Hepetema, who was signed as injury cover for Smith last month, suffered a fractured eye socket in Saturday's Aviva Premiership defeat to Harlequins and will be sidelined for a month-and-a-half.
That length of absence rules him out of the games against Montpellier at Welford Road on Sunday, December 8 and at the Stade Yves du Manoir exactly a week later, although Bowden and Smith will be fit to return in plenty of time. The pair were concussed in the same game and will miss the Ospreys fixture as a result but they could feature as early as a week on Saturday when the Tigers travel to Worcester.
This week's setbacks are the latest in a long line of injury problems for director of rugby Richard Cockerill and co, with Leicester fast running out of midfield option for Friday's fixture.
England star Manu Tuilagi has been out of action since September 21 with a chest injury he picked up in the Aviva Premiership win over Newcastle, while fellow international Anthony Allen hasn't played since the domestic derby with Northampton on October 5.
"The injury curse keeps coming back to get us but we have to keep doing what we are doing," Cockerill told the Leicester Mercury. "The side for Friday will be a youthful one, with three or four senior guys in there who need game time.
"We've had multiple injuries and not one has come at training. They have all happened in games, and that is purely down to bad luck. But for that many injuries to hit us in midfield, you have to keep smiling otherwise you'd cry."
Allen, who was being tipped to challenge for an England Test spot in the absence of Brad Barritt this autumn, was ruled out for 12 weeks with an unusual leg injury that is more commonly associated with road traffic accidents.
Tuilagi should return in time to take on Montpellier in Round 3 but Allen won't be available for selection by then, with the final two pool games away to Benetton Treviso and at home to Ulster a more realistic target.
Niki Goneva is also currently sidelined having picked up a calf injury early on in the Round 2 bonus-point win over Treviso and it remains unclear whether he will line up against the French side at Welford Road after his initial diagnosis suggested a six-week absence.
Wing Adam Thompstone - the man who scored the bonus-point try with the last play of the game against Treviso a fortnight ago - could be asked to move into the midfield this week, as could fly-half Owen Williams.
George Catchpole and Pasqualle Dunn started Leicester's last A League fixture on October 28, with Javiah Pohe coming on as a replacement, but all three are just 19 years of age and are yet to make a senior squad appearance between them.