Italy will be without centre Tommaso Menoncello, scrum-half Martin Page-Relo, back-rower Sebastian Negri and full-back Lorenzo Pani for next month's Nations Championship, the FIR confirmed on Wednesday.
Menoncello, 24, lasted just six minutes of Toulouse's Champions Cup win over Exeter on Sunday before being forced off with a shoulder injury. His absence adds to a growing list of concerns for Gonzalo Quesada, who faces South Africa, Argentina and Fiji across four consecutive weeks of competition.
"We know that major challenges await us this year, starting with the injuries to several players who are very important for our team," Quesada said. "But one year out from the Rugby World Cup, I also see these difficulties as a great opportunity to give playing time to some young players who represent the future of the national team."
The Nations Championship concludes the weekend of 27-29 November, when a final round of matches will determine the overall standings.