ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Acute and prolonged hypotensive episodes, tachycardia, and cardiac arrhythmias have been reported. In addition, weakness, dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting, and diarrhea may occur.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies, mutagenicity studies, and fertility studies have not been conducted with phentolamine.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Phentolamine mesylate produces an alpha-adrenergic block of relatively short duration. It also has direct, but less marked, positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle.Phentolamine has half-life in the blood of 19 minutes following intravenous administration. Approximately 13% of single intravenous dose appears in the urine as unchanged drug.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Myocardial infarction, history of myocardial infarction, coronary insufficiency, angina, or other evidence suggestive of coronary artery disease; hypersensitivity to phentolamine or related compounds.

DESCRIPTION SECTION.

DESCRIPTION. Phentolamine Mesylate for Injection, USP, is an antihypertensive, available in vials for intravenous and intramuscular administration. Each vial contains phentolamine mesylate USP, mg and mannitol USP, 25 mg in sterile, lyophilized form.Phentolamine mesylate is m-[N-(2-Imidazolin-2-ylmethyl)-p-toluidino]phenol monomethanesulfonate (salt), and its structural formula is: Molecular Formula C17H19N3OoCH4O3S M.W. 377.47Phentolamine mesylate USP is white or off-white, odorless crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in alcohol, and slightly soluble in chloroform. It melts at about 178C.. structural formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The reconstituted solution should be used upon preparation and should not be stored.1.Prevention or control of hypertensive episodes in the patient with pheochromo-cytoma. For preoperative reduction of elevated blood pressure, mg of phentolamine mesylate (1 mg for children) is injected intravenously or intramuscularly or hours before surgery, and repeated if necessary. During surgery, phentolamine mesylate (5 mg for adults, mg for children) is administered intravenously as indicated, to help prevent or control paroxysms of hypertension, tachycardia, respiratory depression, convulsions, or other effects of epinephrine intoxication. (Postoperatively, norepinephrine may be given to control the hypotension that commonly follows complete removal of pheochromocytoma.)2.Prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. For Prevention: 10 mg of phentolamine mesylate is added to each liter of solution containing norepinephrine. The pressor effect of norepinephrine is not affected. For Treatment: to 10 mg of phentolamine mesylate in 10 mL of saline is injected into the area of extravasation within 12 hours.3.Diagnosis of pheochromocytoma phentolamine blocking test.The test is most reliable in detecting pheochromocytoma in patients with sustained hypertension and least reliable in those with paroxysmal hypertension. False-positive tests may occur in patients with hypertension without pheochromocytoma.. 1.Prevention or control of hypertensive episodes in the patient with pheochromo-cytoma. For preoperative reduction of elevated blood pressure, mg of phentolamine mesylate (1 mg for children) is injected intravenously or intramuscularly or hours before surgery, and repeated if necessary. During surgery, phentolamine mesylate (5 mg for adults, mg for children) is administered intravenously as indicated, to help prevent or control paroxysms of hypertension, tachycardia, respiratory depression, convulsions, or other effects of epinephrine intoxication. (Postoperatively, norepinephrine may be given to control the hypotension that commonly follows complete removal of pheochromocytoma.). 2.Prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. For Prevention: 10 mg of phentolamine mesylate is added to each liter of solution containing norepinephrine. The pressor effect of norepinephrine is not affected. For Treatment: to 10 mg of phentolamine mesylate in 10 mL of saline is injected into the area of extravasation within 12 hours.. 3.Diagnosis of pheochromocytoma phentolamine blocking test.The test is most reliable in detecting pheochromocytoma in patients with sustained hypertension and least reliable in those with paroxysmal hypertension. False-positive tests may occur in patients with hypertension without pheochromocytoma.. a. Intravenous. Preparation. The CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections should be reviewed. Sedatives, analgesics, and all other medications except those that might be deemed essential (such as digitalis and insulin) are withheld for at least 24 hours, and preferably 48 to 72 hours, prior to the test. Antihypertensive drugs are withheld until blood pressure returns to the untreated, hypertensive level. This test is not preformed on patient who is normotensive.. Procedure. The patient is kept at rest in supine position throughout the test, preferably in quiet, darkened room. Injection of phentolamine is delayed until blood pressure is stabilized, as evidenced by blood pressure readings taken every 10 minutes for at least 30 minutes.Five milligrams of phentolamine mesylate is dissolved in mL of Sterile Water for Injection. The dose for adults is mg; for children, mg.The syringe needle is inserted into the vein, and injection is delayed until pressor response to venipuncture has subsided.Phentolamine is injected rapidly. Blood pressure is recorded immediately after injection, at 30-second intervals for the first minutes, and at 60-second intervals for the next minutes.. Interpretation. positive response, suggestive of pheochromocytoma, is indicated when the blood pressure is reduced more than 35 mm Hg systolic and 25 mm Hg diastolic. typical positive response is reduction in pressure of 60 mm Hg systolic and 25 mm Hg diastolic. Usually, maximal effect is evident within minutes after injection. return to preinjection pressure commonly occurs within 15 to 30 minutes but may occur more rapidly.If blood pressure decreases to dangerous level, the patient should be treated as outlined under OVERDOSAGE.A positive response should always be confirmed by other diagnostic procedures, preferably by measurement of urinary catecholamines or their metabolites.A negative response is indicated when the blood pressure is elevated, unchanged, or reduced less than 35 mm Hg systolic and 25 mm Hg diastolic after injection of phentolamine. negative response to this test does not exclude the diagnosis of pheo-chromocytoma, especially in patients with paroxysmal hypertension in whom the incidence of false-negative responses is high.. b. Intramuscular. If the intramuscular test for pheochromocytoma is preferred, preparation is the same as for the intravenous test. Five milligrams of phentolamine mesylate is then dissolved in mL of Sterile Water for Injection. The dose for adults is mg intramuscularly; for children, mg. Blood pressure is recorded every minutes for 30 to 45 minutes following injection. positive response is indicated when the blood pressure is reduced 35 mm Hg systolic and 25 mm Hg diastolic, or more, within 20 minutes following injection.Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

DRUG INTERACTIONS SECTION.

Drug Interactions. See DOSAGE AND ADMINISTRATION. Diagnosis of pheochromocytoma, Preparation.

GENERAL PRECAUTIONS SECTION.

General. Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. When possible, administration of cardiac glycosides should be deferred until cardiac rhythm returns to normal.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Phentolamine Mesylate for Injection, USP, mg, for intramuscular or intravenous use, is supplied as follows:NDC 0143-9564-01 2 mL vials packaged individually.NDC 0143-9564-10 2 mL vials packaged in cartons of 10 vials.The reconstituted solution should be used upon preparation and should not be stored. Store at 20 to 25 (68 to 77 F) [See USP Controlled Room Temperature]. To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.For Product Inquiry call 1-877-845-0689.Manufactured by:HIKMA FARMACEUTICA (PORTUGAL), S.A.Estrada do Rio da Mo, 8, 8A 8B Fervenca 2705-906 Terrugem SNT, PORTUGALDistributed by:West-Ward PharmaceuticalsEatontown, NJ 07724 USARevised November 2015PIN385-WES/4.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Phentolamine Mesylate for Injection is indicated for the prevention or control of hypertensive episodes that may occur in patient with pheochromocytoma as result of stress or manipulation during preoperative preparation and surgical excision.Phentolamine Mesylate for Injection is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine.Phentolamine Mesylate for Injection is also indicated for the diagnosis of pheochromocytoma by the phentolamine blocking test.

NURSING MOTHERS SECTION.

Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from phentolamine, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

OVERDOSAGE. Acute Toxicity. No deaths due to acute poisoning with phentolamine have been reported.Oral LD50s (mg/kg): mice, 1000; rats, 1250.. Signs and Symptoms. Overdosage with 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; hypoglycemia.. Treatment. There is no specific antidote.A decrease in blood pressure to dangerous levels or other evidence of shocklike conditions should be treated vigorously and promptly. The patients legs should be kept raised and plasma expander should be administered. If necessary, intravenous infusion or norepi-nephrine, titrated to maintain blood pressure at the normotensive level, and all available supportive measures should be included. Epinephrine should not be used, since it may cause paradoxical reduction in blood pressure.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL. NDC 0143-9564-01Rx only Phentolamine Mesylate for Injection, USP5 mg/vialFOR IM OR IV USE LYOPHILIZED USUAL DOSAGE: See package insertStore at 20o to 25oC (68o to 77oF) See USP Controlled Room Temperature]. Phentolamine Mesylate for Injection, USP vial label NDC 0143-9564-01 Rx only Phentolamine Mesylate for Injection, USP mg/vial FOR IM OR IV USE LYOPHILIZED USUAL DOSAGE: See package insert Store at 20o to 25oC (68o to 77oF) See USP Controlled Room Temperature].

PEDIATRIC USE SECTION.

Pediatric Use. See DOSAGE AND ADMINISTRATION.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. When possible, administration of cardiac glycosides should be deferred until cardiac rhythm returns to normal.. Drug Interactions. See DOSAGE AND ADMINISTRATION. Diagnosis of pheochromocytoma, Preparation.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies, mutagenicity studies, and fertility studies have not been conducted with phentolamine.. Pregnancy. Teratogenic Effects-Pregnancy Category C. Administration of phentolamine to pregnant rats and mice at oral doses 24 to 30 times the usual daily human dose (based on 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 doses 60 times the usual daily human dose (based on 60 kg human), slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses 20 times the usual daily human dose (based on 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.There are no adequate and well-controlled studies in pregnant women. Phentolamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from phentolamine, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. Pediatric Use. See DOSAGE AND ADMINISTRATION.

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects-Pregnancy Category C. Administration of phentolamine to pregnant rats and mice at oral doses 24 to 30 times the usual daily human dose (based on 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 doses 60 times the usual daily human dose (based on 60 kg human), slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses 20 times the usual daily human dose (based on 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.There are no adequate and well-controlled studies in pregnant women. Phentolamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects-Pregnancy Category C. Administration of phentolamine to pregnant rats and mice at oral doses 24 to 30 times the usual daily human dose (based on 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 doses 60 times the usual daily human dose (based on 60 kg human), slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses 20 times the usual daily human dose (based on 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.There are no adequate and well-controlled studies in pregnant women. Phentolamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the administration of phentolamine, usually in association with marked hypotensive episodes.For screening tests in patients with hypertension, the generally available urinary assay of catecholamines or other biochemical assays have largely replaced the phentolamine and other pharmacological tests for reasons of accuracy and safety. None of the chemical or pharmacological tests is infallible in the diagnosis of pheochromocytoma. The phentolamine blocking test is not the procedure of choice and should be reserved for cases in which additional confirmatory evidence is necessary and the relative risks involved in conducting the test have been considered.