CLINICAL PHARMACOLOGY
Mechanism Of Action
The mechanism by which OraVerse
accelerates reversal of soft-tissue anesthesia and the associated functional
deficits is not fully understood. Phentolamine mesylate, the active ingredient
in OraVerse, produces an alpha-adrenergic block of relatively short duration
resulting in vasodilatation when applied to vascular smooth muscle. In an
animal model, OraVerse increased local blood flow in submucosal tissue of the
dog when given after an intraoral injection of lidocaine 2% with 1:100,000
epinephrine.
Pharmacokinetics
Following OraVerse administration, phentolamine is 100%
available from the submucosal injection site and peak concentrations are
achieved 10-20 minutes after injection. Phentolamine systemic exposure
increased linearly after 0.8 mg compared to 0.4 mg
OraVerse intraoral submucosallood was approximately 2-3 hours.
Pediatrics
Following OraVerse
administration, the phentolamine Cmax was higher (approximately 3.5-fold) in
children who weighed between 15 and 30 kg (33 and 66 lbs) than in children who
weighed more than 30 kg. However, phentolamine AUC was similar between the two
groups. It is recommended that in children weighing 15-30 kg, the maximum dose
of OraVerse should be limited to ½ cartridge (0.2 mg) (see DOSAGE AND
ADMINISTRATION section). The pharmacokinetics of OraVerse in adults and in
children who weighed more than 30 kg (66 lbs) are similar after intraoral
submucosal injection.
Clinical Studies
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 I) 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.
Figure 1: Kaplan-Meier Plot
of Time to Recovery of Normal Sensation in the Lower Lip (ITT Analysis Data
Set)
Figure 2: Kaplan-Meier Plot
of Time to Recovery of Normal Sensation in the Upper Lip (ITT Analysis Data
Set)
 |
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 ½ 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), ½ 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).