VASOPRESSIN

VASOPRESSIN VASOPRESSIN VASOPRESSIN VASOPRESSIN SODIUM ACETATE SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

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

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 1 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. Vasopressin Injection Solution for Dilution, 20 units/mL Dilute Vasopressin injection 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 Vasopressin injection Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units) 100 mL 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 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 injection by 0.005 units/minute every hour as tolerated to maintain target blood pressure.

<table ID="_Reft1" width="100%"><caption>Table 1 Preparation of diluted solutions </caption><col width="25%"/><col width="25%"/><col width="26%"/><col width="25%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Fluid restriction?</paragraph></td><td rowspan="2" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Final concentration </paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Mix </paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vasopressin injection </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Diluent </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>No </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>0.1 units/mL </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2.5 mL (50 units) </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>500 mL </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Yes </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>1 unit/mL </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>5 mL (100 units) </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>100 mL </paragraph></td></tr></tbody></table>

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

4 CONTRAINDICATIONS Vasopressin injection 1 mL 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. • Vasopressin injection 1 mL 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 )

5 WARNINGS AND PRECAUTIONS • Can worsen cardiac function. ( 5.1 ) • Reversible diabetes insipidus ( 5.2 ) 5.1 Worsening Cardiac Function A 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, a 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.

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 Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS • Pressor effects of catecholamines and Vasopressin injection are expected to be additive. ( 7.1 ) • Indomethacin may prolong effects of Vasopressin 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 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 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 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 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 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 injection may need to be increased [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. Maternal adverse reactions: Vasopressin 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 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 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 )] .

8.1 Pregnancy Risk Summary There are no available data on Vasopressin 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 injection may need to be increased [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. Maternal adverse reactions: Vasopressin injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.

8.4 Pediatric Use Safety and effectiveness of Vasopressin 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 )] .

10 OVERDOSAGE Overdosage with Vasopressin 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 nonspecific gastrointestinal symptoms. Direct effects will resolve within minutes of withdrawal of treatment.

11 DESCRIPTION Vasopressin is a polypeptide hormone. Vasopressin injection 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. Sodium hydroxide and hydrochloric acid are included to adjust to a pH of 3.8. 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: vasop-struc-01.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vasopressin causes vasoconstriction by binding to V 1 receptors on vascular smooth muscle coupled to the Gq/1 1-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. 12.2 Pharmacodynamics At therapeutic doses exogenous vasopressin elicits a 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 V 1 -receptors and release of prolactin and ACTH via V 3 receptors. At lower concentrations typical for the antidiuretic hormone vasopressin inhibits water diuresis via renal V 2 receptors. In addition, vasopressin has been demonstrated to cause vasodilation in numerous vascular beds that are mediated by V 2 , V 3 , 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 μU/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. Elimination At infusion rates used in vasodilatory shock (0.01 to 0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent t 1/2 of vasopressin at these levels is ≤ 10 minutes. Metabolism Serine 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. Excretion Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged into urine. Specific Populations Pregnancy: Because of a spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a 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 vasopressin's 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.

12.1 Mechanism of Action Vasopressin causes vasoconstriction by binding to V 1 receptors on vascular smooth muscle coupled to the Gq/1 1-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.

12.2 Pharmacodynamics At therapeutic doses exogenous vasopressin elicits a 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 V 1 -receptors and release of prolactin and ACTH via V 3 receptors. At lower concentrations typical for the antidiuretic hormone vasopressin inhibits water diuresis via renal V 2 receptors. In addition, vasopressin has been demonstrated to cause vasodilation in numerous vascular beds that are mediated by V 2 , V 3 , 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 μU/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. Elimination At infusion rates used in vasodilatory shock (0.01 to 0.1 units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in patients with vasodilatory shock. The apparent t 1/2 of vasopressin at these levels is ≤ 10 minutes. Metabolism Serine 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. Excretion Vasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged into urine. Specific Populations Pregnancy: Because of a spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of a 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 vasopressin's 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.

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.

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.

14 CLINICAL STUDIES Increases in systolic and mean blood pressure following administration of vasopressin were observed in 7 studies in septic shock and 8 in post-cardiotomy vasodilatory shock.

16 HOW SUPPLIED/STORAGE AND HANDLING Vasopressin injection, USP is a clear, practically colorless solution for intravenous administration available as: Product Code Unit of Sale Strength Unit of Use 930101 NDC 63323-930-01 A tray of 25 Single Dose Vials 20 Units per 1 mL NDC 63323-930-00 1 mL Single Dose Vial 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], [see 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 Vasopressin injection beyond the manufacturer's expiration date stamped on the vial. 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) 1 mL Vial Until manufacturer expiration date 12 months or until manufacturer expiration date, whichever is earlier 451491A Figure

<table width="100%"><col width="14%"/><col width="33%"/><col width="23%"/><col width="31%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Product Code</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Strength</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Use</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>930101 </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 63323-930-01 A tray of 25 Single Dose Vials </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>20 Units per 1 mL </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>NDC 63323-930-00 1 mL Single Dose Vial </paragraph></td></tr></tbody></table> <table width="100%"><col width="16%"/><col width="42%"/><col width="42%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph/></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Unopened Refrigerated 2&#xB0;C to 8&#xB0;C (36&#xB0;F to 46&#xB0;F) </paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Unopened Room Temperature 20&#xB0;C to 25&#xB0;C (68&#xB0;F to 77&#xB0;F) Do not store above 25&#xB0;C (77&#xB0;F) </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1 mL Vial </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>Until manufacturer expiration date </paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>12 months or until manufacturer expiration date, whichever is earlier </paragraph></td></tr></tbody></table>

PACKAGE LABEL- PRINCIPAL DISPLAY PANEL- VASOPRESSIN INJECTION 20 Unit Tray Label NDC 63323-930-01 Rx Only Vasopressin Injection, USP 20 Units per mL For Intravenous Infusion Must be diluted prior to use Store between 2°C and 8°C (36°F and 46°F). Vials may be held at 20°C to 25°C (68°F to 77°F) for up to 12 months. Do not store above 25°C (77°F). Avoid freezing. 25 x 1 mL Single Dose Vials vasop-label-01.jpg PACKAGE LABEL- PRINCIPAL DISPLAY PANEL- VASOPRESSIN INJECTION 20 Unit Vial Label NDC 63323-930-00 930101 Vasopressin Injection, USP 20 Units per mL For Intravenous Infusion Must be diluted prior to use. Usual Dosage: See insert. Store between 2°C and 8°C (36°F and 46°F). Do not store above 25°C (77°F) 1 mL Single Dose Vial Rx Only vasop-label-02.jpg