Holtby set up another four minutes into the second half, with Paulinho stabbing in his second goal in three days, having scored Tottenham's Premier League winner at Cardiff on Sunday.
Winger Nacer Chadli blasted in his first goal since joining from FC Twente in the close season and Defoe wrapped up the victory in stoppage time by rounding the goalkeeper and putting the ball in the net for Tottenham.