The 29-year-old has been forced to withdraw from the Seleccao squad as a precaution after suffering an injury during training ahead of their match on Wednesday
The defender has left the Portugal camp and will return to Madrid to seek treatment although it is not expected that he will be out of action for long.
"The player's condition will not have improved enough in three days [for him to play against Panama]," the head of Portugal's medical team, Henrique Jones, was quoted as saying by Marca.
The former Porto man has made 44 appearances for the Seleccao since making his debut against Finland in 2007.
Paulo Bento is set to call up Deportivo La Coruna defender Andre Santos as replacement for Pepe, while he must also find men to fill in for Braga midfielder Custodio and Zenit St Petersburg defender Bruno Alves after they too withdrew from the squad in recent days.