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Phentolamine mesylate is
(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 sparing soluble in water, soluble in alcohol, and slightly soluble
in chloroform. The empirical formulation is C17H19N30•CH403S,
and the chemical structure is:
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.
Indications & Dosage
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
DOSAGE AND ADMINISTRATION
General Dosing information
The recommended dose of
OraVerse is based on the number of cartridges of local anesthetic with
Amount of Local Anesthetic Administered
Dose of OraVerse [mg]
Dose of OraVerse [Cartridge(s)]
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
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.)
Dosage Forms And Strengths
0.4 mg/1.7 ml solution per
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
What causes tooth decay?See Answer
Side Effects & Drug Interactions
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
(N=83) N (%)
(N=284) N (%)
(N=51) N (%)
(N=418) N (%)
(N=359) N (%)
Patients with AEs
Injection site pain
Post procedural pain
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 Â¼
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
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.
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.
Warnings & Precautions
Included as part of the PRECAUTIONS section.
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.
Impairment Of Fertility
Carcinogenic 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.
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 Category C.
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
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.
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.
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. [see DOSAGE AND ADMINISTRATION]
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.
Overdosage & Contraindications
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
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.
Oraverse is contraindicated in
patients with: Hypersensitivity to the active substance or to any ingredients
in the formulation.
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
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.
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
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 I) 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
Figure 2: Kaplan-Meier Plot
of Time to Recovery of Normal Sensation in the Upper Lip (ITT Analysis Data
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 OraVerse 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 11years 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 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.
Study 4, a pediatric, Phase 4,
double-blinded, randomized, multi-center, controlled study was conducted in
dental patients undergoing mandibular and maxillary procedures after receiving
2% lidocaine with 1:100,000 epinephrine. Patients 2-5 years of age received
sham injection (n=51) or 1/4 cartridge of OraVerse if they weighed ≥ 10 kg
but < 15kg (n=5), ½ cartridge if they weighed ≥ 15 kg but < 30kg
(n=91), and a full cartridge if they weighed > 30kg (n=3). This study was not
designed to demonstrate efficacy.
The median time to normal lip
sensation in patients 4 and 5 years of age who were trainable in the
lip-palpation procedure, for mandibular and maxillary procedures combined, was
reduced by 48 minutes (44%). Within 2 hours after administration of OraVerse,
57 patients (80%) reported normal lip sensation, while 19 patients (51%)
randomized to the sham injection group reported normal lip sensation. There
were no significant differences between OraVerse and sham injection for time to
return of normal function in pediatric functional assessment battery and time
to recovery of normal tongue sensation (for mandibular procedures only).
Patients should be instructed not to eat or drink until normal sensation returns.