Tolvaptan

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 )

DOSAGE AND ADMINISTRATION Recommended dosage ( 2.1 ) Initial Dosage Titration Step Target Dosage 1 st Dose 45 mg 1 st Dose 60 mg 1 st Dose 90 mg 2 nd Dose (8 hours later) 15 mg 2 nd Dose (8 hours later) 30 mg 2 nd Dose (8 hours later) 30 mg Total Daily Dose 60 mg Total Daily Dose 90 mg Total Daily Dose 120 mg Dose adjustment is recommended for patients taking moderate CYP 3A inhibitors ( 2.4 , 5.4 , 7.1 ) 2.1 Recommended Dosage The initial dosage for tolvaptan tablets is 60 mg orally per day as 45 mg taken on waking and 15 mg taken 8 hours later. Titrate to 60 mg plus 30 mg then to 90 mg plus 30 mg per day if tolerated with at least weekly intervals between titrations. Patients may down-titrate based on tolerability. Encourage patients to drink enough water to avoid thirst or dehydration. 2.2 Monitoring To mitigate the risk of significant or irreversible liver injury, perform blood testing for ALT, AST and bilirubin prior to initiation of tolvaptan tablets, at 2 and 4 weeks after initiation, monthly for 18 months and every 3 months thereafter. Monitor for concurrent symptoms that may indicate liver injury [see Warnings and Precautions ( 5.1 )] . 2.3 Missed Doses If a dose of tolvaptan tablets is not taken at the scheduled time, take the next dose at its scheduled time. 2.4 Co-Administration with CYP 3A Inhibitors CYP 3A Inhibitors Concomitant use of strong CYP 3A inhibitors is contraindicated [see Contraindications ( 4 ) and Warnings and Precautions ( 5.4 )] . In patients taking concomitant moderate CYP 3A inhibitors, reduce the dose of tolvaptan tablets per Table 1. Consider further reductions if patients cannot tolerate the reduced dose [see Warnings and Precautions ( 5.4 ) and Drug Interactions ( 7.1)]. Interrupt tolvaptan tablets temporarily for short term therapy with moderate CYP 3A inhibitors if the recommended reduced doses are not available. Table 1: Dose Adjustment for Patients taking Moderate CYP 3A Inhibitors Standard Morning and Afternoon Dose (mg) Dose (mg) with Moderate CYP 3A Inhibitors 90 mg and 30 mg 45 mg and 15 mg 60 mg and 30 mg 30 mg and 15 mg 45 mg and 15 mg 15 mg and 15 mg

WARNINGS AND PRECAUTIONS • Liver injury: Limit treatment duration to 30 days. If hepatic injury is suspected, discontinue tolvaptan tablets. Avoid use in patients with underlying liver disease ( 5.2 ) • Dehydration and hypovolemia may require intervention ( 5.3 ) • Avoid use with hypertonic saline ( 5.4 ) • Avoid use with moderate to strong CYP3A inhibitors ( 5.5 ) • Monitor serum potassium in patients with potassium >5 mEq/L or on drugs known to increase potassium ( 5.6 ) • Urinary outflow obstruction: Urinary output must be secured ( 5.7 ) 5.1 Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which tolvaptan was administered in titrated doses starting at 15 mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated subjects with a serum sodium <130 mEq/L had a rise greater than 8 mEq/L at 8 hours and no patient had a rise greater than 12 mEq/L/24 hours. Osmotic demyelination syndrome has been reported in association with tolvaptan tablets therapy [see Adverse Reactions ( 6.2 )] . Patients treated with tolvaptan tablets should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving tolvaptan tablets who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with tolvaptan tablets and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours of therapy with tolvaptan tablets may increase the likelihood of overly rapid correction of serum sodium and should generally be avoided. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium. 5.2 Liver Injury Tolvaptan can cause serious and potentially fatal liver injury. In placebo-controlled studies and an open-label extension study of chronically administered tolvaptan in patients with ADPKD, cases of serious liver injury attributed to tolvaptan, generally occurring during the first 18 months of therapy, were observed. In postmarketing experience with tolvaptan in ADPKD, acute injury resulting in liver failure requiring liver transplantation has been reported. Tolvaptan should not be used to treat ADPKD outside of the FDA-approved risk evaluation and mitigation strategy (REMS) for ADPKD patients [see Contraindications ( 4 )]. Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with tolvaptan tablets. Limit duration of therapy with tolvaptan tablets to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired [see Adverse Reactions ( 6.1 )]. 5.3 Dehydration and Hypovolemia Tolvaptan tablets therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients. In patients receiving tolvaptan tablets who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue tolvaptan tablets therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with tolvaptan tablets may increase the risk of dehydration and hypovolemia. Patients receiving tolvaptan tablets should continue ingestion of fluid in response to thirst. 5.4 Co-administration with Hypertonic Saline Concomitant use with hypertonic saline is not recommended. 5.5 Drug Interactions Tolvaptan is a substrate of CYP3A. Moderate to strong CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations [see Drug Interactions ( 7.1 )]. Do not use tolvaptan tablets with strong inhibitors of CYP3A [see Contraindications ( 4 )] and avoid concomitant use with moderate CYP3A inhibitors. 5.6 Hyperkalemia or Drugs that Increase Serum Potassium Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increase serum potassium levels. 5.7 Acute Urinary Retention with Outflow Obstruction Patients with partial obstruction of urinary outflow, for example, patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention. Do not administer tolvaptan in patients with uncorrected urinary outflow obstruction.

CONTRAINDICATIONS Tolvaptan tablets are contraindicated in patients: With a history, signs or symptoms of significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver disease [see Warnings and Precautions ( 5.1 )] Taking strong CYP 3A inhibitors With uncorrected abnormal blood sodium concentrations [see Warnings and Precautions ( 5.3 )] Unable to sense or respond to thirst [see Warnings and Precautions ( 5.3 )] Hypovolemia [see Warnings and Precautions ( 5.3 )] Hypersensitivity (e.g., anaphylaxis, rash) to tolvaptan or any component of the product [see Adverse Reactions ( 6 )] Uncorrected urinary outflow obstruction Anuria History of signs or symptoms of significant liver impairment or injury, does not include uncomplicated polycystic liver disease ( 4 ) Concomitant use of strong CYP 3A inhibitors is contraindicated ( 4 ) Uncorrected abnormal blood sodium concentrations ( 4 , 5.3 ) Unable to sense or respond to thirst ( 4 ) Hypovolemia ( 4 ) Hypersensitivity to tolvaptan or any of its components ( 4 ) Uncorrected urinary outflow obstruction ( 4 ) Anuria ( 4 )

DRUG INTERACTIONS Avoid concomitant use with: • Moderate CYP3A inhibitors ( 7.1 ) • Strong CYP3A inducers ( 7.1 ) • V 2 -receptor antagonists ( 7.3 ) Monitor serum potassium during concomitant therapy with ( 7.2 ): • Angiotensin receptor blockers • Angiotensin converting enzyme inhibitors • Potassium sparing diuretics 7.1 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 [see Warnings and Precautions ( 5.5 ) and Clinical Pharmacology ( 12.3 )] . 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 [see Contraindications ( 4 )] . 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 [see Warnings and Precautions ( 5.5 )]. Patients should avoid grapefruit juice beverages while taking tolvaptan [see Clinical Pharmacology ( 12.3 )] . Strong CYP3A Inducers Co-administration of tolvaptan with strong CYP3A inducers reduces exposure to tolvaptan [see Clinical Pharmacology ( 12.3 )] . Avoid concomitant use of tolvaptan with strong CYP3A inducers. 7.2 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. 7.3 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.

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 Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 ( 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 tablets. 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. 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 (13) 9 (4) Constipation 16 (7) 4 (2) General 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 tablets 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 tablets. 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.

Mechanism 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 that for the V 1a - receptor. Decreased binding of vasopressin to the V 2 -receptor in the kidney lowers adenylate cyclase activity resulting in a decrease in intracellular adenosine 3′, 5′-cyclic monophosphate (cAMP) concentrations. Decreased cAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance (aquaresis) and a decrease in urine osmolality. In human ADPKD cyst epithelial cells, tolvaptan inhibited AVP- stimulated in vitro cyst growth and chloride-dependent fluid secretion into cysts. In animal models, decreased cAMP concentrations were associated with decreases in the rate of growth of total kidney volume and the rate of formation and enlargement of kidney cysts. Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan.