Wigan manager Roberto Martinez said on Tuesday that McCarthy has an ankle injury and that medical reports had been sent to the Republic camp.
"They are well, well aware," said the Wigan manager.
Republic manager Giovanni Trapattoni said on Monday that he had received no communication from McCarthy.
Martinez added:"That is where James had an operation earlier this season and it is an area that is a bit of a concern.
"We have to work together to try and get him a speedy recovery but he is not available to play and he will need at least three or four weeks to recover."
On Monday, Trapattoni expressed frustration at both McCarthy and Anthony Stokes who also failed to turn up in Dublin.
The Republic face Scotland - McCarthy's country of birth - on Sunday.
The Irish then face Macedonia in a Euro 2012 qualifier before the concluding friendly against Italy.
On Monday, Trapattoni hit out at Stokes after the Celtic striker pulled out of the end-of-season games citing tiredness.
The Republic begin with Tuesday's Nations Cup game against Northern Ireland and other absentees include injured Richard Dunne.
"It is not a job like the working man's. It is not a difficult job," said Trapattoni of Stokes' absence.
"It is unbelievable...we are lucky and we have to enjoy playing football."
Stokes featured as a substitute in the Scottish Cup final on Saturday but then informed the Football Association of Ireland he was unavailable for all four games.
Trapattoni described a modern footballer's lot as an "11-month holiday" and made clear that he was unhappy at Stokes' refusal to report to Dublin.
"I played 70 games every season - national, championship, Europe," added the Italian.
"It is a new generation. Sometimes there is more pressure now but players should understand how beautiful our job is.
"Injuries are injuries, but they should visit our doctor. That is the rule.
"If they are asked by the national team they must go. If they are in hospital or they are dead, that is okay, but if there is an injury they should see our doctor."
Trapattoni insisted, however, that he would still consider former Sunderland player Stokes for selection in future.
"I don't forget any players, ever," he said.
Dunne has shoulder and Achilles injuries and was already suspended for the only competitive game of the fixtures, the Euro 2012 qualifier against Macedonia.
Ciaran Clark and Caleb Folan had already withdrawn from the squad.
Darron Gibson, Shane Long and Kevin Kilbane are unavailable for the Northern Ireland contest and Sunday's Nations Cup game against Scotland because their club seasons have yet to finish.
"He (Dunne) is suspended also for the Macedonia game so it is better (for him) to stay at home," said Republic manager Giovanni Trapattoni of Dunne's absence.
West Brom forward Simon Cox will win his first cap in Tuesday's game alongside Robbie Keane in attack.
Trapattoni has yet to decide whether Liam Lawrence or Seamus Coleman will patrol the right midfield flank while either Kevin Foley or Keith Fahey will partner Keith Andrews in central midfield.
Republic of Ireland: Given, McShane, Delaney, Kelly, Wilson, Lawrence or Coleman, Andrews, Foley or Fahey, Treacy, Keane, Cox.