Bioequivalence and Bioavailability Forum

Dear all

I would like to know whether we should go ahead with fasting and fed studies for both the strengths (10 mg and 20 mg) of Rivaroxaban or fasting and fed studies for 20 mg and only fasting study for 10 mg (USFDA submission).

I have listed out my learnings on this molecule as below:

1. There is no FDA product specific recommendation on rivaroxaban till date.
   
2. Product label of reference drug mentions that 15 mg, 20 mg tablets are to be taken with food however 10 mg tablets are to be taken with or without food. Also states that there is a lower bioavailability of 66 % reported for 20 mg in fasting state and co administration of food increases the bioavailability (mean AUC and Cmax increasing by 39% and 76% respectively with food). Whereas bioavailability of 10 mg is estimated to be 80% to 100% and is not affected by food.
   
3. Though the USFDA reference product label does not mention anything much on the dose proportionality, the Australian Public Assessment Report for Rivaroxaban concluded that there is a dose proportionality between rivaroxaban 10 mg, 15 mg and 20 mg under fed condition.
   
4. As per the Orange book there are two RLD listed one is for 10 mg and the other is for 20 mg.
   
5. Guidance on “Food-Effect Bioavailability and Fed Bioequivalence Studies” mentions the following:
   “In addition to a BE study under fasting conditions, we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with the following exceptions:
   • When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permeability (BCS Class I)), or
     
   • When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or
     
   • When the RLD label does not make any statements about the effect of food on absorption or administration”

Is there a possibility to have a waiver on the 10 mg strength.

Regards

VG