WARNING: RISK OF SERIOUS LIVER INJURY Tolvaptan tablets can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported [see Warnings and Precautions ( 5.1 ) ] . Measure ALT, AST and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for the first 18 months and every 3 months thereafter [see Warnings and Precautions ( 5.1 ) ] . Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity. Because of the risks of serious liver injury, tolvaptan tablets are available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Tolvaptan for ADPKD Shared System REMS [see Warnings and Precautions ( 5.2 ) ] . WARNING: RISK OF SERIOUS LIVER INJURY See full prescribing information for complete boxed warning . Tolvaptan tablets can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported ( 5.1 ) Measure transaminases and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then continuing monthly for the first 18 months and every 3 months thereafter ( 5.1 ) Tolvaptan tablets are available only through a restricted distribution program called the Tolvaptan for ADPKD Shared System REMS ( 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypernatremia, dehydration and hypovolemia: May require intervention ( 5.3 ) 5.1 Serious Liver Injury Tolvaptan tablets can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported in the post-marketing ADPKD experience. Discontinuation in response to laboratory abnormalities or signs or symptoms of liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) can reduce the risk of severe hepatotoxicity. In a 3-year placebo-controlled trial and its open-label extension (in which patients' liver tests were monitored every 4 months), evidence of serious hepatocellular injury (elevations of hepatic transaminases of at least 3 times ULN combined with elevated bilirubin at least 2 times the ULN) occurred in 0.2% (3/1487) of tolvaptan treated patients compared to none of the placebo treated patients. To reduce the risk of significant or irreversible liver injury, assess ALT, AST and bilirubin prior to initiation of tolvaptan tablets, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter. At the onset of signs or symptoms consistent with hepatic injury or if ALT, AST, or bilirubin increase to >2 times ULN, immediately discontinue tolvaptan tablets, obtain repeat tests as soon as possible (within 48 to 72 hours), and continue testing as appropriate. If laboratory abnormalities stabilize or resolve, tolvaptan tablets may be reinitiated with increased frequency of monitoring as long as ALT and AST remain below 3 times ULN. Do not restart tolvaptan tablets in patients who experience signs or symptoms consistent with hepatic injury or whose ALT or AST ever exceeds 3 times ULN during treatment with tolvaptan, unless there is another explanation for liver injury and the injury has resolved. In patients with a stable, low baseline AST or ALT, an increase above 2 times baseline, even if less than 2 times upper limit of normal, may indicate early liver injury. Such elevations may warrant treatment suspension and prompt (48 to 72 hours) re-evaluation of liver test trends prior to reinitiating therapy with more frequent monitoring. 5.2 Tolvaptan for ADPKD Shared System REMS Tolvaptan tablets are available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Tolvaptan for ADPKD Shared System REMS, because of the risks of liver injury [see Warnings and Precautions ( 5.1 )] . Notable requirements of the Tolvaptan for ADPKD Shared System REMS include the following: Prescribers must be certified by enrolling in the REMS program. Prescribers must inform patients receiving tolvaptan tablets about the risk of hepatotoxicity associated with its use and how to recognize the signs and symptoms of hepatotoxicity and the appropriate actions to take if it occurs. Patients must enroll in the REMS program and comply with ongoing monitoring requirements [see Warnings and Precautions ( 5.1 )] . Pharmacies must be certified by enrolling in the REMS program and must only dispense to patients who are authorized to receive tolvaptan tablets. Further information, including a list of qualified pharmacies/distributors, is available at www.TolvaptanADPKDSharedREMS.com or by telephone at 1-866-244-9446. 5.3 Hypernatremia, Dehydration and Hypovolemia Tolvaptan tablets increase free water clearance and, as a result, may cause dehydration, hypovolemia and hypernatremia. Therefore, ensure abnormalities in sodium concentrations are corrected prior to initiation of therapy. Instruct patients to drink water when thirsty, and throughout the day and night if awake. Monitor for weight loss, tachycardia and hypotension because they may signal dehydration. In the two double-blind, placebo-controlled trials of patients with ADPKD, hypernatremia (defined as any serum sodium concentration >150 mEq/L) was observed in 4% versus 0.6% and 1.4% versus 0% of tolvaptan- treated versus placebo-treated patients, respectively. The rate of dehydration and hypovolemia in the two studies was 2.1% versus 0.7% and 2.3% versus 0.4% for tolvaptan-treated versus placebo-treated patients, respectively. During tolvaptan tablets therapy, if serum sodium increases above normal range or the patient becomes hypovolemic or dehydrated and fluid intake cannot be increased, then suspend tolvaptan tablets until serum sodium, hydration status and volume status is within the normal range. 5.4 Co-Administration with Inhibitors of CYP 3A Concomitant use of tolvaptan tablets with drugs that are moderate or strong CYP 3A inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and conivaptan) increases tolvaptan exposure [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . Use with strong CYP 3A inhibitors is contraindicated; dose reduction of tolvaptan tablets are recommended for patients while taking moderate CYP 3A inhibitors [see Dosage and Administration ( 2.4 ) and Contraindications ( 4 )].
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Serious Liver Injury [see Boxed Warning and Warnings and Precautions ( 5.1 )] Hypernatremia, Dehydration and Hypovolemia [see Warnings and Precautions ( 5.3 )] Drug Interactions with Inhibitors of CYP 3A [see Warnings and Precautions ( 5.4 )] Most common observed adverse reactions with tolvaptan tablets (incidence >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction 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. Tolvaptan tablets have been studied in over 3000 patients with ADPKD. Long-term, placebo-controlled safety information of tolvaptan tablets in ADPKD is principally derived from two trials where 1,413 subjects received tolvaptan and 1,098 received placebo for at least 12 months across both studies. TEMPO 3:4 -NCT00428948: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD The TEMPO 3:4 trial employed a two-arm, 2:1 randomization to tolvaptan or placebo, titrated to a maximally-tolerated total daily dose of 60 to 120 mg. A total of 961 subjects with rapidly progressing ADPKD were randomized to tolvaptan tablets. Of these, 742 (77%) subjects who were treated with tolvaptan tablets remained on treatment for at least 3 years. The average daily dose in these subjects was 96 mg daily. Adverse events that led to discontinuation were reported for 15.4% (148/961) of subjects in the tolvaptan tablets group and 5% (24/483) of subjects in the placebo group. Aquaretic effects were the most common reasons for discontinuation of tolvaptan tablets. These included pollakiuria, polyuria, or nocturia in 63 (6.6%) subjects treated with tolvaptan tablets compared to 1 subject (0.2%) treated with placebo. Table 2 lists the adverse reactions that occurred in at least 3% of ADPKD subjects treated with tolvaptan tablets and at least 1.5% more than on placebo. Table 2: TEMPO 3:4, Treatment Emergent Adverse Reactions in ≥3% of Tolvaptan Tablets Treated Subjects with Risk Difference ≥ 1.5%, Randomized Period Adverse Reaction Tolvaptan (N=961) Placebo (N=483) Number of Subjects Proportion (%) 100x (Number of subjects with an adverse event/N) Annualized Rate 100x (Number of subjects with an adverse event/Total subject years of drug exposure) Number of Subjects Proportion (%) Annualized Rate Increased urination Increased urination includes micturition urgency, nocturia, pollakiuria, polyuria 668 69.5 28.6 135 28 10.3 Thirst Thirst includes polydipsia and thirst 612 63.7 26.2 113 23.4 8.7 Dry mouth 154 16 6.6 60 12.4 4.6 Fatigue 131 13.6 5.6 47 9.7 3.6 Diarrhea 128 13.3 5.5 53 11 4.1 Dizziness 109 11.3 4.7 42 8.7 3.2 Dyspepsia 76 7.9 3.3 16 3.3 1.2 Decreased appetite 69 7.2 3 5 1 0.4 Abdominal distension 47 4.9 2 16 3.3 1.2 Dry skin 47 4.9 2 8 1.7 0.6 Rash 40 4.2 1.7 9 1.9 0.7 Hyperuricemia 37 3.9 1.6 9 1.9 0.7 Palpitations 34 3.5 1.5 6 1.2 0.5 REPRISE-NCT02160145: A Phase 3, Randomized-Withdrawal, Placebo-Controlled, Double-Blind, Trial in Late Stage 2 to Early Stage 4 ADPKD The REPRISE trial employed a 5-week single-blind titration and run-in period for tolvaptan tablets prior to the randomized double-blind period. During the tolvaptan tablets titration and run-in period, 126 (8.4%) of the 1496 subjects discontinued the study, 52 (3.5%) were due to aquaretic effects and 10 (0.7%) were due to liver test findings. Because of this run-in design, the adverse reaction rates observed during the randomized period are not described. Liver Injury: In the two double-blind, placebo-controlled trials, ALT elevations >3 times ULN were observed at an increased frequency with tolvaptan tablets compared with placebo (4.9% [80/1637] versus 1.1% [13/1166], respectively) within the first 18 months after initiating treatment and increases usually resolved within 1 to 4 months after discontinuing the drug. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tolvaptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver failure requiring transplant Immune System Disorders: Anaphylaxis