The 29-year-old has suffered an injury to his left hamstring, meaning he's set to miss the showpiece and possibly the first leg of his side's Champions League semifinal.
The Portugual international limped off in the closing stages of his side's 3-0 Champions League quarterfinal first leg win over Borussia Dortmund.
He subsequently sat out the 4-0 win over Real Sociedad at Anoeta and was an unused substitute in the return game against Jurgen Klopp's side, as Madrid scraped through to the semifinals 3-2 on aggregate after losing 2-0 on Tuesday night.
It has now been confirmed that the 29-year-old has suffered an injury to his left hamstring and is reportedly set to miss around two weeks of action, which would rule him out of the crucial Clasico next Wednesday.
The problem also makes him a doubt for the first leg of his side's Champions League semifinal on April 22 or 23, with Atletico Madrid, Chelsea and Bayern Munich all possible opponents in the last four.