Tolvaptan Drug Information

Recommended Dosage Patients should be in a hospital for initiation and re-initiation

of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. The usual starting dose for tolvaptan tablets is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium.

Do not administer tolvaptan tablets for more than 30 days to minimize the risk of liver injury. During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy.

Patients receiving tolvaptan tablets should be advised that they can continue ingestion of fluid in response to thirst.

Drug Withdrawal Following discontinuation from tolvaptan tablets, patients should be advised to

resume fluid restriction and should be monitored for changes in serum sodium and volume status.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium <135 mEq/L) were treated with tolvaptan.

The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty nine tolvaptan-treated patients had a serum sodium <130 mEq/L, and 52 patients had a serum sodium <125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium). Overall, over 4,000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for 6 months or more.

The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30-day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of >1% in tolvaptan-treated patients. Table 1 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia (serum sodium <135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30-day, double-blind, placebo-controlled trials.

In these studies, 223 patients were exposed to tolvaptan (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in tolvaptan-treated-patients and 6% in placebo-treated patients. Table 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term Tolvaptan 15 mg/day to 60 mg/day (N = 223) n (%) Placebo (N = 220) n (%) Gastrointestinal Disorders Dry mouth 28 9 Constipation 16 4 General Disorders and Administration Site Conditions Thirst a 35 11 Asthenia 19 9 Pyrexia 9 2 Metabolism and Nutrition Disorders Hyperglycemia b 14 2 Anorexia c 8 2 Renal and Urinary Disorders Pollakiuria or polyuria d 25 7 The following terms are subsumed under the referenced ADR in Table 1: a polydipsia; b diabetes mellitus; c decreased appetite; d urine output increased, micturition urgency, nocturia In a subgroup of patients with hyponatremia (N = 475, serum sodium <135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in tolvaptan-treated patients at a rate at least 2% greater than placebo: mortality (42% tolvaptan, 38% placebo), nausea (21% tolvaptan, 16% placebo), thirst (12% tolvaptan, 2% placebo), dry mouth (7% tolvaptan, 2% placebo) and polyuria or pollakiuria (4% tolvaptan, 1% placebo). Gastrointestinal bleeding in patients with cirrhosis In patients with cirrhosis treated with tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients. The following adverse reactions occurred in <2% of hyponatremic patients treated with tolvaptan and at a rate greater than placebo in double-blind placebo-controlled trials (N = 607 tolvaptan; N = 518 placebo) or in <2% of patients in an uncontrolled trial of patients with hyponatremia (N = 111) and are not mentioned elsewhere in the label.

Blood and Lymphatic System Disorders: Disseminated intravascular coagulation Cardiac Disorders: Intracardiac thrombus, ventricular fibrillation Investigations: Prothrombin time prolonged Gastrointestinal Disorders: Ischemic colitis Metabolism and Nutrition Disorders: Diabetic ketoacidosis Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis Nervous System: Cerebrovascular accident Renal and Urinary Disorders: Urethral hemorrhage Reproductive System and Breast Disorders (female): Vaginal hemorrhage Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure Vascular disorder: Deep vein thrombosis

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tolvaptan. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neurologic: Osmotic demyelination syndrome Investigations: Hypernatremia Removal of excess free body water increases serum osmolality and serum sodium concentrations.

All patients treated with tolvaptan, especially those whose serum sodium levels become normal, should continue to be monitored to ensure serum sodium remains within normal limits. If hypernatremia is observed, management may include dose decreases or interruption of tolvaptan treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremic patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving tolvaptan vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving tolvaptan vs. 0.8% in patients receiving placebo.

Immune System Disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized.

CYP3A Inhibitors and Inducers Strong

CYP3A Inhibitors Tolvaptan’s AUC was 5.4 times as large and C max was 3.5 times as large after co-administration of tolvaptan and 200 mg ketoconazole. Larger doses of the strong CYP3A inhibitor would be expected to produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP3A inhibitors is contraindicated.

Moderate CYP3A Inhibitors A substantial increase in the exposure to tolvaptan would be expected when tolvaptan is co-administered with moderate CYP3A inhibitors. Avoid co-administration of tolvaptan with moderate CYP3A inhibitors . Patients should avoid grapefruit juice beverages while taking tolvaptan. Strong CYP3A Inducers Co-administration of tolvaptan with strong CYP3A inducers reduces exposure to tolvaptan.

Avoid concomitant use of tolvaptan with strong CYP3A inducers.

Angiotensin Receptor Blockers, Angiotensin Converting Enzyme Inhibitors and Potassium Sparing Diuretics

Although specific interaction studies were not performed, in clinical studies tolvaptan was used concomitantly with beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1 to 2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.

V 2 -Receptor Agonist As a V 2 -receptor antagonist, tolvaptan may

interfere with the V 2 -agonist activity of desmopressin (dDAVP). Avoid concomitant use of tolvaptan with a V 2 -agonist.

Pregnancy Risk Summary Available data with tolvaptan use in pregnant women are insufficient to determine if there is a drug-associated risk of adverse developmental outcomes. Tolvaptan did not cause any developmental toxicity in rats or in rabbits at exposures approximately 2.8 and 0.8 times, respectively, the exposure in congestive heart failure (CHF) patients at the maximum recommended human dose (MRHD) of 60 mg once daily. However, effects on embryo-fetal development occurred in both species at doses causing significant maternally toxic doses.

In rats, reduced fetal weights and delayed fetal ossification occurred at 11 times the exposure in CHF patients, based on AUC. In rabbits, increased abortions, embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at approximately 1.6 times the exposure in CHF patients (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

Data Animal Data Oral administration of tolvaptan during the period of organogenesis in Sprague-Dawley rats produced no evidence of teratogenesis at doses up to 100 mg/kg/day. Delayed ossification was seen at 1000 mg/kg, which is approximately 11 times the exposure in CHF patients at the MRHD of 60 mg (AUC 24h 10271 ng*h/mL). The fetal effects are likely secondary to maternal toxicity (decreased food intake and low body weights). In a prenatal and postnatal study in rats, tolvaptan had no effect on physical development, reflex function, learning ability or reproductive performance at doses up to 1000 mg/kg/day (11 times the exposure in CHF patients at the MRHD of 60 mg). In rabbits, teratogenicity (microphthalmia, embryo-fetal mortality, cleft palate, brachymelia and skeletal malformations) was observed in rabbits at 1000 mg/kg (approximately 1.6 times the exposure in CHF patients at the MRHD of 60 mg dose). This dose also caused maternal toxicity (lower body weight gains and food consumption).

Pediatric Use Safety and effectiveness of tolvaptan in pediatric patients have not been established.

Tolvaptan tablets are contraindicated in the following conditions: Patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS Unable to sense or respond to thirst Hypovolemic hyponatremia Taking strong CYP3A inhibitors Anuria Hypersensitivity (e.g., anaphylactic shock, rash generalized) to tolvaptan or any components of the product Use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA approved REMS Patients who are unable to respond appropriately to thirst Hypovolemic hyponatremia Concomitant use of strong CYP 3A inhibitors Anuria Hypersensitivity

Single oral doses up to 480 mg (8 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in studies in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.

No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia. In patients with suspected tolvaptan overdosage, assessment of vital signs, electrolyte concentrations, ECG and fluid status are recommended. Continue replacement of water and electrolytes until aquaresis abates.

Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>98%).