OraVerse

Dosage Forms And Strengths

0.4 mg/1.7 ml solution per cartridge

Storage And Handling

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 individual packaged in a separate compartment of a 10 cartridge blister pack.

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

Store at controlled room temperature, 20-25oC (68-77 oF) with brief excursions permitted between 15-30 oC (59-86 oF) (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. Rev. Mar 2016

OraVerse, an alpha adrenergic blocker, is indicated for adult and pediatric patients ages 3 years and older for reversal of the soft-tissue anesthesia, i.e., anesthesia of the lip and tongue, and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor

General Dosing information

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.

Chemically disinfect the carpule cap by wiping with either isopropyl alcohol (91%) or ethyl alcohol (70%). Many commercially available brands of isopropyl (rubbing) alcohol, as well as solutions of ethyl alcohol not of U.S.P. grade, contain denaturants that are injurious to rubber and therefore are not to be used.

Inspect carpules visually prior to administration and do not use if particulate matter, discoloration, cracks in the glass, protruding plungers or other defects are observed.

Note: Do not administer OraVerse if particulate matter, discoloration, cracks in the glass, protruding plungers or other defects are observed.

Dosing In Special Populations

In pediatric patients weighing between ≥ 15 kg and < 30 kg, the maximum dose of OraVerse recommend is ½ cartridge (0.2 mg). (Note: Use in pediatric patients under 3 years of age or weighing less than15 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 4 years of age.)

Oraverse is contraindicated in patients with: Hypersensitivity to the active substance or to any ingredients in the formulation.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Events

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.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk summary

There are no available data with OraVerse in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal toxicology studies, phentolamine administered orally to pregnant mice and rats during the period of organogenesis resulted in skeletal immaturity and decreased growth in the offspring at doses at least 24-times the recommended dose. Additionally, a lower rate of implantation was seen in pregnant rats treated with phentolamine at least 60-times the recommended dose. No malformations or embryofetal deaths were observed in the offspring of pregnant mice, rats, and rabbits administered phentolamine during the period of organogenesis at doses 24-, 60-, and 20-times, respectively, the recommended dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of phentolamine to pregnant rats and mice at doses at least 24-times the recommended dose (based on a mg/m² comparison with 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 calcanei 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 mg/m² comparison with 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 mg/m² comparison with a 60 kg human). No malformations or embryofetal deaths were observed in the rat, mouse or rabbit studies.

Lactation

Risk Summary

There is no information regarding the presence of phentolamine in human milk, the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OraVerse and any potential adverse effects on the breastfed infant from OraVerse, or from the underlying maternal condition.

Pediatric Use

The safety and efficacy of OraVerse has not been established in patients younger than 3 years.

The safety and effectiveness of OraVerse in pediatric patients ages 3 years and older 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)], ages 6-11 years old [Study 3 (mandibular and maxillary procedures)], and another study in patients ages 2-5 years [Study 4]. Study 4 assessed safety and effectiveness in patients 4 to 5 years, but was not designed to demonstrate efficacy. Use in patients 3 to < 4 years is supported by similar pharmacokinetics and safety in these patients compared with older pediatric patients (see CLINICAL PHARMACOLOGY]. Use of OraVerse in this age group (3 to < 4 years) is also supported by the similarity in the exposure response of OraVerse for pediatric and adult patients, and the adequacy of the safety database for patients age ≥ 3. The safety database for patients age < 3 is limited, and therefore, use in patients age < 3 is not recommended. Dosages in pediatric patients may need to be limited based on body weight.

Geriatric Use

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 elder and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

SIDE EFFECTS

In clinical trials, the most common adverse reaction with OraVerse that was greater than the control group was injection site pain.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates moved 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 was equal to or exceeded that of the control group.

Table 1: Adverse Reactions with Frequency Greater Than or Equal to 3% and Equal to or Exceeding Control

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. Study 4 included 150 pediatric patients between 2-5 years of age who received a dose of either ¼ cartridge (0.1 mg), ½ cartridge (0.2 mg) or 1 cartridge (0.4 mg) of OraVerse or sham injection (placebo). Safety in patients in Study 4 was similar to safety in older patients described above. Post-procedural revealed that oral pain was reported in the OraVerse group with a higher frequency (10.1%) than the placebo group (3.9%). The proportion of patients in the OraVerse and placebo groups was comparable with respect to the highest severity of pain experienced: 30.4% of OraVerse patients and 30% of placebo patients reported no pain; 43.1% of OraVerse patients and 45.0% of placebo patients reported mild pain; 19.0% of OraVerse subjects and 17.5% of placebo patients reported moderate pain; and 15.2% of OraVerse patients and 15.0% of placebo patients reported severe pain..

Adverse Reactions In Clinical Trials

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.

Post Marketing Adverse Reactions Reports From Literature And Other Sources

The following adverse reactions have been identified during post approval 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 w h the use of phentolamine. In addition, weakness, dizziness, flushing, orthostatic hypotension, and nasal stuffiness have occurred.

DRUG INTERACTIONS

There are no known drug interactions with OraVerse.

Lidocaine And Epinephrine

When OraVerse was administered as an intraoral submucosal injection 30 minutes after injection of a local anesthetic, 2% lidocaine HCI 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.

Risk summary

There are no available data with OraVerse in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal toxicology studies, phentolamine administered orally to pregnant mice and rats during the period of organogenesis resulted in skeletal immaturity and decreased growth in the offspring at doses at least 24-times the recommended dose. Additionally, a lower rate of implantation was seen in pregnant rats treated with phentolamine at least 60-times the recommended dose. No malformations or embryofetal deaths were observed in the offspring of pregnant mice, rats, and rabbits administered phentolamine during the period of organogenesis at doses 24-, 60-, and 20-times, respectively, the recommended dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of phentolamine to pregnant rats and mice at doses at least 24-times the recommended dose (based on a mg/m² comparison with 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 calcanei 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 mg/m² comparison with 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 mg/m² comparison with a 60 kg human). No malformations or embryofetal deaths were observed in the rat, mouse or rabbit studies.

In clinical trials, the most common adverse reaction with OraVerse that was greater than the control group was injection site pain.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates moved 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 was equal to or exceeded that of the control group.

Table 1: Adverse Reactions with Frequency Greater Than or Equal to 3% and Equal to or Exceeding Control

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. Study 4 included 150 pediatric patients between 2-5 years of age who received a dose of either ¼ cartridge (0.1 mg), ½ cartridge (0.2 mg) or 1 cartridge (0.4 mg) of OraVerse or sham injection (placebo). Safety in patients in Study 4 was similar to safety in older patients described above. Post-procedural revealed that oral pain was reported in the OraVerse group with a higher frequency (10.1%) than the placebo group (3.9%). The proportion of patients in the OraVerse and placebo groups was comparable with respect to the highest severity of pain experienced: 30.4% of OraVerse patients and 30% of placebo patients reported no pain; 43.1% of OraVerse patients and 45.0% of placebo patients reported mild pain; 19.0% of OraVerse subjects and 17.5% of placebo patients reported moderate pain; and 15.2% of OraVerse patients and 15.0% of placebo patients reported severe pain..

Adverse Reactions In Clinical Trials

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.

Post Marketing Adverse Reactions Reports From Literature And Other Sources

The following adverse reactions have been identified during post approval 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 w h the use of phentolamine. In addition, weakness, dizziness, flushing, orthostatic hypotension, and nasal stuffiness have occurred.

No deaths due to acute poisoning with phentolamine have been reported. Overdosage with parenterally administered phentolamine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. In addition, the following might occur: excitation, headache, sweating, pupillary contraction, visual disturbances, nausea, vomiting, diarrhea, or hypoglycemia.

There is no specific antidote; treatment consists of appropriate monitoring and supportive care. Substantial decreases in blood pressure or other evidence of shock-like conditions should be treated vigorous and promptly.

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.