Vasopressin in 0.9% Sodium Chloride

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 )

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 ) 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 a clinically acceptable response. The recommended starting dose is: Post-cardiotomy shock: 0.03 units/minute by intravenous infusion Septic Shock: 0.01 units/minute by intravenous infusion Titrate 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 8 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.

3 DOSAGE FORMS AND STRENGTHS Vasopressin in Sodium Chloride Injection is a clear, colorless premixed solution for intravenous administration in a single-dose, ready to use vial available as: 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 a 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

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 )

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 a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Bleeding/lymphatic system disorders: Hemorrhagic shock, decreased platelets, intractable bleeding Cardiac disorders: Right heart failure, atrial fibrillation, bradycardia, myocardial ischemia Gastrointestinal disorders: Mesenteric ischemia Hepatobiliary: Increased bilirubin levels Renal/urinary disorders: Acute renal insufficiency Vascular disorders: Distal limb ischemia Metabolic: Hyponatremia Skin: 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 Experience Reversible diabetes insipidus [see Warnings and Precautions ( 5.2 )]

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 ) 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.

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 ) 8.1 Pregnancy Risk Summary There are no available data on Vasopressin in Sodium Chloride Injection use in pregnant women to inform a 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 ) ].

12.1 Mechanism of Action Vasopressin causes vasoconstriction by binding to V 1 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 V 2 receptors which are coupled to adenyl cyclase.

11 DESCRIPTION Vasopressin is a polypeptide hormone. Vasopressin in Sodium Chloride Injection is a 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, 9 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, 9 mg sodium chloride and Water for Injection, USP. Each mL of the 1 unit/mL strength contains 1 unit vasopressin, 0.0672 mg aspartic acid, 0.0180 mg boric acid, 0.25 mg chlorobutanol, 9 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 a white to off-white amorphous powder, freely soluble in water. The structural formula is: Molecular Formula: C 46 H 65 N 15 O 12 S 2 Molecular Weight: 1084.23 Structural Formula

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Vasopressin in Sodium Chloride Injection is a clear, colorless solution for intravenous administration available as: NDC 81298-8552-3: A carton of 10 single dose vials. Each vial contains vasopressin 20 units/100 mL (0.2 units/mL). NDC 81298-8554-3: A carton of 10 single dose vials. Each vial contains vasopressin 40 units/100 mL (0.4 units/mL). NDC 81298-8550-3: A carton of 10 single dose vials. Each vial contains vasopressin 50 units/50 mL (1 unit/mL). Store unopened vials refrigerated at 2°C to 8°C (36°F to 46°F). 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 (20°C to 25°C [68°F to 77°F], 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 manufacturer's 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 manufacturer's expiration date stamped on the vial. Manufactured for: Long Grove Pharmaceuticals, LLC Rosemont, IL 60018 Made in India