OraVerse

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 submucosal injection. The terminal elimination half-life of phentolamine in the blood 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.

OraVerse has not been studied in children under 3 years of age or weighing less than 15 kg (33 lbs). The pharmacokinetics of OraVerse after administration of more than 1 cartridge (0.4mg) has not been studied in children.

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 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.

Figure 1: Kaplan-Meier Plot of Time to Recovery of Normal Sensation in the Lower Lip (ITT Analysis Data Set)

Kaplan-Meier Plot of Time to Recovery of Normal Sensation in the Lower Lip - Illustration

Figure 2: Kaplan-Meier Plot of Time to Recovery of Normal Sensation in the Upper Lip (ITT Analysis Data Set)

Kaplan-Meier Plot of Time to Recovery of Normal Sensation in the Upper Lip - Illustration

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 local anesthetic 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 11 years 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 only 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.

Last reviewed on RxList: 9/20/2013
This monograph has been modified to include the generic and brand name in many instances.

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