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.

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.

A decrease in cardiac index may be observed with the use of vasopressin.

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.

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.

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)].

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)].

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.

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.

Risk Summary

There are no available data on Vasostrict^® 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 Vasostrict^® may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Maternal adverse reactions: Vasostrict^® may produce tonic uterine contractions that could threaten the continuation of pregnancy.

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.

Safety and effectiveness of Vasostrict^® in pediatric patients with vasodilatory shock have not been established.

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)].

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.

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.

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.

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.

No toxicology studies were conducted with vasopressin.

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