Tolvaptan 30 mg Tablet, 10-count — NDC 49884-770-54 (Billing 49884-0770-54)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times greater than for the V 1a -receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations.

Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan.

12.2Pharmacodynamics In healthy subjects receiving a single dose of tolvaptan 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time.

Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration. Plasma concentrations of native AVP may increase (avg.

2 to 9 pg/mL) with tolvaptan administration. Cardiac Electrophysiology No prolongation of the QT interval was observed with tolvaptan following multiple doses of 300 mg/day for 5 days.

12.3Pharmacokinetics In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. In hyponatremia subjects, single and multiple doses up to 60 mg have been studied. Absorption In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose.

Peak concentrations increase less than dose proportionally with doses greater than 240 mg. The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42 to 80%).

Co-administration of 90 mg tolvaptan with a high-fat meal (~1000 calories, of which 50% are from fat) doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or without food. Distribution Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is >98%; binding is not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg.

The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. When administered as multiple once-daily 300 mg doses to healthy subjects or to patients with congestive heart failure or ADPKD, tolvaptan’s accumulation factor is <1.2. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.

Metabolism and Elimination Tolvaptan is metabolized almost exclusively by CYP3A. Fourteen metabolites have been identified in plasma, urine and feces; all but one were also metabolized by CYP3A and none are pharmacodynamically active. After oral administration of radiolabeled tolvaptan, tolvaptan was a minor component in plasma, representing 3% of total plasma radioactivity; the oxobutyric acid metabolite was present at 52.5% of total plasma radioactivity with all other metabolites present at lower concentrations than tolvaptan.

The oxobutyric acid metabolite shows a plasma half-life of ~180 h. About 4… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times greater than for the V 1a -receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations.

Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan.

12.3Pharmacokinetics In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. In hyponatremia subjects, single and multiple doses up to 60 mg have been studied. Absorption In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose.

Peak concentrations increase less than dose proportionally with doses greater than 240 mg. The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42 to 80%).

Co-administration of 90 mg tolvaptan with a high-fat meal (~1000 calories, of which 50% are from fat) doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or without food. Distribution Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is >98%; binding is not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg.

The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. When administered as multiple once-daily 300 mg doses to healthy subjects or to patients with congestive heart failure or ADPKD, tolvaptan’s accumulation factor is <1.2. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.

Metabolism and Elimination Tolvaptan is metabolized almost exclusively by CYP3A. Fourteen metabolites have been identified in plasma, urine and feces; all but one were also metabolized by CYP3A and none are pharmacodynamically active. After oral administration of radiolabeled tolvaptan, tolvaptan was a minor component in plasma, representing 3% of total plasma radioactivity; the oxobutyric acid metabolite was present at 52.5% of total plasma radioactivity with all other metabolites present at lower concentrations than tolvaptan.

The oxobutyric acid metabolite shows a plasma half-life of ~180 h. About 40% of radioactivity was recovered in urine (<1% as unchanged tolvaptan) and 59% in feces (19% as unchanged tolvaptan). Following intravenous infusion, tolvaptan half-life is approximately 3 hours.

Following single oral doses to healthy subjects, the estimated half-life of tolvaptan increases from 3 hours for a 15 mg dose to approximately 12 hours for 120 mg and higher doses due to more prolonged absorption of tolvaptan at higher doses; apparent clearance is approximately 4 mL/min/kg and does not appear to change with increasing dose. Specific Populations Hyponatremia In patients with hyponatremia of any origin the clearance of tolvaptan is reduced to about 2 mL/min/kg. Hepatic Impairment Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant.

Exposure and response to tolvaptan in subjects with creatinine clearance ranging between 79 and 10 mL/min and patients with normal renal function are not different. Renal Impairment In a study in patients with creatinine clearances ranging from 10 to 124 mL/min administered a single dose of 60 mg tolvaptan, AUC and C max of plasma tolvaptan were less than doubled in patients with severe renal impairment (creatinine clearance <30 mL/min) relative to the controls. The peak increase in serum sodium was 5 to 6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment [see Use in Specific Populations ( 8.7 ) ].

Drug Interaction Studies Impact of Other Drugs on Tolvaptan Strong CYP3A Inhibitors Ketoconazole: Tolvaptan’s C max and AUC were, respectively, 3.5 times and 5.4 times as high following ketoconazole 200 mg given one day prior to and concomitantly with 30 mg… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In healthy subjects receiving a single dose of tolvaptan 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time.

Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration. Plasma concentrations of native AVP may increase (avg.

2 to 9 pg/mL) with tolvaptan administration. Cardiac Electrophysiology No prolongation of the QT interval was observed with tolvaptan following multiple doses of 300 mg/day for 5 days.

14 CLINICAL STUDIES

14.1Hyponatremia In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone [SIADH] and others) were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal. Symptomatic patients, patients likely to require saline therapy during the course of therapy, patients with acute and transient hyponatremia associated with head trauma or postoperative state and patients with hyponatremia due to primary polydipsia, uncontrolled adrenal insufficiency or uncontrolled hypothyroidism were excluded.

Patients were randomized to receive either placebo (N = 220) or tolvaptan (N = 223) at an initial oral dose of 15 mg once daily. The mean serum sodium concentration at study entry was 129 mEq/L. Fluid restriction was to be avoided if possible during the first 24 hours of therapy to avoid overly rapid correction of serum sodium, and during the first 24 hours of therapy 87% of patients had no fluid restriction.

Thereafter, patients could resume or initiate fluid restriction (defined as daily fluid intake of ≤1.0 liter/day) as clinically indicated. The dose of tolvaptan could be increased at 24 hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) was reached. Serum sodium concentrations were determined at 8 hours after study drug initiation and daily up to 72 hours, within which time titration was typically completed.

Treatment was maintained for 30 days with additional serum sodium assessments on Days 11, 18, 25 and 30. On the day of study discontinuation, all patients resumed previous therapies for hyponatremia and were reevaluated 7 days later. The primary endpoint for these studies was the average daily AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium less than 135 mEq/L.

Compared to placebo, tolvaptan caused a statistically greater increase in serum sodium ( p <0.0001) during both periods in both studies (see Table 2). For patients with a serum sodium of <130 mEq/L or <125 mEq/L, the effects at Day 4 and Day 30 remained significant (see Table 2). This effect was also seen across all disease etiology subsets (e.g., CHF, cirrhosis, SIADH/other).

Table 2. Effects of Treatment with Tolvaptan 15 mg/day to 60 mg/day Tolvaptan 15 mg/day­ to 60 mg/day Placebo Estimated Effect (95% CI) Subjects with Serum Sodium <135 mEq/L (ITT population) Change in average daily serum [Na+] AUC baseline to Day 4 (mEq/L) Mean (SD) N 4.0 (2.8) 213 0.4 (2.4) 203 3.7 (3.3 to 4.2) p <0.0001 Change in average daily serum [Na+] AUC baseline to Day 30 (mEq/L) Mean (SD) N 6.2 (4.0) 213 1.8 (3.7) 203 4.6 (3.9 to 5.2) p <0.0001 Percent of Patients Needing Fluid Restriction* 14% 30/215 25% 51/206 p =0.0017 Subgroup with Serum Sodium <130 mEq/L Change in average daily serum [Na+] AUC baseline to Day 4 (mEq/L) Mean (SD) N 4.8 (3.0) 110 0.7 (2.5) 105 4.2 (3.5 to 5.0) p <0.0001 Change in average daily serum [Na+] AUC baseline to Day 30 (mEq/L) Mean (SD) N 7.9 (4.1) 110 2.6 (4.2) 105 5.5 (4.4 to 6.5) p <0.0001 Percent of Patients Needing Fluid Restriction* 19% 21/110 36% 38/106 p <0.01 Subgroup with Serum Sodium <125 mEq/L Change in average daily serum [Na+] AUC baseline to Day 4 (mEq/L) Mean (SD) N 5.7 (3.8) 26 1.0 (1.8) 30 5.3 (3.8 to 6.9) p <0.0001 Change in average daily serum [Na+] AUC baseline to Day 30 (mEq/L) Mean (SD) N 10.0 (4.8) 26 4.1 (4.5) 30 5.7 (3.1 to 8.3) p <0.0001 Percent of Patients Needing Fluid Restriction* 35% 9/26 50% 15/30 p = 0.14 * Fluid Restriction defined as <1L/day at any time during treatment period.

In patients with hyponatremia (defined as <135 mEq/L), serum sodium concentration increased to a signifi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of tolvaptan was assessed in 2-year carcinogenicity studies in mice and rats. Tolvaptan did not increase tumors in male or female rats at doses up to 1000 mg/kg/day (1.24 to 3.26 times the exposure in CHF patients based on AUC at the MRHD of 60 mg), in male mice at doses up to 60 mg/kg/day (0.3 times the exposure in CHF patients at the MRHD) and to female mice at doses up to 100 mg/kg/day (0.4 times the exposure in CHF patients at the MRHD).

Mutagenesis Tolvaptan was not clastogenic in the in vitro chromosomal aberration test in Chinese hamster lung fibroblast cells or the in vivo rat micronucleus assay and was not mutagenic in the in vitro bacterial reverse mutation assays. Impairment of fertility In a fertility study in which male and female rats were administered tolvaptan orally at 100, 300 or 1000 mg/kg/day, altered estrous cycles due to prolongation of diestrus were observed in dams given 300 and 1000 mg/kg/day (6.2 and 11 times the exposure in CHF patients at the 60 mg dose).

Tolvaptan had no effect on copulation or fertility indices. There were also no effects on the incidences of early or late resorption, dead fetuses, pre-or post-implantation loss, external anomalies, or fetal body weights.