Tolvaptan

TOLVAPTAN — tolvaptan tablet
Camber Pharmaceuticals, Inc.

WARNING: (A) INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM (B) NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

WARNING: (A) INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM
(B) NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)
(A) Initiate and re-initiate in a hospital and monitor serum sodium Tolvaptan tablets should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. (B) Not for use for autosomal dominant polycystic kidney disease (ADPKD) Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS [see Contraindications ( 4)] .

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 provide a symptomatic benefit to patients.

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

Tolvaptan tablets are available in the following dosage forms and strengths:

  • 15 mg tablets are white to off white colored, triangular, bevel edged, biconvex tablets debossed with ‘H’ on one side and ‘T9’ on the other side.
  • 30 mg tablets are blue, round, bevel edged, biconvex tablets debossed with ‘H’ on one side and ‘T10’ on the other side.

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)]

5 WARNINGS AND PRECAUTIONS

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.

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