Phentolamine (OraVerse) is a long-acting alpha-adrenergic receptor blocking drug. It is used to aid in the diagnosis of pheochromocytoma and in the management of extravasation of norepinephrine.

Indications of Phentolamine:

• Pheochromocytoma:

  • It is used for the diagnosis of pheochromocytoma via the phentolamine-blocking test (see "Note"); prevention and management of hypertensive episodes associated with pheochromocytoma resulting from stress or manipulation during the perioperative period.

• Extravasation management:

  • It is effective in preventing and treating of dermal necrosis/sloughing after extravasation of norepinephrine.

• Local anesthesia reversal (OraVerse):

  • It can be used for the reversal of soft tissue (lip, tongue) anesthesia and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor in adult and pediatric patients ≥3 years.

• Off Label Use Phentolamine in Adults:

  • Hypertensive crisis
  • Extravasation of sympathomimetic vasopressors

Phentolamine (OraVerse)  dose in adults:

Phentolamine (OraVerse) dose in the treatment of extravasation of norepinephrine:

• Local infiltration:
  • 5 to 10 mg (diluted in 10 mL 0.9% sodium chloride) injection into extravasation area (as soon as possible after extravasation is noted but within 12 hours of extravasation).

Phentolamine (OraVerse) dose in the treatment of extravasation of sympathomimetic vasopressors other than norepinephrine (off-label):

• Infiltrate the extravasation site with 5 to 10 mg diluted in 10 to 20 mL 0.9% sodium chloride as soon as possible after extravasation.
• If the patient remains symptomatic, the drug can be injected again.

Phentolamine (OraVerse) Dose in the diagnosis of pheochromocytoma (phentolamine-blocking test):

Note:

• The phentolamine blocking test for the diagnosis of pheochromocytoma has largely been supplanted by the measurement of catecholamine concentrations and catecholamine metabolites (eg, metanephrine) in the plasma and urine.
• Phentolamine should be reserved for cases when additional confirmation is necessary to determine diagnosis:
  • IM, IV: 5 mg.

Phentolamine (OraVerse) Dose in the prevention and management of perioperative hypertensive episodes associated with pheochromocytoma:

Note:

• • Due to the slow onset of action and prolonged duration of phentolamine in comparison to the other agents (eg, nitroprusside), alternate agents are preferred in the perioperative period.

• Preoperative:

  • IM, IV: 5 mg given 1 to 2 hours before surgery and repeat if needed.

• Intraoperative:

  • IV: 5 mg, as indicated to prevent or control paroxysms of hypertension, tachycardia, respiratory depression, seizure, or other effects associated with epinephrine intoxication resulting from tumor manipulation or other stressors (eg, intubation).
  • In order to control BP, others have used an intraoperative continuous infusion of 1 to 6 mcg/kg/minute or intermittent boluses of 10 mg, as indicated.

Phentolamine (OraVerse) dose for hypertensive crisis (off-label):

Note: Generally used in the setting of catecholamine excess (eg, pheochromocytoma)

• IV: 1 to 5 mg bolus.
• maximum single dose: 15 mg.
• A continuous infusion may be administered after initial bolus dosing (eg, 1 mg/hour titrated to blood pressure response) to a maximum infusion rate of 40 mg/hour.

Phentolamine (OraVerse) dose for reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse):

• Infiltration or block technique: Submucosal oral injection:
• Note: Dose depends on the number of cartridges of local anesthetic administered. Infiltration or block injection:
  • 1 mg if one-quarter cartridge of anesthesia was administered
  • 2 mg if one-half cartridge of anesthesia was administered
  • 4 mg if 1 cartridge of anesthesia was administered
  • 8 mg if 2 cartridges of anesthesia were administered

Phentolamine (OraVerse) dose in children:

Phentolamine (OraVerse) dose for the extravasation of sympathomimetic vasopressors:

• Manufacturer's labeling: Norepinephrine extravasation:

  • Children and Adolescents:
    • Local infiltration:
      • Infiltrate area of extravasation with a small amount of a 0.5 to 1 mg/ml solution as soon as extravasation is noted but within 12 hours of extravasation.

• Alternate dosing: Extravasation of dopamine, epinephrine, norepinephrine, phenylephrine: Limited data available:

  • Infants, Children, and Adolescents:
    • SubQ: Infiltrate area of extravasation with a small amount (eg, 1 ml given in 0.2 mL aliquots) of a 0.5 to 1 mg/ml solution within 12 hours of extravasation.
    • The total dose required depends on the size of extravasation.
    • A repeated dose can be given if needed. When reported, the total dose needed was 1 to 5 ml of a 1 mg/mL solution; however, other concentrations could be used.

Phentolamine (OraVerse) Dose in the diagnosis of pheochromocytoma (phentolamine blocking test):

Note:

• The phentolamine-blocking test for the diagnosis of pheochromocytoma has largely been supplanted by the measurement of catecholamine concentrations and catecholamine metabolites (eg, metanephrine) in the plasma and urine.
• Phentolamine should be reserved for cases when additional confirmation is necessary to determine diagnosis:

• Manufacturer's labeling:

  • Children and Adolescents:

    • IM: 3 mg.
    • IV: 1 mg.

• Alternate dosing: Limited data available:

  • Children and Adolescents:
    • IV: 0.05 to 0.1 mg/kg/dose.
    • maximum single dose: 5 mg.

Phentolamine (OraVerse) Dose in the prevention and treatment of hypertensive episodes associated with pheochromocytoma:

Note:

• Due to the slow onset of action and prolonged duration of phentolamine in comparison to the other agents (eg, nitroprusside), alternate agents are preferred in the perioperative period.

• Preoperative:

  • Children and Adolescents:
    • IM, IV: 1 mg given 1 to 2 hours before surgery and repeat if needed.

• Intraoperative:

  • Manufacturer's labeling:

    • Children and Adolescents:
      • IV: 1 mg as indicated to prevent or control paroxysms of hypertension, tachycardia, respiratory depression, seizure, or other effects associated with epinephrine intoxication resulting from tumor manipulation.

  • Alternate dosing: Limited data available:

    • Infants, Children, and Adolescents:
      • IV: 0.05 to 0.1 mg/kg/dose.
    • Note: Usual adult dose is 5 mg/dose.

Phentolamine (OraVerse) dose for the reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse):

Note:

• The dose is based upon the number of the cartridge(s) of local anesthetic administered; location and administration technique (infiltration or block injection) should be the same as used for local anesthetic administration.

• Children ≥3 years weighing ≥15 kg and Adolescents:

  • Submucosal oral injection: Infiltration or block technique:

Amount of Local Anesthetic Administered	Dose of OraVerse
¼ Cartridge	¼ 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)

• Maximum dose:

  • 15 to <30 kg:
    • 0.2 mg/dose
  • ≥30 kg:
    • 0.8 mg/dose;
• Note:
  • A dose of >0.4 mg has not been studied in children <4 years

Phentolamine (OraVerse) Pregnancy Risk Factor C

• Some oral animal reproduction studies have revealed adverse outcomes.
• It is critical for favorable maternal and fetal outcomes to diagnose and treat pheochromocytoma.

Phentolamine use during breastfeeding:

• Phentolamine secretion in breast milk is not known.
• Due to the potential for serious adverse reactions in the breastfed infant, the decision to discontinue phentolamine or discontinue breastfeeding during treatment depends on the benefits of treatment to the mother.
• The developmental and health benefits of breastfeeding be taken into account with the mother's clinical need for phentolamine and any potential adverse effects on the breastfed infant from phentolamine, or from the underlying maternal condition as per the manufacturer.

Phentolamine (OraVerse) Dose adjustment in kidney disease:

There are no dosage adjustments provided in the manufacturer’s labeling.

Phentolamine (OraVerse) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer’s labeling.

Side effects of Phentolamine (OraVerse):

• Cardiovascular:

  • Bradycardia
  • Hypertension
  • Cerebrovascular Occlusion
  • Hypotension
  • Myocardial Infarction

• Central Nervous System:

  • Mouth Pain
  • Headache
  • Paresthesia
  • Cerebrovascular Spasm

• Dermatologic:

  • Facial Swelling
  • Pruritus

• Gastrointestinal:

  • Diarrhea
  • Upper Abdominal Pain
  • Vomiting
  • Nausea

• Local:

  • Pain At Injection Site

• Neuromuscular & Skeletal:

  • Jaw Pain

• Miscellaneous:

  • Post-Injection Pain

Contraindications to Phentolamine (OraVerse):

• Hypersensitivity to phentolamine or any other component of the formulation.
• Myocardial Infarction (or History of MI)
• Angina
• Coronary insufficiency or other evidence suggesting coronary artery disease (except OraVerse).

Canadian labeling: Additional contraindications not in the US labeling

• Hypotension

Warnings and precautions

• Cardiovascular effects

  • The effects of phentolamine on the cerebrovascular system can be severe.
  • It can also cause tachycardia or cardiac arrhythmias.
  • Patients with a history or cardiovascular disease should not use it.
  • Therapy should be stopped if angina symptoms worsen or occur.

Phentolamine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Alpha-/Beta-Agonists	Alpha1-Blockers may diminish the vasoconstricting effect of Alpha-/BetaAgonists. Similarly, Alpha-/Beta-Agonists may antagonize Alpha1-Blocker vasodilation.
Alpha1-Agonists	Alpha1-Blockers may diminish the vasoconstricting effect of Alpha1-Agonists. Similarly, Alpha1-Agonists may antagonize Alpha1-Blocker vasodilation.
Amphetamines	May diminish the antihypertensive effect of Antihypertensive Agents.
Antipsychotic Agents (Second Generation [Atypical])	Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]).
Barbiturates	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Benperidol	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Beta-Blockers	May enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Exceptions: Levobunolol; Metipranolol.
Brigatinib	May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents.
Brimonidine (Topical)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Calcium Channel Blockers	Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
Dapoxetine	May enhance the orthostatic hypotensive effect of Alpha1-Blockers.
Dexmethylphenidate	May diminish the therapeutic effect of Antihypertensive Agents.
Diazoxide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
DULoxetine	Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.
Herbs (Hypertensive Properties)	May diminish the antihypertensive effect of Antihypertensive Agents.
Herbs (Hypotensive Properties)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Hypotension-Associated Agents	Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents.
Levodopa-Containing Products	Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products.
Lormetazepam	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Methylphenidate	May diminish the antihypertensive effect of Antihypertensive Agents.
Molsidomine	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicorandil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nitroprusside	Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.
Pentoxifylline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Pholcodine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.
Prostacyclin Analogues	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Quinagolide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Rilmenidine	Alpha1-Blockers may enhance the hypotensive effect of Rilmenidine.
Yohimbine	May diminish the antihypertensive effect of Antihypertensive Agents.
Risk Factor D (Consider therapy modification)
Amifostine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered.
Obinutuzumab	May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion.
Phosphodiesterase 5 Inhibitors	May enhance the hypotensive effect of Alpha1-Blockers (Nonselective). Management: Ensure patient is stable on one agent prior to initiating the other, and always initiate combination using the lowest possible dose of the drug being added. When tadalafil is used for treatment of BPH, concurrent alpha 1-blockers are not recommended.
Risk Factor X (Avoid combination)
Alpha1-Blockers	May enhance the antihypertensive effect of other Alpha1-Blockers.
Bromperidol	Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.

 

Monitoring parameters:

• Heart rate
• Blood pressure
• Monitoring and documentation of extravasation site
• Monitoring of patient for orthostasis
• Patient assistance with ambulation

How to administer Phentolamine (OraVerse)?

Extravasation management (treatment), sympathomimetic gasopressors

• You should stop the vesicant injection immediately. The IV line should also be disconnected.
• You should gently remove the extravasated solution from the IV line, but not flush it.
• The needle/cannula must be removed, and the extremity must be raised.
• Inject small amounts of phentolamine in 10-20 ml of saline into the extravasation site as soon as possible, but no later than 12 hours after extravasation.
• Use dry, warm compression.

Pheochromocytoma diagnosis:

• The patient should be kept in a dark, quiet room with a supine position.
• Monitor blood pressure every 10 minutes for at most 30 minutes.
• Do not administer phentolamine until blood pressure stabilizes (at an untreated hypertensive level).
  • Positive Response:
    • A drop in blood pressure of >35 mm Hg, (systolic), or >25 mmHg (diastolic).
    • Other diagnostic tests should confirm a positive response.
  • Negative Response:
    • If blood pressure is high, it should not be increased or decreased by more than 35mm Hg (systolic), and 25mm Hg [diastolic].
    • A negative response to a pheochromocytoma is not sufficient, especially in cases of high incidence of false positives, such as paroxysmal hypotension.

IM:

• Monitor blood pressure for 35 to 40 minutes after IM injection.
• If blood pressure falls to these parameters within 20 minutes, it is a positive sign.

IV:

• After the venous response has subsided, inject the fluid quickly.
• After injections, blood pressure should be checked immediately.
• Every 30 seconds for three minutes, and every minute for seven minutes.
• The maximum response time is usually within two minutes.
• However, it may take up to 30 minutes for the full effect to occur.

Pheochromocytoma-associated hypertensive episode:

• You should give the injection IM or IV at least 2 hours prior to surgery. If necessary, you can repeat it during surgery (IV).

OraVerse: Reversal of anesthesia for oral soft tissue (lip, or tongue)

• Submucosal injection: Use the same dental technique and location as for local anesthetic administration.

Hypertensive crisis (off label use)

• It should be administered as an IV bolus and then, if necessary, as a continuous IV injection.

Mechanism of action of Phentolamine (OraVerse):

• Phentolamine causes a nonselective competitive blockage of alpha2-adrenergic receptors, thereby causing a brief antagonism in circulating epinephrine or norepinephrine.
• This reduces blood pressure due to the alpha effects of catecholamines.
• Tissue injury from extravasation of these sympathomimetic vasoconstrictors, such as dopamine and phenylephrine, is also reduced.
• Presynaptic alpha-2 receptor blocking is what causes phentolamine to have positive inotropic, chronotropic effects on heart.
• This results in presynaptic norepinephrine being released. OraVerse - Phentolamine causes vasodilation, which increases blood flow to the injection site.
• This accelerates the recovery of soft tissue anesthesia.

The onset of action:

• IM: 15 to 20 minutes; IV: 1 to 2 minutes

Peak effect: OraVerse:

• 10 to 20 minutes

Duration:

• IM: 30 to 45 minutes;
• IV: 10 to 30 minutes

Metabolism:

• Hepatic

Half-life elimination:

• IV: 19 minutes;
• Submucosal injection: ~2 to 3 hours

Excretion:

• Urine (~13% as unchanged drug)

International Brand Names of Phentolamine:

• OraVerse
• Rogitine
• Fentanor
• Phentolmin
• Phentosol
• Regitin
• Regitina
• Regitine
• Rogitamine
• Rogitine

Phentolamine Brand Names in Pakistan:

No Brands Available in Pakistan.