TOLVAPTAN Drug Interactions: What You Need to Know

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.

7 DRUG INTERACTIONS Avoid concomitant use with: Moderate CYP3A inhibitors (7.1) Strong CYP3A inducers (7.1) V2-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 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 ) and Clinical Pharmacology ( 12.3 ) ]</span>. 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. Moderate CYP3A Inhibitors A substantial increase in the exposure to tolvaptan would be expected when tolvaptan tablets are co-administered with moderate CYP3A inhibitors. Avoid co-administration of tolvaptan tablets with moderate CYP3A inhibitors <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span>. Patients should avoid grapefruit juice beverages while taking tolvaptan tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Strong CYP3A Inducers Co-administration of tolvaptan tablets with strong CYP3A inducers reduces exposure to tolvaptan tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Avoid concomitant use of tolvaptan tablets 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 tablets with a V 2 -agonist.

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 )

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., &gt;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 &lt;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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>. Do not use tolvaptan tablets with strong inhibitors of CYP3A <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> 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 &gt;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.