DESCRIPTION SECTION

11 DESCRIPTION

Vasopressin in Sodium Chloride Injection contains vasopressin, a polypeptide hormone. 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: C46H65N15O12S2 Molecular Weight: 1084.23

Vasopressin in Sodium Chloride Injection is a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. Each 100 mL contains 20 units (0.2 units/mL) or 40 units (0.4 units/mL) of vasopressin. Each 100mL also contains 900 mg Sodium Chloride, 33.6 mg Sodium DL-Lactate, and Water for Injection. pH may have been adjusted with sodium hydroxide and/or hydrochloric acid. It has a pH of 3.6 – 4.0.

CLINICAL PHARMACOLOGY SECTION

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 and ACTH 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 are 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 Interaction Studies

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.

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INDICATIONS & USAGE SECTION

Highlight: Vasopressin in Sodium Chloride Injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines. (1)

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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection: 100-mL single dose, ready-to-use containers with (3)

•

20 units vasopressin (0.2 units/mL) in 0.9% sodium chloride.

•

40 units vasopressin (0.4 units/mL) in 0.9% sodium chloride.

3 DOSAGE FORMS AND STRENGTHS

Injection: a clear, practically colorless solution for intravenous infusion, supplied in 100-mL single dose ready-to-use containers as:

•

20 units vasopressin (0.2 units/mL) in 0.9% sodium chloride 

•

40 units vasopressin (0.4 units/mL) in 0.9% sodium chloride

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CONTRAINDICATIONS SECTION

Highlight: •

Vasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin. (4)

4 CONTRAINDICATIONS

Vasopressin in Sodium Chloride Injection is contraindicated in patients with a known allergy or hypersensitivity to 8-L-arginine vasopressin.

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ADVERSE REACTIONS SECTION

Highlight: The most common adverse reactions include decreased cardiac output, bradycardia, tachyarrhythmias, hyponatremia and ischemia (coronary, mesenteric, skin, digital). (6)

**To report SUSPECTED ADVERSE REACTIONS, contactBaxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or **www.fda.gov/medwatch.

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 reliably their frequency or 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)]

CLINICAL STUDIES SECTION

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.

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OVERDOSAGE SECTION

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.

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