Vaprisol Prescribing Information

Drug Detail:Vaprisol (Conivaptan [ koe-nye-vap-tan ])

Vaprisol Description

VAPRISOL® (conivaptan hydrochloride injection) is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V1A and V2 receptors.

Conivaptan hydrochloride is chemically [1,1'-biphenyl]-2-carboxamide, N-[4-[(4,5-dihydro-2-methylimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl]-, monohydrochloride, having a molecular weight of 535.04 and molecular formula C32H26N4O2 .HCl. The structural formula of conivaptan hydrochloride is:

Conivaptan hydrochloride is a white to off-white or pale orange-white powder that is very slightly soluble in water (0.15 mg/mL at 23°C). Conivaptan hydrochloride injection is supplied as a sterile liquid in an ampule and as a sterile premixed solution with dextrose in a flexible plastic container.

VAPRISOL (conivaptan hydrochloride injection) Ampule

Each ampule will deliver 20 mg conivaptan hydrochloride, 1.2 g propylene glycol, 0.4 g ethanol and Water for Injection, q.s. Lactic acid is added for pH adjustment to 3.0.

VAPRISOL (conivaptan hydrochloride injection) Premixed in 5% Dextrose

Each container contains a clear, colorless, sterile, non-pyrogenic solution of conivaptan hydrochloride in dextrose. Each 100 mL, single-use premixed INTRAVIA Container contains 20 mg of conivaptan hydrochloride and 5 g of Dextrose Hydrous, USP. Lactic Acid, USP is added for pH adjustment to pH 3.4 to 3.8. The flexible plastic container is fabricated from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain of the chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The flexible container has a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the premixed solution.

Vaprisol - Clinical Pharmacology

Pharmacodynamics

Conivaptan hydrochloride is a dual 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. 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. Studies in animal models of hyponatremia showed that conivaptan hydrochloride prevented the occurrence of hyponatremia-related physical signs in rats with the syndrome of inappropriate antidiuretic hormone secretion.

Pharmacokinetics

The pharmacokinetics of conivaptan have been characterized in healthy subjects, special populations and patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan following intravenous infusion (40 mg/day to 80 mg/day) and oral administration are non-linear, and inhibition by conivaptan of its own metabolism seems to be the major factor for the non-linearity. The intersubject variability of conivaptan pharmacokinetics is high (94% CV in CL).

The pharmacokinetics of conivaptan and its metabolites were characterized in healthy male subjects administered conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 40 mg/day for 3 days. Mean Cmax for conivaptan was 619 ng/mL and occurred at the end of the loading dose. Plasma concentrations reached a minimum at approximately 12 hours after start of the loading dose, then gradually increased over the duration of the infusion to a mean concentration of 188 ng/mL at the end of the infusion. The mean terminal elimination half-life after conivaptan infusion was 5.0 hours, and the mean clearance was 15.2 L/h.

In an open-label safety and efficacy study, the pharmacokinetics of conivaptan were characterized in hypervolemic or euvolemic hyponatremia patients (ages 20-92 years) receiving conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 20 or 40 mg/day for 4 days. The median-plasma conivaptan concentrations are shown in Figure 1 and pharmacokinetic parameters are summarized in Table 1.

Figure 1. Median Plasma Concentration-Time Profiles From Rich PK Sampling After 20 mg Loading Dose and 20 mg/day (open circle) or 40 mg/day (closed circle) Infusion for 4 Days

Table 1. Pharmacokinetic Parameters After 20 mg Loading Dose for 30 Minutes and 20 mg/day or 40 mg/day Infusion for 4 Days
* number from the rich and the sparse PK sampling † number from the rich PK sampling
Parameter	IV Conivaptan 20 mg/day	IV Conivaptan 40 mg/day
Conivaptan concentration at the end of loading dose (ng/mL, at 0.5 hours) N* Median (range)	31 659.4 (144.5-1587.6)	170 679.5 (0.0-1910.8)
Conivaptan concentration at the end of infusion (ng/mL, at 96 hours) N* Median (range)	30 117.6 (4.9-938.3)	172 215.7 (2.1-1999.3)
Elimination half-life (hr) N† Median (range)	8 5.3 (3.3-9.3)	8 8.1 (4.1-22.5)
Clearance (L/hr) N† Median (range)	8 16.1 (7.2-37.6)	8 8.73 (2.1-20.9)

Distribution

Conivaptan is extensively bound to human plasma proteins, being 99% bound over the concentration range of approximately 10 to 1000 ng/mL.

Metabolism and Excretion

CYP3A4 was identified as the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V1A and V2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. The combined exposure of the metabolites following intravenous administration of conivaptan is approximately 7% that of conivaptan and hence, their contribution to the clinical effect of conivaptan is minimal.

After intravenous (10 mg) or oral (20 mg) administration of conivaptan hydrochloride in a mass balance study, approximately 83% of the dose was excreted in feces as total radioactivity and 12% in urine over several days of collection. Over the first 24 hours after dosing, approximately 1% of the intravenous dose was excreted in urine as intact conivaptan.

Special Populations

Hepatic Impairment

The effect of hepatic impairment (including ascites, cirrhosis, or portal hypertension) on the elimination of conivaptan after intravenous administration has not been systematically evaluated. However, increased systemic exposures after administration of oral conivaptan (up to a mean 2.8-fold increase) have been seen in patients with stable cirrhosis and moderate hepatic impairment. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without hepatic function impairment. Caution should be exercised when administering VAPRISOL to patients with impaired hepatic function.

Renal Impairment

The effect of renal impairment on the elimination of conivaptan after intravenous administration has not been evaluated. However, following administration of oral conivaptan, the AUC for conivaptan was up to 80% higher in patients with renal impairment (CLcr < 60 mL/min/1.73 m2) as compared to those with normal renal function. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without renal function impairment. Caution should be exercised when administering VAPRISOL to patients with impaired renal function.

Geriatric Patients

Following a single oral dose of conivaptan hydrochloride (15, 30 or 60 mg), drug exposure (AUC) in elderly male and female volunteers (65 to 90 years of age) compared to that seen in young male subjects was similar for the 15 and 30 mg doses but increased nearly 2-fold at the 60 mg dose.

In an open label study to assess the safety and efficacy of conivaptan, a subset of geriatric hypervolemic or euvolemic hyponatremia patients (65 to 92 years of age) received a 20 mg intravenous loading dose followed by a 20 mg/day (N = 27) or 40 mg/day (N = 135) intravenous infusion for 4 days. The median conivaptan plasma concentration in these patients at the end of the loading dose infusion was 654 ng/mL. The median conivaptan plasma concentrations at the end of the 4-day continuous infusion were 118 and 215 ng/mL for the 20 mg/day and 40 mg/day regimens, respectively.

Pediatric Patients

The pharmacokinetics of conivaptan in pediatric patients have not been studied.

Drug-Drug Interactions

(See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions)

CYP3A4

Conivaptan is a sensitive substrate of CYP3A4. The effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of intravenous conivaptan has not been evaluated. Coadministration of oral conivaptan hydrochloride 10 mg with ketoconazole 200 mg resulted in 4- and 11-fold increases in Cmax and AUC of conivaptan, respectively.

Conivaptan is a potent inhibitor of CYP3A4. The effect of conivaptan on the pharmacokinetics of CYP3A4 substrates has been evaluated with the coadministration of conivaptan with midazolam, simvastatin, and amlodipine. Intravenous conivaptan hydrochloride 40 mg/day increased the mean AUC values by approximately 2- and 3-fold for 1 mg intravenous or 2 mg oral doses of midazolam, respectively. Intravenous conivaptan hydrochloride 30 mg/day resulted in a 3-fold increase in the AUC of simvastatin. Oral conivaptan hydrochloride 40 mg twice daily resulted in a 2-fold increase in the AUC and half-life of amlodipine.

Digoxin

Coadministration of a 0.5-mg dose of digoxin, a P-glycoprotein substrate, with oral conivaptan hydrochloride 40 mg twice daily resulted in a 30% reduction in clearance and 79% and 43% increases in digoxin Cmax and AUC values, respectively.

Warfarin

The effect of intravenous conivaptan on warfarin pharmacokinetics or pharmacodynamics has not been evaluated. The potential drug-drug interaction of oral conivaptan with warfarin, which undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A4, was investigated in a clinical study.

The effects of oral conivaptan hydrochloride 40 mg twice daily on prothrombin time was assessed in patients receiving stable oral warfarin therapy. After 10 days of oral conivaptan administration, the S- and R-warfarin concentrations were 90% and 98%, respectively, of those prior to conivaptan administration. The corresponding prothrombin time values after 10 days of oral conivaptan administration were 95% of baseline. No effect of oral conivaptan on the pharmacokinetics or pharmacodynamics of warfarin was observed.

Captopril and Furosemide

The effects of captopril (25 mg) on the pharmacokinetics of conivaptan hydrochloride (30 mg) and furosemide (40 mg or 80 mg once daily for 6 days) on the pharmacokinetics of conivaptan hydrochloride (20 mg and 40 mg) were assessed in separate studies. The pharmacokinetics of conivaptan were unchanged with coadministration of either captopril or furosemide.

Electrophysiology

The effect of VAPRISOL 40 mg IV and 80 mg IV on the QT interval was evaluated after the first dose (Day 1) and at the last day during treatment (Day 4) in a randomized, single-blind, parallel group, placebo- and positive-controlled (moxifloxacin 400 mg IV) study in healthy male and female volunteers aged 18 to 45 years. Digital ECGs were obtained at baseline and on Days 1 and 4. The placebo-corrected changes from baseline in individualized QT correction (QTcI) in the VAPRISOL 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec, respectively, on Day 1, and -2.1 msec for both dose groups on Day 4. Similar results were obtained using either the Bazett's or Fridericia's correction methods. Moxifloxacin elicited placebo-corrected changes from baseline in QTcI of +7 to +10 msec on Days 1 and 4, respectively.

Table 2. Individualized QT Correction (QTcI) Mean Change from Baseline at Day 4
Drug and Dose	QTcI
Placebo	-3 msec
Vaprisol 40 mg IV	-5.1 msec
Vaprisol 80 mg IV	-5.1 msec
Moxifloxacin 400 mg IV	+7.4 msec

The results of the central tendency analysis of QTc indicate that VAPRISOL had no effect on cardiac repolarization.

Clinical Studies

In a double-blind, placebo-controlled, randomized, multicenter study, 84 patients with euvolemic or hypervolemic hyponatremia (serum sodium 115-130 mEq/L) due to a variety of underlying causes (malignant or nonmalignant diseases of the central nervous system, lung, or abdomen; congestive heart failure [CHF]; hypertension; myocardial infarction; diabetes; osteoarthritis; or idiopathic) were treated for 4 days with VAPRISOL or placebo. All patients received standard care for hyponatremia, primarily fluid restriction (daily fluid intake restricted to less than or equal to 2.0 liters). Study participants were randomized to receive either placebo IV (N = 29), or VAPRISOL 40 mg/day IV (N = 29), or VAPRISOL 80 mg/day IV (N = 26). VAPRISOL was administered as a continuous infusion following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day. Serum or plasma sodium concentrations were assessed at predose (Hour 0) and at 4, 6, 10, and 24 hours post dose on all treatment days. Mean serum sodium concentration was 123.3 mEq/L at study entry.

The mean change in serum sodium concentration from baseline over the 4-day treatment period is shown in Figure 2.

Figure 2. Mean (SE) Change from Baseline in Sodium Concentrations with VAPRISOL 40 mg/day

Following treatment with 40 mg/day of intravenous VAPRISOL, 79% of patients achieved an increase of ≥ 4 mEq/L in serum sodium concentration. The mean change from baseline in serum sodium concentration at the end of 2 days of treatment with VAPRISOL was 5.3 mEq/L (mean concentration 128.6 mEq/L). At the end of the 4-day treatment period, the mean change from baseline was 6.5 mEq/L (mean concentration 129.8 mEq/L). In addition, after 2 days and 4 days of treatment with VAPRISOL, 41% (after 2 days) and 69% (after 4 days) of patients achieved a ≥ 6 mEq/L increase in serum sodium concentration or a normal serum sodium of ≥ 135 mEq/L. Although 80 mg/day was also studied, it was not significantly more effective than 40 mg/day. The maximum daily dose of VAPRISOL (after the loading dose) is 40 mg/day. Additional efficacy data are summarized in Table 3.

Table 3. Efficacy Outcomes of Treatment with VAPRISOL 40 mg/day
* efficacy variables were assessed on Day 2 of a 4-day treatment period † P ≤ 0.001 vs placebo
Efficacy Variable	Placebo N = 29		VAPRISOL 40 mg/day N = 29
	Day 2*	Day 4	Day 2*	Day 4
Baseline adjusted serum Na+ AUC over duration of treatment (mEq·hr/L) Mean (SD) LS Mean ± SE	6.2 (81.8) 3.8 ± 26.9	61.4 (242.3) 12.9 ± 61.2	205.9 (171.6) 205.6 ± 26.6†	500.8 (365.5) 490.9 ± 56.8†
Number of patients (%) and median event time (h) from first dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum Na+, [95% CI]	2 (7%) Not estimable Not estimable	9 (31%) Not estimable Not estimable	22 (76%) 23.7† [10, 2]	23 (79%) 23.7† [10, 2]

Total time (h) from first dose of study medication to Day 2 or Day 4 end of treatment during which patients had a confirmed ≥ 4 mEq/L increase in serum Na+ from Baseline Mean (SD) LS Mean ± SE	2.2 (5.9) 2.1 ± 2.3	13.7 (20.5) 14.2 ± 5.3	22.3 (16.0) 22.3 ± 2.3†	53.4 (34.3) 53.2 ± 5.2†

Serum Na+ (mEq/L) Baseline mean (SD) Mean (SD) at end of treatment Change from Baseline to end of treatment Mean change (SD) LS Mean change ± SE	124.3 (4.1) 124.5 (4.7) 0.2 (2.5) 0.1 ± 0.7	124.3 (4.1) 125.8 (4.9) 1.5 (4.6) 0.8 ± 0.8	123.3 (4.7) 128.6 (5.9) 5.3 (4.4) 5.2 ± 0.7†	123.3 (4.7) 129.8 (4.8) 6.5 (4.4) 6.3 ± 0.7†

Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase from Baseline in serum Na+ or a normal serum Na+ concentration ≥ 135 mEq/L during treatment	0 (0)	6 (21%)	12 (41%)†	20 (69%)†

The aquaretic effect of VAPRISOL is shown in Figure 3. VAPRISOL produced a baseline-corrected cumulative increase in effective water clearance of over 3800 mL compared to approximately 1300 mL with placebo by Day 4.

Figure 3. Baseline-Corrected Cumulative Effective Water Clearance (EWC)

, where V is urine volume (mL/d), UNa is urine sodium concentration, UK is urine potassium concentration, PNa is plasma/serum sodium concentration, and PK is plasma/serum potassium concentration.

In an open-label study in patients with euvolemic or hypervolemic hyponatremia, 251 patients were treated for 4 days with VAPRISOL 20 or 40 mg/day IV as a continuous infusion following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day. The results are shown in Table 4.

Table 4. Efficacy Outcomes of Treatment with VAPRISOL 20 or 40 mg/day
Primary Efficacy Endpoint	20 mg/day N = 37	40 mg/day N = 214
Baseline adjusted serum Na+ AUC over duration of treatment (mEq·hr/L) Mean (SD)	753.8 (429.9)	689.2 (417.3)

Secondary Efficacy Endpoints
Number of patients (%) and median event time (h) from first dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum Na+, [95% CI]	29 (78%) 23.8 [12.0, 36.0]	178 (83%) 24.0 [24.0, 35.8]

Total time (h) from first dose of study medication to end of treatment during which patients had a confirmed ≥ 4 mEq/L increase in serum Na+ from Baseline Mean (SD)	60.6 (35.2)	59.5 (33.2)

Serum Na+ (mEq/L) Baseline mean (SD) Mean (SD) at end of treatment Mean Change (SD) from Baseline to End of Treatment Mean (SD) at Follow-up Day 11 Mean Change (SD) from Baseline to Follow-up Day 11 Mean (SD) at Follow-up Day 34 Mean Change (SD) from Baseline to Follow-up Day 34	122.5 (5.2) 131.8 (3.9) 9.4 (5.3) 129.9 (6.2) 7.1 (8.2) 134.3 (4.5) 11.5 (7.3)	123.8 (4.6) 132.5 (4.6) 8.8 (5.4) 131.8 (5.8) 8.0 (6.5) 134.3 (5.2) 10.7 (6.7)

Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase from Baseline in serum Na+ or a normal serum Na+ concentration ≥ 135 mEq/L during treatment	26 (70%)	154 (72%)

The effectiveness of VAPRISOL for the treatment of congestive heart failure has not been established.

Indications and Usage for Vaprisol

VAPRISOL is indicated for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients.

Important Limitation:

VAPRISOL is not indicated for the treatment of congestive heart failure. VAPRISOL 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. (See PRECAUTIONS and ADVERSE REACTIONS)

Contraindications

VAPRISOL is contraindicated in patients with hypovolemic hyponatremia.

The coadministration of VAPRISOL with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. (See PRECAUTIONS: Drug Interactions for details and other important considerations)

VAPRISOL (conivaptan hydrochloride injection) Premixed in 5% Dextrose

Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

Precautions

Congestive Heart Failure

The number of heart failure patients with hypervolemic hyponatremia who have been treated with intravenous VAPRISOL is too small to establish safety in patients with underlying congestive heart failure. (See ADVERSE REACTIONS)

Overly Rapid Correction of Serum Sodium

An overly rapid increase in serum sodium concentration (>12 mEq/L/24 hours) may result in serious sequelae. In controlled clinical trials of VAPRISOL, about 9% of patients who received VAPRISOL in doses of 20-40 mg/day IV met laboratory criteria for overly rapid correction of serum sodium, but none of these patients had permanent neurologic sequelae. Although not observed in the clinical studies with VAPRISOL, osmotic demyelination syndrome has been reported following rapid correction of low serum sodium concentrations. Serum sodium concentration and neurologic status should be monitored appropriately during VAPRISOL administration, and VAPRISOL administration should be discontinued if the patient develops an undesirably rapid rate of rise of serum sodium. If the serum sodium concentration continues to rise, VAPRISOL should not be resumed. If hyponatremia persists or recurs (after initial discontinuation of VAPRISOL for an undesirably rapid rate of rise of serum sodium concentration), and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, VAPRISOL may be resumed at a reduced dose.