OraVerse

• Novalar Pharmaceuticals, Inc.

• Septodont, Inc.

In the U.S.

• OraVerse
• Regitine

Available Dosage Forms:

• Solution
• Injectable
• Powder for Solution

Therapeutic Class: Antidote

Pharmacologic Class: Alpha-Adrenergic Blocker

• If you have an allergy to phentolamine or any other part of OraVerse (phentolamine).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have ever had any of these health problems: Chest pain or pressure, diseased arteries in the heart, or heart attack.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take OraVerse with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenic studies with OraVerse have not been conducted.

Mutagenesis
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.

Impairment of Fertility
The effect of phentolamine on female fertility has not been studied. Male rats treated with oral phentolamine for nine weeks (four weeks prior to mating, 3 weeks during the mating period and 2 weeks after mating) were mated with untreated females. At doses up to 143-times human therapeutic exposure levels at the Cmax, no adverse effects on male fertility parameters or on reproductive parameters in the untreated females mated with the treated males were observed.

OraVerse (phentolamine mesylate) Injection 0.4 mg/1.7 mL is supplied in a dental cartridge, in cartons of 10 and 50 cartridges. Each cartridge is individually packaged in a separate compartment of a 10 cartridge blister pack.

NDC 0362-0101-50
NDC 0362-0101-10

Store at controlled room temperature, 20-25°C (68-77°F) with brief excursions permitted between 15-30°C (59-86°F) (see USP Controlled Room Temperature)

Protect from direct heat and light. Do not permit to freeze.

Manufactured by

Novocol Pharmaceutical of Canada, Inc.
Cambridge, Ontario, Canada

for

Septodont, Inc
Louisville, CO 80027

US Patent Nos.: 6,764,678; 6,872,390; 7,229,630
Trademark of Septodont Holdings SAS

The United States Food and Drug Administration (FDA) has approved OraVerse (phentolamine mesylate) for the reversal of soft-tissue anesthesia and the associated functional deficits resulting from a local dental anesthetic.

Applies to phentolamine: injection injectable, injection powder for solution, injection solution

Along with its needed effects, phentolamine (the active ingredient contained in OraVerse) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking phentolamine:

• Dizziness
• erection continuing for more than 4 hours, or painful erection
• lumps in the penis

Some side effects of phentolamine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bruising or bleeding at place of injection
• burning (mild) along penis
• difficulty in ejaculating
• swelling at place of injection

Phentolamine injected into the penis may cause tingling at the tip of the penis. This is no cause for concern.

Phentolamine has been assigned to pregnancy category C by the FDA. Animal data have revealed slightly decreased growth and slight skeletal immaturity of the fetuses after rats and mice were given doses 24 to 30 times the usual daily human doses (UDHD, on a per kg basis). At oral doses 60 times the UDHD (on a per kg basis), 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 20 times the UDHD. No teratogenic or embryotoxic effects were observed in any of the animal studies. There are no reports of adverse effects on the fetus from isolated cases in which the drug has been used to treat pheochromocytoma during human pregnancy. There are no controlled in human pregnancy. Phentolamine is only recommended for use during pregnancy when benefit outweighs risk.

The relationship between with the use of phentolamine and maternal or fetal mortality in patients with pheochromocytoma is not clear because of the significant mortality associated with this tumor. Some experts recommend caution if phentolamine must be used during pregnancy because of the risk of hypotension and decreased placental perfusion pressure. Use of this drug during pregnancy should, therefore, be limited to the treatment of acute episodes of hypertension in patients with pheochromocytoma and for the immediate preoperative and intraoperative management of such a patient undergoing Cesarean section and/or removal of the pheochromocytoma. Phentolamine is not recommended as a diagnostic agent during pregnancy because of the availability of safer methods (urinary catecholamine levels). It is also not recommended for the chronic management of pheochromocytoma during pregnancy. Phentolamine does not appear to adversely affect uterine contractility. Animal studies have revealed evidence of skeletal immaturity associated with phentolamine. Immaturity was manifested by an increased incidence of incomplete or unossified calcaei and phalangeal nuclei of the hind limb and of incompletely ossified sternabrae.