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.

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 lesions. 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 Long Grove Pharmaceuticals LLC at 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Postmarketing ExperienceReversible diabetes insipidus [see Warnings and Precautions (5.2)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

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 micro-units/kg/min to 200 micro-units /kg/min. Steady state plasma concentrations are achieved after 30 minutes of continuous intravenous infusion.. DistributionVasopressin does not appear to bind plasma protein. The volume of distribution is 140 mL/kg.. EliminationAt infusion rates used in vasodilatory shock (0.01 units/minute 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 Populations. Pregnancy: 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 InteractionsIndomethacin 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Vasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol.. Vasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. (4). Vasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. (4).

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.

DESCRIPTION SECTION.

11 DESCRIPTION. Vasopressin is polypeptide hormone. Vasopressin in Sodium Chloride Injection is sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration.Each mL of the 0.2 unit/mL strength contains 0.2 units vasopressin, 0.0672 mg aspartic acid, 0.0180 mg boric acid, 0.05 mg chlorobutanol, mg sodium chloride and Water for Injection, USP. Each mL of the 0.4 unit/mL strength contains 0.4 units vasopressin, 0.0672 mg aspartic acid, 0.0180 mg boric acid, 0.10 mg chlorobutanol, mg sodium chloride and Water for Injection, USP. Each mL of the unit/mL strength contains unit vasopressin, 0.0672 mg aspartic acid, 0.0180 mg boric acid, 0.25 mg chlorobutanol, mg sodium chloride and Water for Injection, USP.The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-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: 1084.23. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. This product does not require further dilution prior to administration. (2.1)Post-cardiotomy shock: 0.03 units/minute to 0.1 units/minute by intravenous infusion (2.2)Septic shock: 0.01 units/minute to 0.07 units/minute by intravenous infusion (2.2). This product does not require further dilution prior to administration. (2.1). Post-cardiotomy shock: 0.03 units/minute to 0.1 units/minute by intravenous infusion (2.2). Septic shock: 0.01 units/minute to 0.07 units/minute by intravenous infusion (2.2). 2.1 Preparation of Solution. Inspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.This product does not require further dilution prior to administration.. 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/minute by intravenous infusionSeptic Shock: 0.01 units/minute by intravenous infusionTitrate 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 postcardiotomy 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 in Sodium Chloride 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 in Sodium Chloride Injection is clear, colorless premixed solution for intravenous administration in single-dose, ready to use vial available as:20 units/100 mL (0.2 units/mL) in 0.9% Sodium Chloride40 units/100 mL (0.4 units/mL) in 0.9% Sodium Chloride50 units/50 mL (1 unit/mL) in 0.9% Sodium Chloride. 20 units/100 mL (0.2 units/mL) in 0.9% Sodium Chloride. 40 units/100 mL (0.4 units/mL) in 0.9% Sodium Chloride. 50 units/50 mL (1 unit/mL) in 0.9% Sodium Chloride. Injection: in premixed single-dose, ready to use vial. (3)20 units/100 mL (0.2 units/mL) in 0.9% Sodium Chloride 40 units/100 mL (0.4 units/mL) in 0.9% Sodium Chloride 50 units/50 mL (1 unit/mL) in 0.9% Sodium Chloride 20 units/100 mL (0.2 units/mL) in 0.9% Sodium Chloride 40 units/100 mL (0.4 units/mL) in 0.9% Sodium Chloride 50 units/50 mL (1 unit/mL) in 0.9% Sodium Chloride.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Pressor effects of catecholamines and Vasopressin in Sodium Chloride Injection are expected to be additive. (7.1)Indomethacin may prolong effects of Vasopressin in Sodium Chloride Injection. (7.2)Co-administration of ganglionic blockers or drugs causing SIADH may increase the pressor response. (7.3, 7.4)Co-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.5). Pressor effects of catecholamines and Vasopressin in Sodium Chloride Injection are expected to be additive. (7.1). Indomethacin may prolong effects of Vasopressin in Sodium Chloride Injection. (7.2). Co-administration of ganglionic blockers or drugs causing SIADH may increase the pressor response. (7.3, 7.4). Co-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.5). 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 in Sodium Chloride Injection 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 in Sodium Chloride Injection 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 in Sodium Chloride Injection. 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 in Sodium Chloride Injection. 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 in Sodium Chloride Injection is clear, colorless solution for intravenous administration available as:NDC 81298-8552-3: carton of 10 single dose vials. Each vial contains vasopressin 20 units/100 mL (0.2 units/mL).NDC 81298-8554-3: carton of 10 single dose vials. Each vial contains vasopressin 40 units/100 mL (0.4 units/mL).NDC 81298-8550-3: carton of 10 single dose vials. Each vial contains vasopressin 50 units/50 mL (1 unit/mL).Store unopened vials refrigerated at 2C to 8C (36F to 46F). Do not freeze. Keep vials in original carton to protect from light.Vials may be held up to three (3) 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 three (3) months 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 in Sodium Chloride Injection beyond the manufacturers expiration date stamped on the vial.Manufactured for:Long Grove Pharmaceuticals, LLCRosemont, IL 60018Made in India.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Vasopressin in Sodium Chloride Injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines.. Vasopressin in Sodium Chloride Injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines. (1). Vasopressin in Sodium Chloride Injection 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 in Sodium Chloride Injection in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage with Vasopressin in Sodium Chloride Injection 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel 20 Units per 100 mL Carton LabelVasopressinin 0.9% Sodium Chloride Injection20 Units per 100 mL (0.2 units per mL)For intravenous infusionReady to use10 100 mL Single-Dose VialsDiscard Unused PortionNDC 81298-8552-3Rx onlyRecommended Dosage: SeePrescribing Information.LONG GROVE(TM)PHARMACEUTICALS. Principal Display Panel 20 Units per 100 mL Carton Label.

PEDIATRIC USE SECTION.

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

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 micro-units/kg/min to 200 micro-units /kg/min. Steady state plasma concentrations are achieved after 30 minutes of continuous intravenous infusion.. DistributionVasopressin does not appear to bind plasma protein. The volume of distribution is 140 mL/kg.. EliminationAt infusion rates used in vasodilatory shock (0.01 units/minute 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 Populations. Pregnancy: 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 InteractionsIndomethacin 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 in Sodium Chloride Injection 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.. Clinical Considerations. Dose adjustments during pregnancy and the postpartum period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin in Sodium Chloride Injection may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].. Maternal adverse reactions: Vasopressin in Sodium Chloride Injection 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.This product does not require further dilution prior to administration.

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 in Sodium Chloride Injection 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.. Clinical Considerations. Dose adjustments during pregnancy and the postpartum period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin in Sodium Chloride Injection may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].. Maternal adverse reactions: Vasopressin in Sodium Chloride Injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.. 8.2 Lactation. There are no data on the presence of Vasopressin in Sodium Chloride 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 in Sodium Chloride Injection 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.. 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.