CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Vasopressin Injection, USP mL single dose vial is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol.. Vasopressin Injection, USP mL single dose vial is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. (4). Vasopressin Injection, USP mL single dose vial is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. (4).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL TEXT CARTONNDC 0548-9701-00 Rx OnlyVasopressinInjection, USP20 Units per mLFor Intravenous InfusionMust be diluted prior to use10 1 mL Single Dose Vials5297016D/6-19Store between 2C and 8C (36F and46F). Do not store above 25C (77F).Vials may be held at 20C to 25C(68F to 77F) for up to 12 months.Do not freeze.Usual Dosage: See fullprescribing information.Stock No. 9701AMPHASTAR PHARMACEUTICALS, INC.Rancho Cucamonga, CA 91730 U.S.A.. carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of Vasopressin Injection, USP in pediatric patients with vasodilatory shock have not been established.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions associated with the use of vasopressin were identified in the literature. Because these reactions are reported voluntarily from population of uncertain size, it is not possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Bleeding/lymphatic system disorders: Hemorrhagic shock, decreased platelets, intractable bleedingCardiac disorders: Right heart failure, atrial fibrillation, bradycardia, myocardial ischemiaGastrointestinal disorders: Mesenteric ischemiaHepatobiliary: Increased bilirubin levelsRenal/urinary disorders: Acute renal insufficiencyVascular disorders: Distal limb ischemiaMetabolic: HyponatremiaSkin: Ischemic lesionsPostmarketing ExperienceReversible diabetes insipidus [see Warnings and Precautions (5.2)].. The most common adverse reactions include decreased cardiac output, bradycardia, tachyarrhythmias, hyponatremia and ischemia (coronary, mesenteric, skin, digital). (6) To report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. No toxicology studies were conducted with vasopressin.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Vasopressin causes vasoconstriction by binding to V1 receptors on vascular smooth muscle coupled to the Gq/11-phospholipase C-phosphatidyl-inositol-triphosphate pathway, resulting in the release of intracellular calcium. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase.. 12.2 Pharmacodynamics. At therapeutic doses exogenous vasopressin elicits vasoconstrictive effect in most vascular beds including the splanchnic, renal and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone vasopressin inhibits water diuresis via renal V2 receptors. In addition, vasopressin has been demonstrated to cause vasodilation in numerous vascular beds that are mediated by V2, V3, oxytocin and purinergic P2 receptors.In patients with vasodilatory shock vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. The pressor effect reaches its peak within 15 minutes. After stopping the infusion the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients.. 12.3 Pharmacokinetics. Vasopressin plasma concentrations increase linearly with increasing infusion rates from 10 to 200 uU/kg/min. Steady state plasma concentrations are achieved after 30 minutes of continuous intravenous infusion.Distribution Vasopressin does not appear to bind plasma protein. The volume of distribution is 140 mL/kg.EliminationAt infusion rates used in vasodilatory shock (0.01 to 0.1 units/minute), the clearance of vasopressin is to 25 mL/min/kg in patients with vasodilatory shock. The apparent t1/2 of vasopressin at these levels is <=10 minutes.MetabolismSerine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity.ExcretionVasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged into urine.Specific PopulationsPregnancy: Because of spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of pregnancy. During the first trimester of pregnancy, the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. After delivery, the clearance of vasopressin returns to preconception baseline within two weeks.Drug Interactions Indomethacin more than doubles the time to offset for vasopressins effect on peripheral vascular resistance and cardiac output in healthy subjects [see Drug Interactions (7.2)].The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects [see Drug Interactions (7.3)].Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Increases in systolic and mean blood pressure following administration of vasopressin were observed in studies in septic shock and in post-cardiotomy vasodilatory shock.

DESCRIPTION SECTION.

11 DESCRIPTION. Vasopressin is polypeptide hormone. Vasopressin Injection, USP is sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration.The mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as preservative, and Water for Injection, USP adjusted with acetic acid to pH 3.4-3.6.The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-LGlutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. It is white to off-white amorphous powder, freely soluble in water. The structural formula is:Molecular Formula: C46H65N15O12S2 Molecular Weight: 1084.23One mg is equivalent to 530 units.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Dilute 20 units/mL, single dose vial contents with normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) to either 0.1 units/mL or unit/mL for intravenous administration. Discard unused diluted solution after 18 hours at room temperature or 24 hours under refrigeration. (2.1)Post-cardiotomy shock: 0.03 to 0.1 units/minute (2.2)Septic shock: 0.01 to 0.07 units/minute (2.2). Dilute 20 units/mL, single dose vial contents with normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) to either 0.1 units/mL or unit/mL for intravenous administration. Discard unused diluted solution after 18 hours at room temperature or 24 hours under refrigeration. (2.1). Post-cardiotomy shock: 0.03 to 0.1 units/minute (2.2). Septic shock: 0.01 to 0.07 units/minute (2.2). 2.1 Preparation of Solution. Inspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.Dilute Vasopressin Injection, USP in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use for intravenous administration. Discard unused diluted solution after 18 hours at room temperature or 24 hours under refrigeration.Table Preparation of diluted solutions Fluid restriction Final concentration Mix VasopressinInjection, USP Diluent No0.1 units/mL 2.5 mL (50 units) 500 mL Yes unit/mL mL (100 units) 100 mL. 2.2 Administration. In general, titrate to the lowest dose compatible with clinically acceptable response.The recommended starting dose is:Post-cardiotomy shock: 0.03 units/minuteSeptic Shock: 0.01 units/minuteTritate up by 0.005 units/minute at 10- to 15-minute intervals until the target blood pressure is reached. There are limited data for doses above 0.1 units/minute for post-cardiotomy shock and 0.07 units/minute for septic shock. Adverse reactions are expected to increase with higher doses.After target blood pressure has been maintained for hours without the use of catecholamines, taper vasopressin injection by 0.005 units/minute every hour as tolerated to maintain target blood pressure.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Vasopressin Injection, USP is clear, practically colorless solution for intravenous administration available as 20 units/mL in single dose vial. To be used after dilution.. Injection: 20 units per mL in single dose vial. To be used after dilution. (3). Injection: 20 units per mL in single dose vial. To be used after dilution. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Pressor effects of catecholamines and Vasopressin Injection, USP are expected to be additive. (7.1)Indomethacin may prolong effects of Vasopressin Injection, USP. (7.2)Co-administration of ganglionic blockers or drugs causing SIADH may increase the pressor response. (7.3, 7.5)Co-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.6). Pressor effects of catecholamines and Vasopressin Injection, USP are expected to be additive. (7.1). Indomethacin may prolong effects of Vasopressin Injection, USP. (7.2). Co-administration of ganglionic blockers or drugs causing SIADH may increase the pressor response. (7.3, 7.5). Co-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.6). 7.1 Catecholamines. Use with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.. 7.2 Indomethacin. Use with indomethacin may prolong the effect of Vasopressin Injection, USP on cardiac index and systemic vascular resistance. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)].. 7.3 Ganglionic Blocking Agents. Use with ganglionic blocking agents may increase the effect of Vasopressin Injection, USP on mean arterial blood pressure. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)].. 7.4 Drugs Suspected of Causing SIADH. Use with drugs suspected of causing SIADH (e.g., SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, felbamate) may increase the pressor effect in addition to the antidiuretic effect of Vasopressin Injection, USP. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.. 7.5 Drugs Suspected of Causing Diabetes Insipidus. Use with drugs suspected of causing diabetes insipidus (e.g., demeclocycline, lithium, foscarnet, clozapine) may decrease the pressor effect in addition to the antidiuretic effect of Vasopressin Injection, USP. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of vasopressin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Vasopressin Injection, USP is clear, practically colorless solution for intravenous administration available as:A carton of 10 single dose vials. Each vial contains vasopressin mL at 20 units/mL.NDC 0548-9701-00 Stock No. 9701Store between 2C and 8C (36F and 46F). Do not freeze.Vials may be held up to 12 months upon removal from refrigeration to room temperature storage conditions (20C to 25C [68F to 77F], USP Controlled Room Temperature), anytime within the labeled shelf life. Once removed from refrigeration, unopened vial should be marked to indicate the revised 12 month expiration date. If the manufacturers original expiration date is shorter than the revised expiration date, then the shorter date must be used. Do not use Vasopressin Injection, USP beyond the manufacturers expiration date stamped on the vial. The storage conditions and expiration periods are summarized in the following table. UnopenedRefrigerated2C to 8C (36F to 46F) UnopenedRoom Temperature20C to 25C (68F to 77F)Do not store above 25C (77F) Opened (AfterFirst Puncture) mL Vial Until manufacturerexpiration date 12 months or until manufacturerexpiration date, whichever is earlier N/A.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Vasopressin Injection, USP is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines.. Vasopressin Injection, USP is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines. (1). Vasopressin Injection, USP is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines. (1).

LACTATION SECTION.

8.2 Lactation. There are no data on the presence of vasopressin injection in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Vasopressin causes vasoconstriction by binding to V1 receptors on vascular smooth muscle coupled to the Gq/11-phospholipase C-phosphatidyl-inositol-triphosphate pathway, resulting in the release of intracellular calcium. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No formal carcinogenicity or fertility studies with vasopressin have been conducted in animals. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin has been reported to have an effect on function and fertilizing ability of spermatozoa.. 13.2 Animal Toxicology and/or Pharmacology. No toxicology studies were conducted with vasopressin.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage with Vasopressin Injection, USP can be expected to manifest as consequences of vasoconstriction of various vascular beds (peripheral, mesenteric, and coronary) and as hyponatremia. In addition, overdosage may lead less commonly to ventricular tachyarrhythmias (including Torsade de Pointes), rhabdomyolysis, and non-specific gastrointestinal symptoms.Direct effects will resolve within minutes of withdrawal of treatment.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. At therapeutic doses exogenous vasopressin elicits vasoconstrictive effect in most vascular beds including the splanchnic, renal and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone vasopressin inhibits water diuresis via renal V2 receptors. In addition, vasopressin has been demonstrated to cause vasodilation in numerous vascular beds that are mediated by V2, V3, oxytocin and purinergic P2 receptors.In patients with vasodilatory shock vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. The pressor effect reaches its peak within 15 minutes. After stopping the infusion the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Vasopressin plasma concentrations increase linearly with increasing infusion rates from 10 to 200 uU/kg/min. Steady state plasma concentrations are achieved after 30 minutes of continuous intravenous infusion.Distribution Vasopressin does not appear to bind plasma protein. The volume of distribution is 140 mL/kg.EliminationAt infusion rates used in vasodilatory shock (0.01 to 0.1 units/minute), the clearance of vasopressin is to 25 mL/min/kg in patients with vasodilatory shock. The apparent t1/2 of vasopressin at these levels is <=10 minutes.MetabolismSerine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity.ExcretionVasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged into urine.Specific PopulationsPregnancy: Because of spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of pregnancy. During the first trimester of pregnancy, the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. After delivery, the clearance of vasopressin returns to preconception baseline within two weeks.Drug Interactions Indomethacin more than doubles the time to offset for vasopressins effect on peripheral vascular resistance and cardiac output in healthy subjects [see Drug Interactions (7.2)].The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects [see Drug Interactions (7.3)].Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on Vasopressin Injection, USP use in pregnant women to inform drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with vasopressin.Clinical ConsiderationsDose adjustments during pregnancy and the postpartum period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin Injection, USP may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].Maternal adverse reactions: Vasopressin Injection, USP may produce tonic uterine contractions that could threaten the continuation of pregnancy.

SPL UNCLASSIFIED SECTION.

2.1 Preparation of Solution. Inspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.Dilute Vasopressin Injection, USP in normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) prior to use for intravenous administration. Discard unused diluted solution after 18 hours at room temperature or 24 hours under refrigeration.Table Preparation of diluted solutions Fluid restriction Final concentration Mix VasopressinInjection, USP Diluent No0.1 units/mL 2.5 mL (50 units) 500 mL Yes unit/mL mL (100 units) 100 mL.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May induce uterine contractions. (8.1)Pediatric Use: Safety and effectiveness have not been established. (8.4)Geriatric Use: No safety issues have been identified in older patients. (8.5). Pregnancy: May induce uterine contractions. (8.1). Pediatric Use: Safety and effectiveness have not been established. (8.4). Geriatric Use: No safety issues have been identified in older patients. (8.5). 8.1 Pregnancy. Risk SummaryThere are no available data on Vasopressin Injection, USP use in pregnant women to inform drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with vasopressin.Clinical ConsiderationsDose adjustments during pregnancy and the postpartum period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin Injection, USP may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].Maternal adverse reactions: Vasopressin Injection, USP may produce tonic uterine contractions that could threaten the continuation of pregnancy.. 8.2 Lactation. There are no data on the presence of vasopressin injection in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.. 8.4 Pediatric Use. Safety and effectiveness of Vasopressin Injection, USP in pediatric patients with vasodilatory shock have not been established.. 8.5 Geriatric Use. Clinical studies of vasopressin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Can worsen cardiac function. (5.1)Reversible diabetes insipidus (5.2). Can worsen cardiac function. (5.1). Reversible diabetes insipidus (5.2). 5.1 Worsening Cardiac Function. decrease in cardiac index may be observed with the use of Vasopressin Injection, USP.. 5.2 Reversible Diabetes Insipidus. Patients may experience reversible diabetes insipidus, manifested by the development of polyuria, dilute urine, and hypernatremia, after cessation of treatment with vasopressin. Monitor serum electrolytes, fluid status, and urine output after vasopressin discontinuation. Some patients may require readministration of vasopressin or administration of desmopressin to correct fluid and electrolyte shifts.