CONIVAPTAN

1. CONIVAPTAN

2. CONIVAPTAN • Conivaptan hydrochloride is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V1A and V2 receptors.

3. CONIVAPTAN MECHANISM OF ACTION: • Conivaptan hydrochloride is a dual AVP antagonist with nanomolar affinity for human V1A and V2 receptors. • 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.

4. CONIVAPTAN MECHANISM OF ACTION (Cont.) • 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. • The pharmacodynamic effects of conivaptan hydrochloride include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality.

5. CONIVAPTAN INDICATIONS: • CONIVAPTAN is indicated for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Important Limitation: • CONVAPTAN is not indicated for the treatment of congestive heart failure. • CONIVAPTAN should only be used for the treatment of hyponatremia in patients with underlying heart failure when the expected clinical benefit of raising serum sodium outweighs the increased risk of adverse events for heart failure patients.

6. CONIVAPTAN DOSAGE AND ADMINISTRATION: • CONIVAPTAN therapy should begin with a loading dose of 20 mg IV administered over 30 minutes. • The loading dose should be followed by 20 mg of CONIVAPTAN administered in a continuous intravenous infusion over 24 hours. • Following the initial day of treatment, CONIVAPATAN is to be administered for an additional 1 to 3 days in a continuous infusion of 20 mg/day.

7. CONIVAPTAN DOSAGE AND ADMINISTRATION (Cont.) • If serum sodium is not rising at the desired rate, CONIVAPTAN may be titrated upward to a dose of 40 mg daily, again administered in a continuous intravenous infusion. • The total duration of infusion of CONIVAPTAN (after the loading dose) should not exceed four days. • The maximum daily dose of CONIVAPTAN (after the loading dose) is 40 mg/day.

8. CONIVAPTAN CONTRAINDICATIONS: • CONIVAPTAN is contraindicated in patients with hypovolemic hyponatremia. • The coadministration of CONIVAPTAN with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated.

9. CONIVAPTAN SPECIAL PRECAUTIONS: • Congestive Heart Failure • Overly Rapid Correction of Serum Sodium • Hepatic Impairment • Renal Impairment • Injection Site Reactions

10. CONIVAPTAN DRUG INTERACTIONS: • Conivaptan is a substrate of CYP3A4. • Coadministration of CONIVAPTAN with CYP3A4 inhibitors could lead to an increase in conivaptan concentrations. • The consequences of increased conivaptan concentrations are unknown. • Concomitant use of CONIVAPTAN with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir is contraindicated.

11. CONIVAPTAN ADVERSE EFFECTS: • The most common adverse reactions reported with CONIVAPTAN administration were infusion site reactions. • Other common adverse reactions were headaches, hypokalemia, orthostatic hypotension and pyrexia.