January 3, 2007 Conivaptan (Vaprisol ®) DESCRIPTION WHAT YOU MAY NOT BE TOLD Conivaptan (Vaprisol ®) is an inhibitor of arginine Conivaptan is currently approved for euvolemic vasopressin that prevents its binding to V1a and V2 hyponatremia, but the only peer-reviewed published receptors located within the vasculature and renal data is in acute exacerbations of heart failure. It is tubules, respectively. Conivaptan was approved likely that the drug manufacturer will pursue this December 30, 2005, and is a first-in-class agent indication in the future. Conivaptan is also a potent approved for euvolemic hyponatremia. Conivaptan is inhibitor of CYP 3A4 and, as an oral formulation, available in 20 mg/5mL glass ampules. increases the area under the curve of midazolam 2- to 3-fold, simvastatin 3-fold, and amlodipine 2-fold. This WHAT THE PHARMACIST SHOULD KNOW level of interaction is what prevented the oral Euvolemic hyponatremia is most commonly associated formulation from being pursued for FDA approval. with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Causes of this syndrome WHAT THE PATIENT SHOULD KNOW include pulmonary disease (e.g., pneumonia, Conivaptan is used to treat euvolemic hyponatremia, tuberculosis, pleural effusion) and CNS disease (e.g., manifested when a patient has too little sodium in the tumor, subarachnoid hemorrhage, meningitis). SIADH bloodstream but a normal amount of fluid in the body. also occurs with malignancies (e.g., small cell Conivaptan should not be used at this time for heart carcinoma of the lung) and can be caused by drugs failure. Conivaptan has relatively few adverse effects (e.g., chlorpropamide, carbamazepine, narcotic and is well tolerated. Common adverse events include analgesics, cyclophosphamide). The current headache (12%), infusion site reactions (20.2%), and treatment of SIADH includes fluid restriction, thirst (9.8%). In heart failure patients, low blood hypertonic saline, a combination of loop diuretics with pressure, light-headedness and constipation were all a high-sodium diet, lithium and demeclocycline. reported as non-serious drug-related reactions. Conivaptan’s antagonism at V2 receptors causes a Conivaptan increases urine output significantly. In the reduction in water retention (increasing effective water study of heart failure patients, at the 20mg/day dose, clearance), which reduces preload. Conivaptan’s urine output increased by 152 mL/hr and at the antagonism at V1a receptors will cause vasodilatation, 40mg/day dose increased by 176 mL/hr during the effectively reducing afterload. The recommended infusion. dose of conivaptan is a loading dose of 20 mg IV TYPICAL NURSING QUESTIONS administered over 30 minutes followed by 20 mg of How should the drug be administered? Conivaptan conivaptan infused over 24 hours. Following the initial should be administered through large veins only and day of therapy, conivaptan should be administered for the infusion site should be rotated every 24 hours to an additional 1 to 3 days as a continuous infusion of minimize the risk of vascular irritation if given 20 mg/day. If the serum sodium fails to rise at the peripherally. What is conivaptan compatible with? desired rate, conivaptan can be titrated upward to a Conivaptan should not be mixed with Lactated dose of 40 mg/day by continuous infusion. The Ringer’s or 0.9% sodium chloride; it has only been duration of treatment should not exceed four days. tested in 5% dextrose solution. Conivaptan should not The bolus dose should be added to a 100 mL bag of be combined with any other product in the same 5% dextrose and inverted several times. The intravenous line or bag. What should be monitored continuous infusion is prepared in a 250 mL bag of 5% during infusion of Conivaptan? Frequent monitoring of dextrose. The prepared bag should be used within 72 serum sodium and volume status is required. A rapid hours. Conivaptan ampules should be protected from rise in serum sodium (>12 mEq/L/24 hours) may result light. in serious sequelae. Conivaptan should be discontinued in patients who develop an undesirable rapid rise in serum sodium. Patients who develop

The information provided was developed by the Center for Drug Policy at the University of Wisconsin Hospitals and Clinics and published by the Pharmacy Society of Wisconsin. hypovolemia or hypotension while receiving HOW DOES THIS MEDICATION COMPARE TO OTHERS USED conivaptan should have the drug discontinued. In TO TREAT SIADH ? either case, if vital signs become stable or if Conivaptan is the first rationally designed agent for hyponatremia recurs, conivaptan can be resumed at a SIADH. In published SIADH trials, fluid restriction was reduced dose. What is the onset of action and undertaken in both treatment and placebo groups. duration of Conivaptan’s effect? The peak effect of the Conivaptan is likely more easily monitored and does drug occurs at the end of bolus infusion, and the effect increase serum sodium concentrations more will last for 5 hours following the bolus in non-heart effectively than fluid restriction alone. This medication failure patients and for 8 hours in heart failure patients. is also well tolerated as compared to other agents for the treatment of SIADH; however, the drug is only HOW DOES THIS MEDICATION COMPARE TO OTHERS IN THE available IV, so if the SIADH is caused by malignancy CLASS ? that will not resolve, this agent cannot be continued in There are no other medications in this drug class. the outpatient setting, and therefore is not a reasonable choice.

WHAT ARE THE COST CONSIDERATIONS ? Generic Product Dose Cost per Day (AWP) Conivaptan Vaprisol ® 20 mg/day $393.75 Lithium Eskalith ® 900-1200 mg/day $0.48-$0.64 Demeclocycline Declomycin ® 600-1200 mg/day $42.52-$85.04 Furosemide Lasix ® 20-80 mg/day $0.15-$0.59 Bumetanide Bumex ® 0.5-2 mg/day $0.37-$0.86

RESOURCES Additional information is available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ (search for Vaprisol ®)

Prescribing information: http://www.astellas.us/docs/vaprisol.pdf

DISCLAIMER This publication is intended to provide key practical information regarding this drug product in a brief format. It does not contain sufficient information upon which to base formulary or other medication use policy decisions.

The information provided was developed by the Center for Drug Policy at the University of Wisconsin Hospitals and Clinics and published by the Pharmacy Society of Wisconsin.