Oraverse

Phentolamine Mesylate · Injection, Solution · Submucosal

Prescription (Rx) alpha-Adrenergic Blocker 2 recalls

Uses

1. INDICATONS AND USAGE OraVerse an alpha adrenergic blocker, is indicated for adult and pediatric patients ages 3 years and older for the reversal of 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. OraVerse, an alpha adrenergic blocker, is indicated for adult and pediatric patients ages 3 years and older for the reversal of 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. ( 1 )

Dosage and administration

2. DOSAGE AND ADMINISTRATION Amount of Local Anesthetic Administered Dose of OraVerse 1 / 4 Cartridge 1 / 4 Cartridge (0.1 mg) ½ Cartridge ½ Cartridge (0.2 mg) 1 Cartridge 1 Cartridge (0.4 mg) 2 Cartridges 2 Cartridges (0.8 mg) OraVerse is administered using the same location(s) and same technique(s) (infiltration or block injection) used for the administration of local anesthetic. ( 2.1 ) 2.1 General Dosing information The recommended dose of OraVerse is based on the number of cartridges of local anesthetic with vasoconstrictor administered: Amount of Local Anesthetic Administered Dose of OraVerse [mg] Dose of OraVerse [Cartridge(s)] 1 / 4 Cartridge 0.1 1 / 4 ½ Cartridge 0.2 ½ 1 Cartridge 0.4 1 2 Cartridges 0.8 2 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. 2.2 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 3years 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.)

Dosage forms and strengths

3. DOSAGE FORMS AND STRENGTHS 0.4 mg/1.7 mL solution per cartridge 0.4 mg/1.7 mL solution per cartridge ( 3 )

Contraindications

4. CONTRAINDICATIONS OraVerse is contraindicated in patients with: Hypersensitivity to the active substance or to any ingredients in the formulation OraVerse is contraindicated in patients with: Hypersensitivity to the active substance or to any ingredients in the formulation. ( 4 )

Warnings and precautions

5. WARNINGS AND PRECAUTIONS Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the intravenous or intramuscular administration of phentolamine, usually in association with marked hypotensive episodes or shock-like states which occasionally follow parenteral administration. Tachycardia and cardiac arrhythmiasmay occur with the use of phentolamine or other alpha-adrenergic blocking agents. ( 5.1 ) 5.1 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.

Side effects

6. ADVERSE REACTIONS In clinical trials, the most common adverse reaction with OraVerse that was greater than the control group was injection site pain. The most common adverse reaction with OraVerse (incidence ≥5% and > control) is injection-site pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Septodont at 1-888-888-1441 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 0.8mg 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. Table 1: Adverse Reactions with Frequency Greater Than or Equal to 3% and Equal to or Exceeding Control Adverse Event OraVerse Control 0.2 mg (N = 83) 0.4 mg (N = 284) 0.8 mg (N = 51) Total (N = 418) Total (N = 359) N (%) N (%) N (%) N (%) N (%) Patients with AEs 15 (18) 82 (29) 20 (39) 117 (28) 96 (27) Tachycardia 0 (0) 17 (6) 2 (4) 19 (5) 20 (6) Bradycardia 0 (0) 5 (2) 2 (4) 7 (2) 1 (0.3) Injection site pain 5 (6) 15 (5) 2 (4) 22 (5) 14 (4) Post procedural pain 3 (4) 17 (6) 5 (10) 25 (6) 23 (6) Headache 0 (0) 10 (4) 3 (6) 13 (3) 14 (4) 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. 6.2 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. 6.3 Post Marketing Adverse Reactions Reports from Literature and Other Sources 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.

Drug interactions

7. DRUG INTERACTIONS There are no known drug interactions with OraVerse. 7.1 Lidocaine and Epinephrine 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.

Use in specific populations

8. USE IN SPECIFIC POPULATIONS Use in pediatric patients less than 3 years of age or <15 kg (33 lbs) has not been established. ( 8.4 ) In pediatric patients weighing at least 10 kg (22 lbs), the maximum dose of OraVerse recommended is 1/4cartridge (0.1 mg). ( 8.4 ) 8.1 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 [see Data]. 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. 8.2 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. 8.4 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 (12.3)]. 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. [see Dosage and Administration (2) ] 8.5 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 elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pregnancy

8.1 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 [see Data]. 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. 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 [see Data]. 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.

Pediatric use

8.4 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 (12.3)]. 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. [see Dosage and Administration (2) ]

Geriatric use

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

Overdosage

10. OVERDOSAGE 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 vigorously and promptly.

Description

11. DESCRIPTION Phentolamine mesylate is phenol,3-[[(4,5-dihydro-1 H -imidazol-2-yl)methyl](4-methyl-phenyl)amino]-,methanesulfonate (salt), a non-specific alpha adrenergic blocker. Phentolamine mesylate USP is a white to off-white, odorless crystalline powder with a molecular weight of 377.46. It is sparingly soluble in water, soluble in alcohol, and slightly soluble in chloroform. The empirical formulation is C 17 H 19 N 3 O
• CH 4 O 3 S, and the chemical structure is: OraVerse (phentolamine mesylate) Injection is a clear, colorless, sterile, non pyrogenic, isotonic, preservative free solution. Each 1.7 mL cartridge contains 0.4 mg phentolamine mesylate, D-mannitol, edetate disodium, and sodium acetate. Either acetic acid or sodium hydroxide is used as necessary to adjust the pH. Chemical Structure

Mechanism of action

12.1 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.

How supplied

16. HOW SUPPLIED/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 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.

Storage

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.

Patient information

17. PATIENT COUNSELING INFORMATION Patients should be instructed not to eat or drink until normal sensation returns.

Label text from the FDA structured product label by Septodont, Inc. (revised Dec 5, 2018). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Oraverse NDC products (1)

NDCStrength & formLabelerType
0362-0101Phentolamine Mesylate .235 mg/mL
Injection, Solution		Septodont, Inc.NDA

Oraverse recalls

Frequently asked questions

What is Oraverse used for?

1. INDICATONS AND USAGE OraVerse an alpha adrenergic blocker, is indicated for adult and pediatric patients ages 3 years and older for the reversal of 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. OraVerse, an alpha adrenergic blocker, is…

What are the side effects of Oraverse?

6. ADVERSE REACTIONS In clinical trials, the most common adverse reaction with OraVerse that was greater than the control group was injection site pain. The most common adverse reaction with OraVerse (incidence ≥5% and > control) is injection-site pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Septodont at 1-888-888-1441 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical… See the full label for the complete list.

Who makes Oraverse?

Oraverse is listed by 1 labeler in the FDA NDC directory, including Septodont, Inc..

Has Oraverse been recalled?

The FDA enforcement database lists 2 recalls for Oraverse, most recently D-0234-2026 (class ii): Defective container: cracked/broken cartridges