WARNING: RISK OF SERIOUS LIVER INJURY

• JYNARQUE (tolvaptan) can cause serious and potentially fatal liver
  injury. Acute liver failure requiring liver transplantation has been
  reported.
• Measure transaminases (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. 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, JYNARQUE is available only
  through a Risk Evaluation and Mitigation Strategy program called the
  JYNARQUE REMS Program.

INDICATION and IMPORTANT SAFETY INFORMATION

JYNARQUE is indicated to slow kidney function decline in adults at risk of
rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

CONTRAINDICATIONS:

• History, signs or symptoms of significant liver impairment or injury.
  This contraindication does not apply to uncomplicated polycystic liver
  disease
• Taking strong CYP3A inhibitors
• With uncorrected abnormal blood sodium concentrations
• Unable to sense or respond to thirst
• Hypovolemia
• Hypersensitivity (e.g., anaphylaxis, rash) to JYNARQUE or any component
  of the product
• Uncorrected urinary outflow obstruction
• Anuria

Serious Liver Injury: JYNARQUE 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. To reduce the risk
of significant or irreversible liver injury, assess ALT, AST and bilirubin
prior to initiating JYNARQUE, at 2 weeks and 4 weeks after initiation,
then monthly for 18 months and every 3 months thereafter.

Hypernatremia, Dehydration and Hypovolemia: JYNARQUE therapy
increases free water clearance which can lead to dehydration, hypovolemia
and hypernatremia. 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. Ensure
abnormalities in sodium concentrations are corrected before initiating
therapy. If serum sodium increases above normal or the patient becomes
hypovolemic or dehydrated and fluid intake cannot be increased, suspend
JYNARQUE until serum sodium, hydration status and volume status parameters
are within the normal range.

Inhibitors of CYP3A: Concomitant use of JYNARQUE with drugs that
are moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole,
lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and conivaptan)
increases tolvaptan exposure. Use with strong CYP3A inhibitors is
contraindicated; dose reduction of JYNARQUE is recommended for patients
taking moderate CYP3A inhibitors. Patients should avoid grapefruit juice
beverages while taking JYNARQUE.

Adverse Reactions: Most common observed adverse reactions with
JYNARQUE (incidence >10% and at least twice that for placebo) were
thirst, polyuria, nocturia, pollakiuria and polydipsia.

Other Drug Interactions:

• Strong CYP3A Inducers: Co-administration with strong CYP3A
  inducers reduces exposure to JYNARQUE. Avoid concomitant use of JYNARQUE
  with strong CYP3A inducers.
• V₂-Receptor Agonist: Tolvaptan interferes with the
  V₂-agonist activity of desmopressin (dDAVP). Avoid
  concomitant use of JYNARQUE with a V₂-agonist.

Pregnancy and Lactation: Based on animal data, JYNARQUE may cause
fetal harm. In general, JYNARQUE should be discontinued during pregnancy.
Advise women not to breastfeed during treatment with JYNARQUE.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America
Pharmaceutical, Inc. at
1-800-438-9927 or
FDA at 1-800-FDA-1088
(www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including
BOXED WARNING.