These Highlights Do Not Include All The Information Needed To Use Vasopressin Injection Safely And Effectively. See Full Prescribing Information For Vasopressin Injection.

Rx Only

© 2021 Amphastar Pharmaceuticals, Inc.

Amphastar Pharmaceuticals, Inc.

Rancho Cucamonga, CA 91730 U.S.A.

Rev. 07/21

6997016F

PRINCIPAL DISPLAY PANEL TEXT - CARTON

NDC 0548-9701-00   Rx Only

Vasopressin

Injection, USP

20 Units per mL

For Intravenous Infusion

Must be diluted prior to use

10 x 1 mL Single Dose Vials

5297016D/6-19

Store between 2°C and 8°C (36°F and

46°F). Do not store above 25°C (77°F).

Vials may be held at 20°C to 25°C

(68°F to 77°F) for up to 12 months.

Do not freeze.

Usual Dosage: See full

prescribing information.

Stock No. 9701

AMPHASTAR PHARMACEUTICALS, INC.

Rancho Cucamonga, CA 91730 U.S.A.

Overdosage with Vasopressin Injection, USP 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.

Risk Summary

There are no available data on Vasopressin Injection, USP 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, USP may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Maternal adverse reactions: Vasopressin Injection, USP 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.

Vasopressin is a polypeptide hormone. Vasopressin Injection, USP is a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration.

The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and Water for Injection, USP adjusted with acetic acid to pH 3.4-3.6.

The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-LGlutaminyl-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: C ₄₆ H ₆₅ N ₁₅ O ₁₂ S ₂       Molecular Weight: 1084.23

One mg is equivalent to 530 units.

Use with indomethacin may prolong the effect of Vasopressin Injection, USP on cardiac index and systemic vascular resistance. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)].

Safety and effectiveness of Vasopressin Injection, USP 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)].

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

Tritate 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.

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.

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.

Vasopressin Injection, USP 1 mL single dose vial is contraindicated in patients with known allergy or hypersensitivity to 8‑L-arginine vasopressin or chlorobutanol.

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)].

• Pressor effects of catecholamines and Vasopressin Injection, USP are expected to be additive. (7.1)

• Indomethacin may prolong effects of Vasopressin Injection, USP. (7.2)

• Co-administration of ganglionic blockers or drugs causing SIADH may increase the pressor response. (7.3, 7.5)

• Co-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.6)

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.

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

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.

Inspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.

Dilute Vasopressin Injection, USP 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

Vasopressin Injection, USP is a clear, practically colorless solution for intravenous administration available as 20 units/mL in a single dose vial. To be used after dilution.

A decrease in cardiac index may be observed with the use of Vasopressin Injection, USP.

Use with ganglionic blocking agents may increase the effect of Vasopressin Injection, USP on mean arterial blood pressure. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)].

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.

Vasopressin Injection, USP is a clear, practically colorless solution for intravenous administration available as:

A carton of 10 single dose vials. Each vial contains vasopressin 1 mL at 20 units/mL.

NDC 0548-9701-00 Stock No. 9701

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 Vasopressin Injection, USP beyond the manufacturer’s expiration date stamped on the vial. The storage conditions and expiration periods are summarized in the following table.

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, USP. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

No toxicology studies were conducted with vasopressin.

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, USP. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

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.

Rx Only

© 2021 Amphastar Pharmaceuticals, Inc.

Amphastar Pharmaceuticals, Inc.

Rancho Cucamonga, CA 91730 U.S.A.

Rev. 07/21

6997016F

PRINCIPAL DISPLAY PANEL TEXT - CARTON

NDC 0548-9701-00   Rx Only

Vasopressin

Injection, USP

20 Units per mL

For Intravenous Infusion

Must be diluted prior to use

10 x 1 mL Single Dose Vials

5297016D/6-19

Store between 2°C and 8°C (36°F and

46°F). Do not store above 25°C (77°F).

Vials may be held at 20°C to 25°C

(68°F to 77°F) for up to 12 months.

Do not freeze.

Usual Dosage: See full

prescribing information.

Stock No. 9701

AMPHASTAR PHARMACEUTICALS, INC.

Rancho Cucamonga, CA 91730 U.S.A.

Overdosage with Vasopressin Injection, USP 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.

Risk Summary

There are no available data on Vasopressin Injection, USP 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, USP may need to be increased [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Maternal adverse reactions: Vasopressin Injection, USP 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.

Vasopressin is a polypeptide hormone. Vasopressin Injection, USP is a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration.

The 1 mL solution contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a preservative, and Water for Injection, USP adjusted with acetic acid to pH 3.4-3.6.

The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-LGlutaminyl-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: C ₄₆ H ₆₅ N ₁₅ O ₁₂ S ₂       Molecular Weight: 1084.23

One mg is equivalent to 530 units.

Use with indomethacin may prolong the effect of Vasopressin Injection, USP on cardiac index and systemic vascular resistance. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)].

Safety and effectiveness of Vasopressin Injection, USP 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)].

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

Tritate 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.

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.

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.

Vasopressin Injection, USP 1 mL single dose vial is contraindicated in patients with known allergy or hypersensitivity to 8‑L-arginine vasopressin or chlorobutanol.

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)].

• Pressor effects of catecholamines and Vasopressin Injection, USP are expected to be additive. (7.1)

• Indomethacin may prolong effects of Vasopressin Injection, USP. (7.2)

• Co-administration of ganglionic blockers or drugs causing SIADH may increase the pressor response. (7.3, 7.5)

• Co-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.6)

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.

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

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.

Inspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit.

Dilute Vasopressin Injection, USP 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

Vasopressin Injection, USP is a clear, practically colorless solution for intravenous administration available as 20 units/mL in a single dose vial. To be used after dilution.

A decrease in cardiac index may be observed with the use of Vasopressin Injection, USP.

Use with ganglionic blocking agents may increase the effect of Vasopressin Injection, USP on mean arterial blood pressure. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)].

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.

Vasopressin Injection, USP is a clear, practically colorless solution for intravenous administration available as:

A carton of 10 single dose vials. Each vial contains vasopressin 1 mL at 20 units/mL.

NDC 0548-9701-00 Stock No. 9701

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 Vasopressin Injection, USP beyond the manufacturer’s expiration date stamped on the vial. The storage conditions and expiration periods are summarized in the following table.

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, USP. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

No toxicology studies were conducted with vasopressin.

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, USP. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

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.