Label: VASOPRESSIN injection, solution

  • NDC Code(s): 0517-1020-01, 0517-1020-25
  • Packager: American Regent, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated July 1, 2020

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use VASOPRESSIN INJECTION safely and effectively. See full prescribing information for VASOPRESSIN INJECTION.

    Vasopressin Injection, for intravenous use
    Initial U.S. Approval: 2014

    INDICATIONS AND USAGE

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

    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 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)

    DOSAGE FORMS AND STRENGTHS

    • Injection: 20 units per mL (3)

    CONTRAINDICATIONS

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

    WARNINGS AND PRECAUTIONS

    • Can worsen cardiac function. (5.1)
    • Reversible diabetes insipidus (5.2)

    ADVERSE REACTIONS

    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.

    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)

    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)

    Revised: 7/2020

  • Table of Contents
  • 1 INDICATIONS AND USAGE

    Vasopressin injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines.

  • 2 DOSAGE AND ADMINISTRATION

    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 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

    Inspect 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 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

    Vasopressin injection, USP is a clear, colorless solution available as 20 units/mL in a single-dose vial.

  • 4 CONTRAINDICATIONS

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

  • 5 WARNINGS AND PRECAUTIONS

    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, 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)].

  • 7 DRUG INTERACTIONS

    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.

  • 8 USE IN SPECIFIC POPULATIONS

    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 with vasopressin.

    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. Vasopressin receptors are present in human uterine muscle and might not be distinguishable from oxytocin receptors.

    8.2 Lactation

    Risk Summary

    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 (5.1, 5.2), 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 non-specific 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, chlorobutanol 5 mg, sodium chloride 9 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 a white to off-white amorphous powder, freely soluble in water. The structural formula is:

    Chemical Structure

    Molecular Formula: C46H65N15O12S2                 Molecular Weight: 1084.23

  • 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 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 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 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 t1/2 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 pre-conception 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 sperm function, including motility, fertilization and embryonic development. 

    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 studies 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:

    NDC 0517-1020-25: A carton of 25 single-dose vials each containing vasopressin 1 mL at 20 units/mL.

    Store between 2°C and 8°C (36°F and 46°F). Do not freeze.

    Storage is permitted for up to 12 months at controlled room temperature (USP) 20°C to 25°C (68°F to 77°F) 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.

    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)

    Until manufacturer expiration date

    12 months or until manufacturer expiration date, whichever is earlier

  • SPL UNCLASSIFIED SECTION

    American Regent, Inc.
    Shirley, NY 11967

    RQ1093-A

  • PRINCIPAL DISPLAY PANEL – Container Label

    NDC 0517-1020-01

    Rx Only

    Vasospressin Injection, USP

    20 Units per mL

    For Intravenous Infusion
    Must be diluted prior to use

    1 mL Single-Dose Vial -
    Discard Unused Portion

    Container Label

  • PRINCIPAL DISPLAY PANEL – Carton Labeling

    NDC 0517-1020-25

    Vasopressin Injection, USP

    20 Units per mL

    For Intravenous Infusion
    Must be diluted prior to use

    25 x 1 mL Single Dose Vials
    Discard Unused Portion

    Rx  Only

    AMERICAN REGENT, INC.
    SHIRLEY, NY 11967

    Carton Labeling

  • Serialization Label

    Vasopressin Serialization Label
  • INGREDIENTS AND APPEARANCE
    VASOPRESSIN 
    vasopressin injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0517-1020
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    VASOPRESSIN (UNII: Y4907O6MFD) (VASOPRESSIN - UNII:Y4907O6MFD) VASOPRESSIN20 [USP'U]  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    WATER (UNII: 059QF0KO0R)  
    ACETIC ACID (UNII: Q40Q9N063P)  
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg  in 1 mL
    CHLOROBUTANOL (UNII: HM4YQM8WRC) 5 mg  in 1 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0517-1020-2525 in 1 CARTON02/03/2022
    1NDC:0517-1020-011 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21259302/03/2022
    Labeler - American Regent, Inc. (002033710)
    Establishment
    NameAddressID/FEIBusiness Operations
    American Regent, Inc.606821721manufacture(0517-1020)