Sundowns beat the Ghanaian Premier League side 3-1 at the Lucas Moripe Stadium earlier this month.
Medeama scored an away goal that could come in handy in the return leg at home in Ghana.
Mosimane thinks the away goal could spare Medeama’s comeback as they will look to build on it to overturn the 3-1 score line from the first leg.
“Medeama had a goal in South Africa and that is a great headache to us,” Mosimane told Ghanasoccernet.
“That away goal is a great advantage for them. They will try to make good use of it in the second leg and that is a problem.
“If the first leg had ended without Medeama having a goal, it would have been different. It is difficult, but my boys are ready for the job.”