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Phentolamine

Pronunciation

(fen TOLE a meen)

Index Terms

  • Phentolamine Mesylate
  • Regitine [DSC]

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection, as mesylate:

Generic: 5 mg/mL (1 mL [DSC])

Solution, Injection, as mesylate [preservative free]:

OraVerse: 0.4 mg/1.7 mL (1.7 mL) [contains edetate disodium; dental cartridge]

Solution Reconstituted, Injection, as mesylate:

Generic: 5 mg (1 ea)

Brand Names: U.S.

  • OraVerse

Pharmacologic Category

  • Alpha1 Blocker
  • Antidote, Extravasation
  • Antihypertensive

Pharmacology

Competitively blocks alpha-adrenergic receptors (nonselective) to produce brief antagonism of circulating epinephrine and norepinephrine to reduce hypertension caused by alpha effects of these catecholamines and minimizes tissue injury due to extravasation of these and other sympathomimetic vasoconstrictors (eg, dopamine, phenylephrine); also has a positive inotropic and chronotropic effect on the heart thought to be due to presynaptic alpha-2 receptor blockade which results in release of presynaptic norepinephrine (Hoffman 1980)

OraVerse: Causes vasodilation and increased blood flow in injection area via alpha-adrenergic blockade to accelerate reversal of soft tissue anesthesia

Metabolism

Hepatic

Excretion

Urine (~13% as unchanged drug)

Onset of Action

IM: 15 to 20 minutes; IV: 1 to 2 minutes (Chobanian 2003)

Peak effect: OraVerse: 10 to 20 minutes

Duration of Action

IM: 30 to 45 minutes; IV: 10 to 30 minutes (Chobanian 2003)

Half-Life Elimination

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

Special Populations: Children

OraVerse Cmax ~3.5-fold higher in children weighing 15 to 30 kg compared with children weighing >30 kg.

Use: Labeled Indications

Pheochromocytoma: 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: Prevention and treatment of dermal necrosis/sloughing after extravasation of norepinephrine

Local anesthesia reversal (OraVerse): 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.

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; reserve phentolamine for cases when additional confirmation is necessary to determine diagnosis.

Off Label Uses

Hypertensive crisis

Data from a limited number of patients (case reports) with pheochromocytoma suggest that phentolamine used as a bolus dose followed by a continuous infusion may be beneficial for reducing high blood pressure associated with high catecholamine states (eg, pheochromocytoma) [McMillian 2011], [Myklejord 2004]. Clinical experience also suggests phentolamine as a therapeutic option in this setting [Marik 2007], [Tuncel 2003]. Additional data may be necessary to further define the role of phentolamine in the treatment of this condition.

Extravasation of sympathomimetic vasopressors

Based on the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, the use of phentolamine is effective and recommended for the management of extravasations due to sympathomimetic agents other than norepinephrine (labeled use), such as dopamine, epinephrine, and phenylephrine. Clinical experience also suggests the utility of phentolamine in the management of sympathomimetic vasopressor extravasations [Reynolds 2014].

Contraindications

Hypersensitivity to phentolamine, any component of the formulation, or related compounds; MI (or history of MI), coronary insufficiency, angina, or other evidence suggestive of coronary artery disease (excluding OraVerse)

Canadian labeling: Additional contraindications (not in the US labeling): Hypotension

Dosing: Adult

Extravasation of norepinephrine, management (manufacturer’s labeling): Local infiltration: Inject 5 to 10 mg (diluted in 10 mL 0.9% sodium chloride) into extravasation area (as soon as possible after extravasation is noted but within 12 hours of extravasation).

Extravasation of other sympathomimetic vasopressors, management (off-label use): Infiltrate extravasation site with 5 to 10 mg diluted in 10 to 20 mL 0.9% sodium chloride as soon as possible after extravasation; may readminister if patient remains symptomatic (Reynolds 2014).

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; reserve phentolamine for cases when additional confirmation is necessary to determine diagnosis: IM, IV: 5 mg

Hypertensive episodes associated with pheochromocytoma, prevention and management: Note: In the perioperative period, the use of other agents may be preferred due to slow onset of action and prolonged duration of phentolamine in comparison to the other agents (eg, nitroprusside) (Miller 2010).

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

Intraoperative: IV: Administer 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 stressor (eg, intubation) (Miller 2010).

Hypertensive crisis (off-label use): Note: Generally used in the setting of catecholamine excess (eg, pheochromocytoma) (Marik 2007): 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 (McMillian 2011).

Reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse): Infiltration or block technique: Submucosal oral injection: Note: Dose is based upon the number of cartridges of local anesthetic administered. Infiltration or block injection:

0.1 mg if one-quarter cartridge of anesthesia was administered

0.2 mg if one-half cartridge of anesthesia was administered

0.4 mg if 1 cartridge of anesthesia was administered

0.8 mg if 2 cartridges of anesthesia were administered

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Extravasation of sympathomimetic vasopressors, treatment:

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 (Flemmer 1993; Hill 1991; MacCara 1983; Montgomery 1999). Total dose required depends on the size of extravasation; dose may be repeated if required. When reported, the total dose needed was 1 to 5 mL of a 1 mg/mL solution; however, other concentrations could be used (Montgomery 1999).

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; reserve phentolamine 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 (Kliegman 2007)

Hypertensive episodes associated with pheochromocytoma, prevention and treatment: Note: In the perioperative period, the use of other agents may be preferred due to slow onset of action and prolonged duration of phentolamine in comparison to the other agents (eg, nitroprusside) (Miller 2010).

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 (Coté 2013). Note: Usual adult dose is 5 mg/dose (Miller 2010).

Reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse): Note: Dose is based upon the number of 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

1/4 Cartridge

1/4 Cartridge (0.1 mg)

1/2 Cartridge

1/2 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

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

Reconstitution

Powder for injection: Reconstitute 5 mg vial with 1 mL sterile water for injection. For treatment of extravasation, further dilute 5 to 10 mg in 10 mL of normal saline (manufacturer’s recommendation) or in 10 to 20 mL of saline (Reynolds 2014).

Administration

Extravasation management (treatment), sympathomimetic vasopressors: Stop vesicant infusion immediately and disconnect IV line (leave needle/cannula in place); gently aspirate extravasated solution from the IV line (do NOT flush the line); remove needle/cannula; elevate extremity. Inject small amounts of phentolamine 5 to 10 mg in 10 to 20 mL saline into extravasation site (as soon as possible but within 12 hours of extravasation). Apply dry warm compresses (Hurst 2004; Reynolds 2014).

Pheochromocytoma diagnosis: Patient should be supine throughout test, preferable in a quiet, dark room. Blood pressure should be monitored every 10 minutes for at least 30 minutes, delay phentolamine administration until after blood pressure is stable (at an untreated, hypertensive level). A drop in blood pressure >35 mm Hg (systolic) and >25 mm Hg (diastolic) is considered a positive response. If blood pressure is elevated, unchanged, or decrease is <35 mm Hg (systolic) and <25 mm Hg (diastolic), then response is negative. Confirm positive response with other diagnostic measure. Negative responses do not exclude a pheochromocytoma diagnosis, particularly in patients with paroxysmal hypertension where an incidence of false negatives is high.

IM: After IM injection, monitor blood pressure every 5 minutes for 35 to 40 minutes. Blood pressure drops to above parameters within 20 minutes are considered positive.

IV: Inject rapidly (after venous response to venipuncture has subsided); then monitor blood pressure immediately after injection, every 30 seconds for 3 minutes, then every minute for 7 minutes. Maximum response is generally achieved within 2 minutes; duration may last 15 to 30 minutes (although return to prior blood pressure may be sooner).

Pheochromocytoma-associated hypertensive episode: Administer IM or IV 1 to 2 hours prior to surgery and repeat during surgery (IV) if necessary.

Reversal of oral soft tissue (lip, tongue) anesthesia (OraVerse): Submucosal oral injection: Use the same location and dental technique employed for administration of the local anesthetic.

Hypertensive crisis (off-label use): Administer as an IV bolus (Marik 2007); may follow with a continuous IV infusion (McMillian 2011).

Storage

Powder for injection: Store intact vials 20°C to 25°C (68°F to 77°F). Reconstituted solution should be used immediately after preparation (per manufacturer).

Solution for injection (OraVerse): Store at 20°C to 25°C (68°F to 77°F); brief excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from direct heat and light. Do not freeze.

Drug Interactions

Alpha-/Beta-Agonists: Alpha1-Blockers may diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly, Alpha-/Beta-Agonists may antagonize Alpha1-Blocker vasodilation. Monitor therapy

Alpha1-Agonists: Alpha1-Blockers may diminish the vasoconstricting effect of Alpha1-Agonists. Similarly, Alpha1-Agonists may antagonize Alpha1-Blocker vasodilation. Monitor therapy

Alpha1-Blockers: May enhance the antihypertensive effect of other Alpha1-Blockers. Avoid combination

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. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Channel Blockers: Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of Alpha1-Blockers. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

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. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Alpha1-Blockers. 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. Consider therapy modification

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Rilmenidine: Alpha1-Blockers may enhance the hypotensive effect of Rilmenidine. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

Frequency not always defined.

Cardiovascular: Bradycardia (OraVerse 2% to 4%), hypertension (OraVerse <3%), cerebrovascular occlusion, hypotension, myocardial infarction

Central nervous system: Mouth pain (OraVerse ≤19%), headache (OraVerse 6%), paresthesia (OraVerse <3%; mild, transient), cerebrovascular spasm

Dermatologic: Facial swelling (OraVerse <3%), pruritus (OraVerse <3%)

Gastrointestinal: Diarrhea (OraVerse <3%), upper abdominal pain (OraVerse <3%), vomiting (OraVerse <3%), nausea

Local: Pain at injection site (OraVerse 6%)

Neuromuscular & skeletal: Jaw pain (OraVerse <3%)

Miscellaneous: Postinjection pain (10%)

Postmarketing and/or case reports (Limited to important or life-threatening): Cardiac arrhythmia, orthostatic hypotension

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: MI, cerebrovascular spasm, and cerebrovascular occlusion have been reported following administration, usually associated with hypotensive episodes producing shock-like states. Tachycardia and cardiac arrhythmias may occur. Use with caution in patients with a history of cardiovascular disease. Discontinue if symptoms of angina occur or worsen.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: The use of phentolamine as a blocking agent in the screening of patients with hypertension has predominantly been replaced with urinary/biochemical assays; phentolamine use should be reserved for situations where additional confirmation is necessary and after risks associated with use have been considered.

Monitoring Parameters

Blood pressure, heart rate; monitor and document extravasation site; monitor patient for orthostasis; assist patient with ambulation

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some oral animal reproduction studies. Diagnosing and treating pheochromocytoma is critical for favorable maternal and fetal outcomes (Schenker 1971; Schenker 1982).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, flushing, rhinorrhea, nausea, vomiting, diarrhea, or injection site pain. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), angina, tachycardia, arrhythmia, severe dizziness, or passing out (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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