TOLVAPTAN

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 72205-130

Application: ANDA216949

Effective: 20230614

1 INDICATIONS AND USAGE Tolvaptan tablets are indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Limitations of Use Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with tolvaptan tablets. It has not been established that raising serum sodium with tolvaptan tablets provides a symptomatic benefit to patients. Tolvaptan tablets are a selective vasopressin V 2 -receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia [serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction], including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) ( 1 ) Limitations of Use: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with tolvaptan tablets ( 1 ) It has not been established that tolvaptan tablets provides a symptomatic benefit to patients ( 1 )

2 DOSAGE AND ADMINISTRATION Tolvaptan tablets should be initiated and re-initiated in a hospital ( 2.1 ) The recommended starting dose is 15 mg once daily. Dosage may be increased at intervals ≥24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium. ( 2.1 ) 2.1 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 [ see Warnings and Precautions (5.2) ]. 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 [ see Warnings and Precautions (5.1) ]. 2.2 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.

4 CONTRAINDICATIONS Tolvaptan tablets are contraindicated in the following conditions: • Patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS [see Warnings and Precautions (5.2) ] • Unable to sense or respond to thirst • Hypovolemic hyponatremia • Taking strong CYP3A inhibitors [see Warnings and Precautions (5.5) ] • Anuria • Hypersensitivity (e.g., anaphylactic shock, rash generalized) to tolvaptan or any components of the product [see Adverse Reactions (6) ] Use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS ( 4 ) Patients who are unable to respond appropriately to thirst ( 4 ) Hypovolemic hyponatremia ( 4 ) Concomitant use of strong CYP3A inhibitors ( 4 ) Anuria ( 4 ) Hypersensitivity ( 4 )

Not available.

6 ADVERSE REACTIONS Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 (189) 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. 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 (13) 9 (4) Constipation 16 (7) 4 (2) Ge neral Disorders and Administration Site Conditions Thirst * 35 (16) 11 (5) Asthenia 19 (9) 9 (4) Pyrexia 9 (4) 2 (1) Metabolism and Nutrition Disorders Hyperglycemia † 14 (6) 2 (1) Anorexia ‡ 8 (4) 2 (1) Renal and Urinary Disorders Pollakiuria or polyuria § 25 (11) 7 (3) The following terms are subsumed under the referenced ADR in Table 1: * polydipsia, † diabetes mellitus, ‡ decreased appetite, § 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 6.2 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.