DRUG INTERACTIONS SECTION.

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 (syndrome of inappropriate antidiuretic hormone secretion) 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 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 (syndrome of inappropriate antidiuretic hormone secretion) 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 (Syndrome of Inappropriate Antidiuretic Hormone Secretion). 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.

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 (5.1, 5.2), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

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 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 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 American Regent at 1-800-734-9236 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, 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 sperm function, including motility, fertilization and embryonic development.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism 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, ACTH and catecholamines 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 is 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. 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 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 pre-conception 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 studies in post-cardiotomy vasodilatory shock.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Vasopressin is polypeptide hormone. Vasopressin injection is sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. The mL solution contains vasopressin 20 units, chlorobutanol mg, sodium chloride mg, water for injection, and acetic acid to adjust pH to 3.5.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. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Dilute vasopressin injection 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 vasopressin injection 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 Diluted Solutions. 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 Preparation of diluted solutionsFluid restrictionFinal concentrationMixVasopressin InjectionDiluentNo0.1 units/mL2.5 mL (50 units)500 mLYes1 unit/mL5 mL (100 units)100 mLInspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.. 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/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 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, colorless solution available as 20 units/mL in single-dose vial.. Injection: 20 units per mL (3). Injection: 20 units per mL (3).

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. Vasopressin injection, USP is clear, practically colorless solution for intravenous administration available as:NDC 0517-1020-25: carton of 25 single-dose vials each containing vasopressin mL at 20 units/mL. Store between 2C and 8C (36F and 46F). Do not freeze. Storage is permitted for up to 12 months at controlled room temperature (USP) 20C to 25C (68F to 77F) within the expiry date. Once removed from refrigeration, mark the unopened vial with the revised 12-month expiration date. Do not return Vasopressin to the refrigerator after it has been stored at room temperature. Discard the product after 12 months at room temperature or at the expiry date, whichever is earlier. The storage conditions and expiration periods are summarized in the following table.UnopenedRefrigerated2C to 8C (36F to 46F)Unopened Room Temperature 20C to 25C (68F to 77F)Until manufacturer expiration date12 months or until manufacturer expiration date, whichever is earlier.

INDICATIONS & USAGE SECTION.

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). Vasopressin 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. Risk SummaryThere 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.

12.1Mechanism 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. 13.1Carcinogenesis, 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 sperm function, including motility, fertilization and embryonic development. 13.2 Animal Toxicology and/or Pharmacology. No toxicology studies were conducted with vasopressin.

OVERDOSAGE SECTION.

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 non-specific gastrointestinal symptoms.Direct effects will resolve within minutes of withdrawal of treatment.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL Container Label. NDC 0517-1020-01 Rx Only Vasospressin Injection, USP 20 Units per mLFor Intravenous InfusionMust be diluted prior to use mL Single-Dose Vial -Discard Unused Portion Container Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of vasopressin 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, ACTH and catecholamines 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 is 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. 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 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 pre-conception 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 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 with vasopressin. Clinical ConsiderationsDose Adjustments during Pregnancy and the Postpartum PeriodBecause 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 reactionsVasopressin injection may produce tonic uterine contractions. Vasopressin receptors are present in human uterine muscle and might not be distinguishable from oxytocin receptors.

SPL UNCLASSIFIED SECTION.

2.1 Preparation of Diluted Solutions. 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 Preparation of diluted solutionsFluid restrictionFinal concentrationMixVasopressin InjectionDiluentNo0.1 units/mL2.5 mL (50 units)500 mLYes1 unit/mL5 mL (100 units)100 mLInspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.

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 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 PeriodBecause 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 reactionsVasopressin injection may produce tonic uterine contractions. Vasopressin receptors are present in human uterine muscle and might not be distinguishable from oxytocin receptors. 8.2 Lactation. Risk SummaryThere 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 (5.1, 5.2), 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. Use in patients with impaired cardiac response may worsen cardiac output.. 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.