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boxed warning
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) See full prescribing information for complete boxed warning. (A) Initiate and re-initiate in a hospital and monitor serum sodium SAMSCA 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 (4) (A) Initiate and re-initiate in a hospital and monitor serum sodium SAMSCA 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) ].
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Liver injury: Limit treatment duration to 30 days. If hepatic injury is suspected, discontinue SAMSCA. 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
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adverse reactions
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 Otsuka at 1-877-726-7220 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
adverse reactions table
Table 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia TrialsSystem Organ Class MedDRA Preferred TermTolvaptan 15 mg/day to 60 mg/day (N =223) n (%)Placebo (N =220) n (%)The following terms are subsumed under the referenced ADR in Table 1:Gastrointestinal DisordersDry mouth28 (13)9 (4)Constipation16 (7)4 (2)General Disorders and Administration Site ConditionsThirstpolydipsia,35 (16)11 (5)Asthenia19 (9)9 (4)Pyrexia9 (4)2 (1)Metabolism and Nutrition DisordersHyperglycemiadiabetes mellitus,14 (6)2 (1)Anorexiadecreased appetite,8 (4)2 (1)Renal and Urinary DisordersPollakiuria or polyuriaurine output increased, micturition urgency, nocturia25 (11)7 (3)