An Extension Follow-up Trial to Evaluate the Long-term Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia

Core Safety Follow-up Component • For all subjects: To evaluate the post-treatment safety
follow-up of children and adolescent subjects with dilutional (euvolemic or hypervolemic)
hyponatremia who have previously participated in a tolvaptan hyponatremia trial.

Optional Tolvaptan Treatment Component

• For subjects who receive optional tolvaptan treatment: To demonstrate that tolvaptan safely
and effectively achieves and maintains increased serum sodium concentrations in children and
adolescent subjects with dilutional (euvolemic or hypervolemic) hyponatremia when used for
both multiple short-term treatments, and/or longer chronic treatments.

Core Safety Follow-up Component:

Inclusion Criteria:

Participation in a prior pediatric trial with Tolvaptan for euvolemic or hypervolemic
hyponatremia.Exclusion Criteria: None

Optional Tolvaptan Treatment Component (per treatment cycle):

Eligibility Criteria:

1. Male and female subjects ≥ 4 years of age (or per local Health Authority age
restrictions) and ≥ 10kg

2. Subject must have been off treatment with the investigational medicinal product for at
least 7 days following the end of treatment in the previous tolvaptan trial for
hyponatremia .

3. Persistent dilutional (euvolemic or hypervolemic) hyponatremia defined as being
documented as present for at least 48 hours, evidenced by at least 2 serum sodium
assessments < 130 mEq/L (mmol/L) drawn at least 12 hours apart (these values can be
documented using historical values previously obtained per standard of care); a third
(STAT) serum sodium assessment < 130 mEq/L (mmol/L), which will serve as the baseline
value for efficacy endpoints, is to be obtained within 2 to 4 hours prior to the first
dose of tolvaptan

4. Ability to swallow tablets

5. Ability to maintain adequate fluid intake whether orally or via IV support with
adequate monitoring

6. Ability to comply with all requirements of the trial

7. Trial-specific written informed consent/assent obtained from a parent/legal guardian
or legally acceptable representative, as applicable per age of subject or local laws,
prior to the initiation of any protocol required procedures. In addition, the subject
as required by local laws must provide informed assent at the pretreatment baseline
for this trial and must be able to understand that he or she can withdraw from the
trial at any time. All informed consent/assent procedures must be in accordance with
the trial center's IRB/IEC and local regulatory requirements.

8. Ability to commit to remain fully abstinent (periodic abstinence [eg, calendar,
ovulation, symptothermal, post-ovulation methods] or withdrawal are not acceptable
methods of contraception) or practice double-barrier birth control during the trial
and for 30 days following the last dose of IMP for sexually active females of
childbearing potential

Ineligibility Criteria:

1. Has evidence of hypovolemia or intravascular volume depletion (eg, hypotension,
clinical evidence of volume depletion, response to saline challenge); if the subject
has systolic blood pressure or heart rate outside of the normal range for that age
volume status should be specifically clinically assessed to rule out volume depletion

2. Has serum sodium < 120 mEq/L (mmol/L), with or without associated neurologic
impairment (ie, symptoms such as apathy, confusion, or seizures)

3. Use of potent CYP3A4 inhibitors in subjects ≤ 50 kg or moderate CYP3A4 inhibitors in
subjects < 20 kg

4. Lacks free access to water (inability to respond to thirst) or without ICU-level fluid
monitoring and management

5. Has a history or current diagnosis of nephrotic syndrome

6. Has transient hyponatremia likely to resolve (eg, head trauma or post-operative state)

7. Has hyperkalemia defined as serum potassium above the ULN for the appropriate
pediatric age range

8. Has eGFR < 30 mL/min/1.73 m2 calculated by the following equation:

eGFR (mL/min/1.73 m2) = 0.413 x height (cm)/serum creatinine (mg/dL)

9. Has AKI defined as: Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within
48 hours; or Increase in serum creatinine to ≥ 1.5 times baseline, which is known or
presumed to have occurred within the prior 7 days; or Urine volume < 0.5 mL/kg/h for 6
hours

10. Has severe or acute neurological symptoms requiring other intervention
(eg,hyperemesis, obtundation, seizures)

11. Has had treatment for hyponatremia with:

- Hypertonic saline (including normal saline challenge) within 8 hours of
qualifying sodium assessments;

- Urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of
qualifying serum sodium assessments;

- Other treatment for the purpose of increasing serum sodium concurrent with dosing
of trial medication

12. Has anuria or urinary outflow obstruction, unless the subject is, or can be,
catheterized during the trial

13. Has a history of drug or medication abuse within 3 months prior to the pretreatment
visit or current alcohol abuse

14. Has a history of hypersensitivity and/or idiosyncratic reaction to benzazepine or
benzazepine derivatives (such as benazepril)

15. Has psychogenic polydipsia (subjects with other psychiatric illness may be included
per medical monitor approval)

16. Has uncontrolled diabetes mellitus, defined as fasting glucose > 300 mg/dL (16.7 mEq/L
[mmol/L])

17. Has screening liver function values > 3 x ULN

18. Has cirrhosis and meets any of the following conditions: a major GI bleed within the
past 6 months, evidence of active bleeding (eg, epistaxis, petechiae/purpura,
hematuria, or hematochezia), platelet count < 50,000/μL, or use of concomitant
medications known to increase bleeding risk

19. Has hyponatremia due to the result of any medication that can safely be withdrawn (eg,
thiazide diuretics)

20. Has hyponatremia (eg, hyponatremia in the setting of adrenal insufficiency, untreated
hypothyroidism, or hypotonic fluid administration) that is most appropriately
corrected by alternative therapies

21. Is currently pregnant or breastfeeding

22. Has any medical condition that, in the opinion of the investigator, could interfere
with evaluation of the trial objectives or safety of the subjects.

23. Is deemed unsuitable for trial participation in the opinion of the investigator

24. Participation in another investigational drug trial within the past 30 days, without
prior approval from the sponsor medical monitor

25. Subjects < 4 years of age (or per local Health Authority age restrictions), weight <
10 kg, or who are unable to swallow tablets