Vasostrict

1 INDICATIONS AND USAGE Vasostrict ® is indicated to increase blood pressure in adults with vasodilatory shock (e.g., post-cardiotomy or sepsis) who remain hypotensive despite fluids and catecholamines. Vasostrict ® is indicated to increase blood pressure in adults with vasodilatory shock (e.g., post-cardiotomy or sepsis) who remain hypotensive despite fluids and catecholamines. ( 1 )

2 DOSAGE AND ADMINISTRATION Dilute 20 units/mL single dose vial or 200 units/10 mL (20 units/mL) multiple dose vial contents with normal saline (0.9% sodium chloride) or 5% dextrose in water (D5W) to either 0.1 units/mL or 1 unit/mL for intravenous administration. Discard unused diluted solution after 18 hours at room temperature or 24 hours under refrigeration. ( 2.1 ) The 20 units/100 mL, 40 units/100 mL, 60 units/100 mL and 50 units/50 mL single dose vials do not require further dilution prior to administration. ( 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. Vasostrict ® Solution for Dilution, 20 units/mL and 200 units/10 mL (20 units/mL) Dilute Vasostrict ® 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 1 Preparation of diluted solutions Fluid restriction? Final concentration Mix Vasostrict ® Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL Vasostrict ® Premixed Solution, 20 units/100 mL (0.2 units/mL), 40 units/100 mL (0.4 units/mL), 60 units/100 mL (0.6 units/mL) and 50 units/50 mL (1 unit/mL) 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 Septic Shock: 0.01 units/minute 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 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 8 hours without the use of catecholamines, taper vasopressin injection by 0.005 units/minute every hour as tolerated to maintain target blood pressure.

3 DOSAGE FORMS AND STRENGTHS Injection: vasopressin injection, USP is a clear, practically colorless solution available as: 20 units/mL in a single dose vial. To be used after dilution. 200 units/10 mL (20 units/mL) in a multiple dose vial. To be used after dilution. 20 units/100 mL (0.2 units/mL) premixed in dextrose in a single dose vial. Ready to use. 40 units/100 mL (0.4 units/mL) premixed in dextrose in a single dose vial. Ready to use. 60 units/100 mL (0.6 units/mL) premixed in dextrose in a single dose vial. Ready to use. 50 units/50 mL (1 unit/mL) premixed in dextrose in a single dose vial. Ready to use. Injection: 20 units/mL in a single dose vial. To be used after dilution. 200 units/10 mL (20 units/mL) in a multiple dose vial. To be used after dilution. 20 units/100 mL (0.2 units/mL) premixed in dextrose in a single dose vial. Ready to use. 40 units/100 mL (0.4 units/mL) premixed in dextrose in a single dose vial. Ready to use. 60 units/100 mL (0.6 units/mL) premixed in dextrose in a single dose vial. Ready to use. 50 units/50 mL (1 unit/mL) premixed in dextrose in a single dose vial. Ready to use.

4 CONTRAINDICATIONS Vasostrict ® 10 mL multiple dose vial is contraindicated in patients with known allergy or hypersensitivity to 8‐L-arginine vasopressin or chlorobutanol. The 1 mL single dose vial, 50 mL and 100 mL pre-mixed single dose vial does not contain chlorobutanol and is therefore contraindicated only in patients with a known allergy or hypersensitivity to 8-L-arginine vasopressin. Vasostrict ® 10 mL multiple dose vial is contraindicated in patients with known allergy or hypersensitivity to 8‐L-arginine vasopressin or chlorobutanol. The 1 mL single dose vial, 50 mL and 100 mL pre-mixed single dose vial does not contain chlorobutanol and is therefore contraindicated only in patients with a known allergy or hypersensitivity to 8-L-arginine vasopressin. (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 Postmarketing Experience Reversible 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 Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Pressor effects of catecholamines and Vasostrict ® are expected to be additive. ( 7.1 ) Indomethacin may prolong effects of Vasostrict ® . ( 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 Vasostrict ® 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 Vasostrict ® 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 Vasostrict ® . 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 Vasostrict ® . 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 Pregnancy Category C Risk Summary: There are no adequate or well-controlled studies of Vasostrict ® in pregnant women. It is not known whether vasopressin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with vasopressin [see Clinical Pharmacology (12.3) ]. Clinical Considerations: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasostrict ® may need to be up-titrated to doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07 units/minute in septic shock. Vasostrict ® may produce tonic uterine contractions that could threaten the continuation of pregnancy . 8.3 Nursing Mothers It is not known whether vasopressin is present in human milk. However, oral absorption by a nursing infant is unlikely because vasopressin is rapidly destroyed in the gastrointestinal tract. Consider advising a lactating woman to pump and discard breast milk for 1.5 hours after receiving vasopressin to minimize potential exposure to the breastfed infant. 8.4 Pediatric Use Safety and effectiveness of Vasostrict ® 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. Vasostrict ® is a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The 1 mL solution contains vasopressin 20 units/mL, 1.36 mg sodium acetate buffer and Water for Injection, USP. The 10 mL solution contains vasopressin 20 units/mL, 1.36 mg sodium acetate buffer, chlorobutanol, NF 0.5% as a preservative and Water for Injection, USP. Sodium hydroxide and hydrochloric acid are included to adjust to a pH of 3.8. The 50 mL solution contains vasopressin 1 unit/mL. Each mL of the 1 unit/mL strength also contains dextrose anhydrous, 0.0546 mg acetic acid, 0.012 mg sodium acetate and Water for Injection, USP. Sodium hydroxide and hydrochloric acid are included to adjust to a pH of 3.8. The 100 mL solution contains vasopressin 0.2 units/mL, 0.4 units/mL, or 0.6 units/mL. Each mL of the 0.2 unit/mL strength also contains dextrose anhydrous, 0.0546 mg acetic acid, 0.012 mg sodium acetate and Water for Injection, USP. Each mL of the 0.4 unit/mL strength also contains dextrose anhydrous, 0.0546 mg acetic acid, 0.012 mg sodium acetate and Water for Injection, USP. Each mL of the 0.6 unit/mL strength also contains dextrose anhydrous, 0.0546 mg acetic acid, 0.012 mg sodium acetate and Water for Injection, USP. Sodium hydroxide and hydrochloric acid are included to adjust to a pH of 3.8. Each vial of the Vasostrict ® premixed solutions contains 5% Dextrose in approximately 100 mL Water for Injection. 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 One mg is equivalent to 530 units. Chemical Structure

10 OVERDOSAGE Overdosage with Vasostrict ® 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 Vasostrict ® (vasopressin injection, USP) is a clear, practically colorless solution for intravenous administration available as: NDC 42023-164-10: A carton of 10 single dose vials. Each vial contains vasopressin 1 mL at 20 units/mL. NDC 42023-164-25: A carton of 25 single dose vials. Each vial contains vasopressin 1 mL at 20 units/mL. NDC 42023-190-01: A carton of 1 multiple dose vial. Each vial contains vasopressin 10 mL at 200 units/10 mL (20 units/mL). NDC 42023-219-10: A carton of 10 single dose vials. Each vial contains vasopressin premixed in dextrose 100 mL at 40 units/100 mL (0.4 units/mL). NDC 42023-220-10: A carton of 10 single dose vials. Each vial contains vasopressin premixed in dextrose 100 mL at 60 units/100 mL (0.6 units/mL). NDC 42023-237-10: A carton of 10 single dose vials. Each vial contains vasopressin premixed in dextrose 100 mL at 20 units/100 mL (0.2 units/mL). NDC 42023-268-10: A carton of 10 single dose vials. Each vial contains vasopressin premixed in dextrose 50 mL at 50 units/50 mL (1 unit/mL). Store between 2°C and 8°C (36°F and 46°F). Do not freeze. Vials may be held up to 12 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 12 month 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 Vasostrict ® beyond the manufacturer’s expiration date stamped on the vial. After initial entry into the 10 mL vial, the remaining contents must be refrigerated. Discard the refrigerated 10 mL vial after 30 days after first puncture. The storage conditions and expiration periods are summarized in the following table. Unopened Refrigerated 2°C to 8°C (36°F to 46°F) Unopened Room Temperature 20°C to 25°C (68°F to 77°F) Do not store above 25°C (77°F) Opened (After First Puncture) 1 mL Vial Until manufacturer expiration date 12 months or until manufacturer expiration date, whichever is earlier N/A 10 mL Vial Until manufacturer expiration date 12 months or until manufacturer expiration date, whichever is earlier 30 days 50 mL Vial Until manufacturer expiration date 12 months or until manufacturer expiration date, whichever is earlier N/A 100 mL Vial Until manufacturer expiration date 12 months or until manufacturer expiration date, whichever is earlier N/A