Vaprisol ® – conivaptan

VAPRISOL ® (conivaptan hydrochloride) Injection

Usual Diluents

Standard Dilution [Amount of drug] [Infusion volume] [Infusion rate]

Stability / Miscellaneous

CLINICAL PHARMACOLOGY
Mechanism of Action:
Conivaptan hydrochloride is a dual arginine vasopressin (AVP) antagonist with nanomolar affinity for human V1A and V2 receptors in vitro. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range. The predominant pharmacodynamic effect of conivaptan hydrochloride in the treatment of hyponatremia is through its V2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water.

INDICATIONS AND USAGE
VAPRISOL® is a vasopressin receptor antagonist indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.

Important Limitations:
VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure.

It has not been established that raising serum sodium with VAPRISOL provides a symptomatic benefit to patients.

DOSAGE AND ADMINISTRATION 

• Loading Dose: 20 mg IV administered over 30 minutes, followed by
• Continuous infusion: 20 mg/day over 24 hours for 2 to maximum 4 days.
• Following initial day of treatment, dosage may be increased to
  40 mg/day continuous infusion as needed to raise serum sodium.
• Monitor volume status and serum sodium frequently and discontinue if patient develops hypovolemia, hypotension or an undesirably rapid rate of rise of serum sodium.

General Dosing Information
VAPRISOL is for intravenous use only.
VAPRISOL is for use in hospitalized patients only.

Administer VAPRISOL through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation [see package insert for Warnings and Precautions].

Initiate with a loading dose of 20 mg IV administered over 30 minutes.

Follow the loading dose with 20 mg of VAPRISOL administered in a continuous intravenous infusion over 24 hours. After the initial day of treatment, administer VAPRISOL for an additional 1 to 3 days in a continuous infusion of 20 mg/day. If serum sodium is not rising at the desired rate, VAPRISOL may be titrated upward to a dose of 40 mg daily, administered in a continuous intravenous infusion.

The total duration of infusion of VAPRISOL (after the loading dose) should not exceed four days. The maximum daily dose of VAPRISOL (after the loading dose) is 40 mg/day.

Patients receiving VAPRISOL must have frequent monitoring of serum sodium and volume status. An overly rapid rise in serum sodium (> 12 mEq/L/24 hours) may result in serious neurologic sequelae. For patients who develop an undesirably rapid rate of rise of serum sodium, VAPRISOL should be discontinued, and serum sodium and neurologic status should be carefully monitored. If the serum sodium continues to rise, VAPRISOL should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, VAPRISOL may be resumed at a reduced dose [see Warnings and Precautions (5.2)]. For patients who develop hypovolemia or hypotension while receiving VAPRISOL, VAPRISOL should be discontinued, and volume status and vital signs should be frequently monitored. Once the patient is again euvolemic and is no longer hypotensive, VAPRISOL may be resumed at a reduced dose if the patient remains hyponatremic.

Preparation, Compatibility and Stability
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, discoloration or cloudiness is observed, the drug solution should not be used.

VAPRISOL is supplied in a single-use 100 mL flexible INTRAVIA Container containing a sterile premixed dilute, ready-to-use, nonpyrogenic solution of conivaptan hydrochloride, 0.2 mg per mL (20 mg/100 mL) in 5% Dextrose. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY.

VAPRISOL is compatible with 5% Dextrose Injection. VAPRISOL is physically and chemically compatible with 0.9% Sodium Chloride Injection for up to 22 hours when the two solutions are co-administered via a Y-site connection at a flow rate for VAPRISOL of 4.2 mL/hour and at flow rates for 0.9% Sodium Chloride Injection of either 2.1 mL/hour or 6.3 mL/hour. VAPRISOL should not be administered with Lactated Ringer’s Injection.

VAPRISOL should not be combined with any other product in the same intravenous line or container.

Loading Dose -------------------
Administer the content of a 20 mg/100 mL VAPRISOL flexible plastic container over 30 minutes.

Continuous Infusion---------------------
For patients requiring 20 mg VAPRISOL injection per day, administer the content of one 20 mg/100 mL VAPRISOL flexible plastic container over 24 hours.

For patients requiring 40 mg VAPRISOL injection per day, administer the content of two consecutive 20 mg/100 mL VAPRISOL flexible plastic containers over 24 hours.

Since the flexible container is for single-use only, any unused portion should be discarded.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

Do not remove container from overwrap until ready for use. The overwrap is a moisture and light barrier. The inner container maintains the sterility of the product.

Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner container firmly. If leaks are found, discard solution as sterility may be impaired. Do not use if the solution is cloudy or a precipitate is present.

DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:

1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.

DOSAGE FORMS AND STRENGTHS
Intravenous injection solution: conivaptan hydrochloride 20 mg/100 mL premixed in 5% Dextrose.

CONTRAINDICATIONS:

• Hypovolemic hyponatremia.
• Coadministration with potent CYP3A inhibitor.
• Anuria: no benefit can be expected.
• Known allergy to corn or corn products.

WARNINGS AND PRECAUTIONS:

• Hypervolemic hyponatremia associated with heart failure: The amount of safety data is limited. VAPRISOL should be used to raise serum sodium in such patients only after consideration of other treatment options.
• Overly rapid correction of serum sodium: Monitor serum sodium and neurologic status as serious neurologic sequelae can result from over rapid correction of serum sodium.
• Hepatic impairment: Decrease the dose of VAPRISOL.
• Renal impairment: Decrease the dose of VAPRISOL. Use in patients with severe renal impairment is not recommended.
• Infusion site reactions: Serious reactions have occurred. Administer through large veins and change infusion site every 24 hours.

ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 10%) are infusion site reactions (including phlebitis), pyrexia, hypokalemia, headache and orthostatic hypotension.

To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:

• Potent CYP3A inhibitors may increase the exposure of conivaptan and are contraindicated.
• Generally avoid CYP3A substrates.
• Exposure to coadministered digoxin may be increased and digoxin levels should be monitored.

USE IN SPECIFIC POPULATIONS:

• Pregnancy: Based on animal data, may cause fetal harm.
• Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
• Pediatric Use: There are no studies.

HOW SUPPLIED/STORAGE AND HANDLING

VAPRISOL (conivaptan hydrochloride) Injection is supplied as a single-use, premixed solution, containing 20 mg of conivaptan hydrochloride in 5% Dextrose in 100 mL INTRAVIA Plastic Containers.

1 container/carton (NDC 0469-1602-10)

VAPRISOL in INTRAVIA Plastic Containers should be stored at 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely affect the product. Avoid excessive heat. Protect from freezing. Protect from light until ready to use.

Reference(s)

Marketed by:
Astellas Pharma US, Inc.
Deerfield, IL 60015-2548

Manufactured by:
Baxter Healthcare Corporation
Deerfield, IL 60015

VAPRISOL is a registered trademark of Astellas Pharma US, Inc.
INTRAVIA is a registered trademark of Baxter International, Inc.

11A003-VAP-SPL
Revised 02/2011