tolvaptan 30 MG Oral Tablet

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 )

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.