PHENTOLAMINE MESYLATE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution
-Dissolve 5 mg of phentolamine in 1 mL of Sterile Water for Injection.
-Storage: Do not store reconstituted solution; use upon preparation.

IV Push
-Inject the desired dosage of the reconstituted solution IV rapidly.

Continuous IV infusion
-For prevention of necrosis/sloughing after extravasation from continuous IV norepinephrine, 10 mg of phentolamine may be added to each 1,000 mL of norepinephrine infusion. The pressor effect of norepinephrine is not altered.

Intramuscular Administration
Reconstitution
-Dissolve 5 mg of phentolamine in 1 mL of Sterile Water for Injection.
-Storage: Do not store reconstituted solution; use upon preparation.

Intramuscular injection
-Inject deeply into a large muscle.

Subcutaneous Administration
-For extravasation treatment, make a solution by diluting phentolamine in 0.9% Sodium Chloride Injection according to desired dosage.
--Neonates: Dilute to a concentration of 0.25 to 0.5 mg/mL.
-Pediatric patients: Dilute to a concentration of 0.5 to 1 mg/mL.

-Use a 27- to 30-gauge needle and make multiple small injections around the extravasation site.

Other Injectable Administration
Submucosal Administration
-Administer following the dental procedure using the same location(s) and technique(s) (infiltration or nerve block injection) used for the administration of the local anesthetic.



Ophthalmic Administration
-One single-patient-use vial can be used to dose both dilated eyes.
-Discard the single-patient-use vial immediately after use.
-Do not touch vial tip to the eye or to any other surface to prevent eye injury or contamination.

Acute and prolonged hypotensive episodes, sinus tachycardia, cardiac arrhythmias, and/or angina have all occurred with parenteral administration of phentolamine. These effects may be due to the drug's cardiac-stimulating and vasodilatory effects. Other adverse effects seen with phentolamine therapy include weakness, dizziness, flushing, and orthostatic hypotension. Flushing may be due to dilation of the facial blood vessels. During reversal of soft tissue anesthesia in studies of pediatric and adult patients (n = 418), phentolamine (OraVerse) was associated with tachycardia, bradycardia, and elevations in blood pressure (hypertension) in 5%, 2%, and < 3% of patients, respectively.

Nasal congestion can occur with the parenteral use of phentolamine and is probably caused by phentolamine's vasodilatory effect on blood vessels in the nasal mucosa. Nasal congestion has also been reported post-marketing with OraVerse.

Nausea and vomiting can occur with the parenteral use of phentolamine. Diarrhea secondary to phentolamine may result from stimulation of GI smooth muscle. During reversal of soft tissue anesthesia in studies of pediatric and adult patients (n = 418), phentolamine (OraVerse) was associated with diarrhea, vomiting, and upper abdominal pain in less than 3% of patients. Dysgeusia was reported in 6% of patients treated with phentolamine ophthalmic solution in clinical trials.

Cerebrovascular spasm and cerebrovascular occlusion have been reported following phentolamine administration. During reversal of soft tissue anesthesia in studies of pediatric and adult patients (n = 418), phentolamine (OraVerse) was associated with headache in 3% of patients. The incidence of headache increased with increasing dosage. Paresthesias occurred in < 3% of patients. Paraesthesias were transient and resolved within 48 hours.

During reversal of soft tissue anesthesia in 2 studies of pediatric and adult patients (n = 418) who underwent mandibular or maxillary procedures, phentolamine (OraVerse) was associated with moderate dental pain in < 10% of patients. Pain specific to the injection site occurred in 5% of patients, and post-procedural pain was reported in 6% of patients. Injection site reaction was reported in < 3% of patients; symptoms included facial swelling, jaw pain, oral pain, pruritus, and tenderness. No severe pain was reported.

The most common ocular adverse reactions reported in patients receiving phentolamine ophthalmic solution in clinical trials were ocular pain, stinging, and burning (16%) and conjunctival hyperemia. (12%).

Phentolamine injection is contraindicated for use in patients with acute myocardial infarction, a history of myocardial infarction, coronary insufficiency, angina, or any evidence of coronary artery disease due to the drug's cardiac stimulating effects and corresponding increase in myocardial oxygen demand. Reflex tachycardia can exacerbate angina. Use of the OraVerse phentolamine product is not contraindicated in these conditions, as tachycardia and cardiac arrhythmias are uncommon with administration; however, use precaution in patients with a history of cardiovascular disease.

Phentolamine should be used with caution in patients with gastric and duodenal ulcers because the drug has a histamine-like effect. Phentolamine can stimulate secretion of gastric acid and pepsin in the stomach, which can aggravate peptic ulcer disease.

Phentolamine ophthalmic solution is not recommended when active ocular inflammation (e.g., iritis or uveitis) is present because adhesions (synechiae) may form between the iris and the lens.

Advise contact lens wearers to remove their contact lenses prior to the instillation of phentolamine ophthalmic solution and wait 10 minutes after dosing before reinserting their contact lenses.

Description: Phentolamine is an alpha-adrenergic receptor antagonist administered parentally and ophthalmically. Phentolamine is similar in action to phenoxybenzamine and has a shorter duration of action. Approved uses of parenteral phentolamine include diagnosis of pheochromocytoma and treatment of hypertension in pheochromocytoma, prevention of tissue necrosis after norepinephrine extravasation, and reversal of soft tissue anesthesia. Ophthalmic phentolamine is approved for reversal of mydriasis produced by adrenergic agonists (e.g., phenylephrine) or parasympatholytic (e.g., tropicamide) agents. Phentolamine injection is contraindicated for use in patients with any coronary artery disease due to cardiac stimulating effects and corresponding increase in myocardial oxygen demand. Phentolamine is FDA-approved for use in pediatric patients as young as neonates; the OraVerse formulation of phentolamine is FDA-approved for use in children as young as 3 years weighing at least 15 kg; phentolamine ophthalmic solution is FDA-approved in pediatric patients as young as 3 years.

General Dosing Information
-For the diagnosis of pheochromocytoma, urinary assay of catecholamines and other biochemical assays have generally replaced the phentolamine blocking test for reasons of accuracy and safety. The phentolamine blocking test should be only be used when additional confirmatory evidence is needed and the risks involved in conducting the test have been considered.
-The phentolamine blocking test is most reliable in detecting pheochromocytoma in patients with sustained hypertension and is somewhat reliable in those with paroxysmal hypertension. Patients with hypertension without pheochromocytoma may get false-positive test results.

For pheochromocytoma diagnosis:
Intravenous dosage:
Children and Adolescents: 0.05 to 0.1 mg/kg/dose IV with a maximum single dose of 5 mg has been suggested. The manufacturer recommends a dose of 1 mg IV for children and 5 mg IV for adults (adolescents not specified). For at least 24 hours before the test (preferably 48 to 72 hours), all non-essential medication should be withheld. Prior to administration, the patient should be resting in a supine position until blood pressure is stabilized and a base pressure is established by blood pressure readings taken every 10 minutes for at least 30 minutes. Following needle insertion, delay drug administration until a pressor response to venipuncture has subsided. Inject phentolamine rapidly and record pressure immediately following injection, at 30-second intervals for the first 3 minutes, and at 60-second intervals for the next 7 minutes. A blood pressure reduction more than 35 mm Hg systolic and 25 mm Hg diastolic is considered a positive test. Return to pre-injection pressures should occur within 15 to 30 minutes following administration. Confirm any positive response with diagnostic procedures, preferably by measurement of urinary catecholamines and their metabolites.
Intramuscluar dosage:
Children and Adolescents: 0.05 to 0.1 mg/kg/dose IM with a maximum single dose of 5 mg has been suggested. The manufacturer recommends a dose of 3 mg IM for children and 5 mg IM for adults (adolescents not specified). For at least 24 hours before the test (preferably 48 to 72 hours), all non-essential medication should be withheld. Prior to administration, the patient should be resting in a supine position until blood pressure is stabilized and a base pressure is established by blood pressure readings taken every 10 minutes for at least 30 minutes. Record pressure every 5 minutes for 30 to 45 minutes following injection. A blood pressure reduction more than 35 mm Hg systolic and 25 mm Hg diastolic within 20 minutes following injection is considered a positive test. Confirm any positive response with diagnostic procedures, preferably by measurement of urinary catecholamines and their metabolites.

For the treatment of hypertension before or during pheochromocytomectomy:
Intravenous or Intramuscular dosage:
Children and Adolescents: 0.05 to 0.1 mg/kg/dose IV or IM up to a maximum dose of 5 mg given 1 to 2 hours prior to surgery has been suggested. The manufacturer recommends a dose of 1 mg IV/IM for children and 5 mg IV/IM for adults (adolescents are not specified). Repeat every 2 to 4 hours as needed to control blood pressure. During surgery, repeat IV as needed to control symptoms of epinephrine intoxication.

For the prevention or treatment of dermal necrosis or sloughing following extravasation of IV norepinephrine or other drugs* associated with alpha-adrenergic effects (e.g., dopamine, dobutamine, epinephrine, phenylephrine):
Subcutaneous dosage:
Neonates: Infiltrate area with 1 mL of solution made by diluting 2.5 to 5 mg in 10 mL of 0.9% Sodium Chloride injection. Give 5 divided doses subcutaneously around the site. Inject into affected area within 12 hours of extravasation. Do not exceed 0.1 mg/kg or 2.5 mg total. Visible hyperemia and increased tissue warmth at the site of extravasation are signs of effective treatment.
Infants, Children, and Adolescents: Infiltrate area with 1 to 5 mL (in 5 divided doses) of a 0.5 to 1 mg/mL solution (made by diluting 5 to 10 mg in 10 mL 0.9% Sodium Chloride injection). Inject into affected area within 12 hours of extravasation. Do not exceed 0.1 to 0.2 mg/kg or 5 mg total. Visible hyperemia and increased tissue warmth at the site of extravasation are signs of effective treatment.
Intravenous dosage:
Neonates, Infants, Children, and Adolescents: The manufacturer suggests that to prevent extravasation, 10 mg of phentolamine can be added to each 1,000 mL of norepinephrine IV infusion solution without affecting the pressor effects of norepinephrine.

For soft-tissue anesthesia reversal including the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor:
Submucosal Dosage:
Children 3 years and older weighing 15 to 29 kg: 0.1 to 0.2 mg/dose (0.25 to 0.5 cartridge) administered by infiltration or nerve block injection; the same location and technique used for local anesthetic administration should be used. Recommended dose is based on the number of cartridges of local anesthetic with vasoconstrictor used. For one-fourth cartridge of local anesthetic, give 0.1 mg (0.25 cartridge of phentolamine); for one-half cartridge of local anesthetic, give 0.2 mg (0.5 cartridge of phentolamine). The maximum recommended dose is 0.2 mg (0.5 cartridge).
Children and Adolescents weighing 30 kg or more: 0.1 to 0.8 mg/dose (0.25 to 2 cartridges) administered by infiltration or nerve block injection; the same location and technique used for local anesthetic administration should be used. Recommended dose is based on the number of cartridges of local anesthetic with vasoconstrictor used. For one-fourth cartridge of local anesthetic, give 0.1 mg (0.25 cartridge of phentolamine); for one-half cartridge of local anesthetic, give 0.2 mg (0.5 cartridge of phentolamine); for 1 cartridge of local anesthetic, give 0.4 mg (1 cartridge of phentolamine); for 2 cartridges of local anesthetic, give 0.8 mg (2 cartridges of phentolamine).

For mydriasis reversal following pharmacologically-induced mydriasis produced by adrenergic agonists or parasympatholytic agents:
Ophthalmic dosage:
Children 3 to 11 years: Instill 1 drop in each dilated eye following the completion of the ophthalmic examination or procedure.
Children and Adolescents 12 to 17 years: Instill 1 or 2 drops in each dilated eye following the completion of the ophthalmic examination or procedure. If 2 drops are instilled, the second drop should be administered 5 minutes after the first drop.

Maximum Dosage Limits:
-Neonates
0.1 mg/kg subcutaneously; safety and efficacy of other formulations have not been established.
-Infants
0.2 mg/kg subcutaneously; safety and efficacy of other formulations have not been established.
-Children
1 to 2 years: 0.2 mg/kg subcutaneously; 5 mg/dose IV/IM. Safety and efficacy of other formulations have not been established.
3 to 11 years weighing less than 15 kg: 0.2 mg/kg subcutaneously; 5 mg/dose IV/IM; 1 drop/eye/day for ophthalmic solution. Safety and efficacy of other formulations have not been established.
3 to 11 years weighing 15 to 29 kg: 0.2 mg/kg (Max: 5 mg/dose) subcutaneously; 5 mg/dose IV/IM; 0.2 mg/dose submucosal injection; 1 drop/eye/day for ophthalmic solution.

3 to 11 years weighing 30 kg or more: 0.2 mg/kg (Max: 5 mg/dose) subcutaneously; 5 mg/dose IV/IM; 0.8 mg/dose submucosal injection; 1 drop/eye/day for ophthalmic solution.
12 years weighing 15 to 29 kg: 0.2 mg/kg (Max: 5 mg/dose) subcutaneously; 5 mg/dose IV/IM; 0.2 mg/dose submucosal injection; 2 drops/eye/day for ophthalmic solution.
12 years weighing 30 kg or more: 0.2 mg/kg (Max: 5 mg/dose) subcutaneously; 5 mg/dose IV/IM; 0.8 mg/dose submucosal injection; 2 drops/eye/day for ophthalmic solution.


-Adolescents
0.2 mg/kg (Max: 5 mg/dose) subcutaneously; 5 mg/dose IV/IM; 0.8 mg/dose submucosal injection; 2 drops/eye/day for ophthalmic solution.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Cardiovascular effects
Phentolamine is a potent short-acting, competitive antagonist of alpha-adrenergic receptors. Like phenoxybenzamine, phentolamine antagonizes both alpha1- and alpha2-receptors. Prazosin, another alpha-receptor antagonist, differs from both of these agents in that it is selective for the alpha1-receptor. Phentolamine reduces peripheral resistance via antagonism of the alpha1-receptors and possibly alpha2-receptors on vascular smooth muscle. Antagonism at alpha2-receptors cause cardiac stimulation due to an enhanced release of norepinephrine from sympathetic nerves. Phentolamine has positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle. The clinical effects of phentolamine include cardiac stimulation caused by a decrease in peripheral resistance and an increase in cardiac output. Postural hypotension is often observed accompanied by reflex tachycardia that can precipitate cardiac arrhythmias and myocardial ischemia. These actions make phentolamine useful in treating hypertension caused by increased circulating levels of epinephrine and norepinephrine, as occurs in pheochromocytoma.

Mydriasis reversal
Phentolamine is a relatively non-selective alpha-1 and alpha-2 adrenergic antagonist. Phentolamine reversibly binds to alpha-1 adrenergic receptors on the iris dilator muscle, thereby reducing pupil diameter. Phentolamine directly antagonizes the mydriatic effect of an alpha-1 adrenergic agonist, and indirectly reverses mydriasis induced by muscarinic antagonist effects on the iris sphincter muscle.

Reversal of soft tissue anesthesia
The mechanism by which OraVerse (phentolamine injection for dental use) produces reversal of soft tissue anesthesia and associated functional deficits is not fully understood.

Pharmacokinetics: Phentolamine is primarily administered intravenously and intramuscularly as an injection solution or ophthalmically as an ocular solution. The injection can also be given subcutaneously to prevent local tissue necrosis when vasoconstrictor drugs extravasate, or it can be given by infiltration or nerve block for reversal of soft tissue anesthesia. The pharmacokinetics of phentolamine are largely unknown. Following IV administration of a single dose, approximately 13% of the dose is excreted in urine unchanged. The half-life of the drug in blood is 19 minutes following intravenous administration.


-Route-Specific Pharmacokinetics
Other Route(s)
Submucosal Route
After phentolamine (OraVerse) administration, 100% of the drug is available. Peak concentrations occur in 10 to 20 minutes, and systemic exposure increases linearly with increasing dosages. The half-life of phentolamine after submucosal administration is 2 to 3 hours.

Ophthalmic Route
The onset of action after administration of phentolamine ophthalmic solution generally occurs in 30 minutes, with the maximal effect seen in 60 to 90 minutes, and the effect lasting at least 24 hours. The peak concentrations are achieved between 15 minutes and 1 hour after dosing with the median value of 0.45 ng/mL.


-Special Populations
Pediatrics
The Cmax of phentolamine (OraVerse) was approximately 3.5-fold higher in children who weighed 15 to 30 kg compared to children who weighed more than 30 kg. The AUC was similar between the 2 groups. The pharmacokinetics in children weighing 30 kg or more are similar to the pharmacokinetics observed in adults.