism by SSRIs and antiretroviral drugs, this should be addressed in the label and potentially addressed with a literature search and, if necessary, followed by a drug interaction study in vivo.  Thiotepa has also been demonstrated in vitro to be a substrate and inhibitor of CYP2B6, and this information should be added to the label.

 

 

4.4.4        What issues related to dose, dosing regimen, or administration are unresolved, and represent significant omissions?

 

If a significant increase in exposure were observed following inhibitors of CYP2B6, a determination of the need for dosage adjustment would be required.

 

Currently the potential for CYP2B6-mediated interactions is addressed in the Clinical Pharmacology section of the label with a focus on interaction with agents that are metabolized by CYP2B6.  The Drug Interactions section of the label states that the potential exists for a drug interaction with drugs that affect the CYP2B6 isoenzyme, and lists only orphenadrine and cyclophosphamide as examples.

 

 

4.5              General Biopharmaceutics

 

4.5.1        If the NDA is for a modified release formulation of an approved immediate product with supportive safety/efficacy studies, what dosing regimen changes are necessary, if any, in the presence or absence of PK-PD relationship?

·         What is the bioavailability of WELLBUTRIN XL 300 mg relative to immediate release WELLBUTRIN tablets (100

   mg three times daily)?

 

Study AK1BIOVAIL2543 assessed the relative oral bioavailability of a once daily 300 mg WELLBUTRIN XL tablet (test) compared to the reference WELLBUTRIN immediate release tablets given 100 mg three times daily (tid) under steady-state fasting conditions.  The full study review can be found in the Appendix, Section 6.2.4.  This was a randomized, 2-period, 2-

 

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