The safety and efficacy of OraVerse when used for reversal of soft-tissue anesthesia (STA), i.e., anesthesia of the lips and tongue following a dental procedure that required local anesthesia containing a vasoconstrictor, were evaluated in the following clinical studies. OraVerse-induced reversal of local anesthetic effects on the teeth, mandible and maxilla has not been assessed.

Two Phase 3, double-blinded, randomized, multi-center, controlled studies were conducted in dental patients who had mandibular (Study 1) or maxillary (Study 2) restorative or periodontal maintenance procedures and who had received a local anesthetic that contained a vasoconstrictor. The primary endpoint was time to normal lip sensation as measured by patient reported responses to lip palpation. The secondary endpoints included patients' perception of altered function, sensation and appearance, and their actual functional deficits in smiling, speaking, drinking and drooling, as assessed by both the patient and an observer blinded to the treatment. In the mandibular study, the time to recovery of tongue sensation was also a secondary endpoint. Patients were stratified by type and amount of anesthetic administered. OraVerse was administered at a cartridge ratio of 1:1 to local anesthetic. The control was a sham injection.

OraVerse reduced the median time to recovery of normal sensation in the lower lip by 85 minutes (55%) compared to control. The median time to recovery of normal sensation in the upper lip was reduced by 83 minutes (62%). The differences between these times for both studies are depicted in Kaplan-Meier plots for time to normal lip sensation in

Figures 1 and 2. Within 1 hour after administration of OraVerse, 41% of patients reported normal lower lip sensation as compared to 7% in the control group, and 59% of patients in the OraVerse group reported normal upper lip sensation as compared to 12% in the control group.

In Study 1 (mandibular), OraVerse accelerated: a) the recovery of the perception of normal appearance and function by 60 minutes (40%), b) the recovery of normal function by 60 minutes (50%), and c) the recovery of normal sensation in the tongue by 65 minutes (52%). In Study 2 (maxillary), the recovery of the perception of normal appearance and function was reduced by 60 minutes (50%) and the recovery of normal function was reduced by 45 minutes (43%).

  
Study 3, a pediatric, Phase 2, double-blinded, randomized, multi-center, controlled study was conducted in dental patients who had received 2% lidocaine with 1:100,000 epinephrine. Dental patients (n=152, ages 4-11 years) received 1/2 cartridge of OraVerse if they weighed ≥15 kg but <30 kg, and one-half or one full cartridge if they weighed ≥30 kg at a cartridge ratio of 1:1 to local anesthetic.  
The median time to normal lip sensation in patients 6 to 11years of age who were trainable in the lip-palpation procedures, for mandibular and maxillary procedures combined, was reduced by 75 minutes (56%). Within 1 hour after administration of OraVerse, 44 patients (61%) reported normal lip sensation, while 9 patients (21%) randomized to the control group reported normal lip sensation. In this study, neither the patients' perception of their appearance or ability to function nor their actual ability to function was evaluated.

  
Study 4, a pediatric, Phase 4, double-blinded, randomized, multi-center, controlled study was conducted in dental patients undergoing mandibular and maxillary procedures after receiving 2% lidocaine with 1:100,000 epinephrine. Patients 2-5 years of age received sham injection (n=51) or 1/4 cartridge of OraVerse if they weighed ≥10 kg but <15kg (n=5), 1/2 cartridge if they weighed ≥15 kg but <30kg (n=91), and a full cartridge if they weighed >30kg (n=3). This study was not designed to demonstrate efficacy.

  
The median time to normal lip sensation in patients 4 and 5 years of age who were trainable in the lip-palpation procedure, for mandibular and maxillary procedures combined, was reduced by 48 minutes (44%). Within 2 hours after administration of OraVerse, 57 patients (80%) reported normal lip sensation, while 19 patients (51%) randomized to the sham injection group reported normal lip sensation. There were no significant differences between OraVerse and sham injection for time to return of normal function in pediatric functional assessment battery and time to recovery of normal tongue sensation (for mandibular procedures only).