OraVerse - Novalar Pharmaceuticals

The recommended dose of OraVerse is based on the number of cartridges of local anesthetic with vasoconstrictor administered:

OraVerse should be administered following the dental procedure using the same location(s) and technique(s) (infiltration or block injection) employed for the administration of the local anesthetic.

Note: Do not administer OraVerse if the product is discolored or contains particulate matter.

In pediatric patients weighing 15-30 kg, the maximum dose of OraVerse recommended is 1/2 cartridge (0.2 mg).

(Note: Use in pediatric patients under 6 years of age or weighing less than 15 kg (33 lbs) is not recommended. A dose of more than 1 cartridge [0.4 mg] of OraVerse has not been studied in children less than 12 years of age.)

Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the parenteral administration of phentolamine. These events usually occurred in association with marked hypotensive episodes producing shock-like states.

Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. Although such effects are uncommon after administration of OraVerse, clinicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of cardiovascular disease.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Dental patients were administered a dose of either 0.2, 0.4 or 0.8 mg of OraVerse. The majority of adverse reactions were mild and resolved within 48 hours. There were no serious adverse reactions and no discontinuations due to adverse reactions.

Table 1 lists adverse reactions where the frequency was greater than or equal to 3% in any OraVerse dose group and was equal to or exceeded that of the control group.

An examination of population subgroups did not reveal a differential adverse reaction incidence on the basis of age, gender, or race.

Results from the pain assessments in Study 1 and Study 2, involving mandibular and maxillary procedures, respectively, indicated that the majority of dental patients in both OraVerse and control groups experienced no or mild oral pain, with less than 10% of patients in each group reporting moderate oral pain with a similar distribution between the OraVerse and control groups. No patient experienced severe pain in these studies.

Adverse reactions reported by less than 3% but at least 2 dental patients receiving OraVerse and occurring at a greater incidence than those receiving control, included diarrhea, facial swelling, increased blood pressure/hypertension, injection site reactions, jaw pain, oral pain, paresthesia, pruritus, tenderness, upper abdominal pain and vomiting. The majority of these adverse reactions were mild and resolved within 48 hours. The few reports of paresthesia were mild and transient and resolved during the same time period.

The following adverse reactions have been identified during postapproval parenteral use of phentolamine mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Acute and prolonged hypotensive episodes and cardiac arrhythmias have been reported with the use of phentolamine. In addition, weakness, dizziness, flushing, orthostatic hypotension, and nasal stuffiness have occurred.

When OraVerse was administered as an intraoral submucosal injection 30 minutes after injection of a local anesthetic, 2% lidocaine HCl with 1:100,000 epinephrine, the lidocaine concentration increased immediately after OraVerse intraoral injection. Lidocaine AUC and Cmax values were not affected by administration of OraVerse. OraVerse administration did not affect the PK of epinephrine.

Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. OraVerse should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of phentolamine to pregnant rats and mice at doses at least 24 times the recommended dose (based on a 60 kg human) resulted in slightly decreased growth and slight skeletal immaturity of the fetuses. Immaturity was manifested by increased incidence of incomplete or unossified calcaneal and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae. At oral phentolamine doses at least 60 times the recommended dose (based on a 60 kg human), a slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses at least 20 times the recommended dose (based on a 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.

It is not known whether OraVerse is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when OraVerse is administered to a nursing woman. The unknown risks of limited infant exposure to phentolamine through breast milk following a single maternal dose should be weighed against the known benefits of breastfeeding.

In clinical studies, pediatric patients between the ages of 3 and 17 years received OraVerse. The safety and effectiveness of OraVerse have been established in the age group 6-17 years. Effectiveness in pediatric patients below the age of 6 years has not been established. Use of OraVerse in patients between the ages of 6 and 17 years old is supported by evidence from adequate and well-controlled studies of OraVerse in adults, with additional adequate and well-controlled studies of OraVerse in pediatric patients ages 12-17 years old [Studies 1 (mandibular procedures) and 2 (maxillary procedures)] and ages 6-11 years old [Study 3 (mandibular and maxillary procedures)]. The safety, but not the efficacy, of OraVerse has been evaluated in pediatric patients under the age of 6 years old. Dosages in pediatric patients may need to be limited based on body weight. [see Dosage and Administration (2)]

Of the total number of patients in clinical studies of OraVerse, 55 were 65 and over, while 21 were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.

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 C_max 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.

Carcinogenicity studies with OraVerse have not been conducted.

Phentolamine was not mutagenic in the in-vitro bacterial reverse mutation (Ames) assay. In the in-vitro chromosomal aberration study in Chinese hamster ovary cells, numerical aberrations were slightly increased after a 4-hour exposure to phentolamine without metabolic activation and structural aberrations were slightly increased after a 4-hour exposure to phentolamine with metabolic activation only at the highest concentrations tested, but neither numerical nor structural aberrations were increased after a 20-hour exposure without metabolic activation. Phentolamine was not clastogenic in two in-vivo mouse micronucleus assays. At doses up to 150 mg/kg (143 times human therapeutic exposure levels at the C_max), phentolamine mesylate was shown to have no adverse effects on male fertility in the rat.