HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use -------------------------------CONTRAINDICATIONS-----------------------------
JYNARQUE safely and effectively. See full prescribing information for • History of signs or symptoms of significant liver impairment or injury,
JYNARQUE. does not include uncomplicated polycystic liver disease (4)
JYNARQUE® (tolvaptan) tablets for oral use • Concomitant use of strong CYP 3A inhibitors is contraindicated (4)
Initial U.S. Approval: 2009 • Uncorrected abnormal blood sodium concentrations (4, 5.3)
• Unable to sense or respond to thirst (4)
WARNING: RISK OF SERIOUS LIVER INJURY
• Hypovolemia (4)
See full prescribing information for complete boxed warning.
• Hypersensitivity to tolvaptan or any of its components (4)
• JYNARQUE (tolvaptan) can cause serious and potentially fatal liver
• Uncorrected urinary outflow obstruction (4)
injury. Acute liver failure requiring liver transplantation has been
reported (5.1) • Anuria (4)
• Measure transaminases and bilirubin before initiating treatment, at
2 weeks and 4 weeks after initiation, then continuing monthly for the -----------------------WARNINGS AND PRECAUTIONS--------------------
first 18 months and every 3 months thereafter (5.1) • Hypernatremia, dehydration and hypovolemia: May require intervention
• JYNARQUE is available only through a restricted distribution (5.3)
program called the JYNARQUE REMS Program (5.2)
------------------------------ADVERSE REACTIONS-------------------------------
Most common observed adverse reactions with JYNARQUE (incidence >10%
----------------------------INDICATIONS AND USAGE--------------------------- and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria
JYNARQUE is a selective vasopressin V2-receptor antagonist indicated to and polydipsia (6.1)
slow kidney function decline in adults at risk of rapidly progressing autosomal
dominant polycystic kidney disease (ADPKD) (1) To report SUSPECTED ADVERSE REACTIONS, contact Otsuka
America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-
----------------------DOSAGE AND ADMINISTRATION----------------------- 1088 or www.fda.gov/medwatch.
• Recommended dosage (2.1)
-------------------------------DRUG INTERACTIONS------------------------------
Avoid concomitant use with:
Initial Dosage Titration Step Target Dosage
• Strong CYP 3A Inducers (7.1)
• V2-Receptor Agonists (7.2)
1st Dose 45 mg 1st Dose 60 mg 1st Dose 90 mg
----------------------- USE IN SPECIFIC POPULATIONS-----------------------
2nd Dose 2nd Dose 2nd Dose • Pregnancy: May cause fetal harm (8.1)
15 mg 30 mg 30 mg
(8 hours later) (8 hours later) (8 hours later)
• Lactation: Breastfeeding not recommended (8.2)
Total Daily Total Daily Total Daily
60 mg 90 mg 120 mg See 17 for PATIENT COUNSELING INFORMATION and Medication
Dose Dose Dose
Guide.
• Dose adjustment is recommended for patients taking moderate CYP 3A Revised: 10/2020
inhibitors (2.4, 5.4, 7.1)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

• Tablets: 15 mg, 30 mg, 45 mg, 60 mg and 90 mg (3)
_______________________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation

8.4 Pediatric Use
WARNING: RISK OF SERIOUS LIVER INJURY 8.5 Geriatric Use
1 INDICATIONS AND USAGE 8.6 Use in Patients with Hepatic Impairment
2 DOSAGE AND ADMINISTRATION 8.7 Use in Patients with Renal Impairment
2.1 Recommended Dosage 10 OVERDOSAGE
2.2 Monitoring 11 DESCRIPTION
2.3 Missed Doses 12 CLINICAL PHARMACOLOGY
2.4 Co-Administration with CYP 3A Inhibitors 12.1 Mechanism of Action
3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics
4 CONTRAINDICATIONS 12.3 Pharmacokinetics
5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY
5.1 Serious Liver Injury 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.2 JYNARQUE REMS Program 14 CLINICAL STUDIES
5.3 Hypernatremia, Dehydration and Hypovolemia 16 HOW SUPPLIED/STORAGE AND HANDLING
5.4 Co-Administration with Inhibitors of CYP 3A 16.1 How Supplied
6 ADVERSE REACTIONS 16.2 Storage and Handling
6.1 Clinical Trials Experience 17 PATIENT COUNSELING INFORMATION
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
*Sections or subsections omitted from the full prescribing information are not
7.1 CYP 3A Inhibitors and Inducers
listed.
7.2 V2-Receptor Agonist
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy

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 __________________________________________________________________________________________
FULL PRESCRIBING INFORMATION

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 [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, JYNARQUE is available only through a restricted
distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the JYNARQUE
REMS Program [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal
dominant polycystic kidney disease (ADPKD).
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The initial dosage for JYNARQUE is 60 mg orally per day as 45 mg taken on waking and 15 mg taken 8 hours
later. Titrate to 60 mg plus 30 mg then to 90 mg plus 30 mg per day if tolerated with at least weekly intervals
between titrations. Patients may down-titrate based on tolerability. Encourage patients to drink enough water to
avoid thirst or dehydration.
2.2 Monitoring
To mitigate the risk of significant or irreversible liver injury, perform blood testing for ALT, AST and bilirubin
prior to initiation of JYNARQUE, at 2 and 4 weeks after initiation, monthly for 18 months and every 3 months
thereafter. Monitor for concurrent symptoms that may indicate liver injury [see Warnings and Precautions
(5.1)].
2.3 Missed Doses
If a dose of JYNARQUE is not taken at the scheduled time, take the next dose at its scheduled time.
2.4 Co-Administration with CYP 3A Inhibitors
CYP 3A Inhibitors
Concomitant use of strong CYP 3A inhibitors is contraindicated [see Contraindications (4) and Warnings and
Precautions (5.4)].
In patients taking concomitant moderate CYP 3A inhibitors, reduce the dose of JYNARQUE per Table 1.
Consider further reductions if patients cannot tolerate the reduced dose [see Warnings and Precautions (5.4)
and Drug Interactions (7.1)]. Interrupt JYNARQUE temporarily for short term therapy with moderate CYP 3A
inhibitors if the recommended reduced doses are not available.

Table 1: Dose adjustment for patients taking moderate CYP 3A inhibitors

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 Standard Morning and Afternoon Dose (mg) with Moderate CYP 3A
Dose (mg) Inhibitors
90 mg and 30 mg 45 mg and 15 mg
60 mg and 30 mg 30 mg and 15 mg
45 mg and 15 mg 15 mg and 15 mg

3 DOSAGE FORMS AND STRENGTHS

JYNARQUE (tolvaptan) is supplied as non-scored, blue, shallow-convex, immediate release tablets, debossed
with “OTSUKA” and the tablet strength (mg) on one side.
JYNARQUE 15 mg tablets are triangular, 30 mg tablets are round, 45 mg tablets are square, 60 mg tablets are
rectangular, and 90 mg tablets are pentagonal.
4 CONTRAINDICATIONS
JYNARQUE is contraindicated in patients:
• With a history, signs or symptoms of significant liver impairment or injury. This contraindication does
not apply to uncomplicated polycystic liver disease [see Warnings and Precautions (5.1)]
• Taking strong CYP 3A inhibitors
• With uncorrected abnormal blood sodium concentrations [see Warnings and Precautions (5.3)]
• Unable to sense or respond to thirst [see Warnings and Precautions (5.3)]
• Hypovolemia [see Warnings and Precautions (5.3)]
• Hypersensitivity (e.g., anaphylaxis, rash) to tolvaptan or any component of the product [see Adverse
Reactions (6)]
• Uncorrected urinary outflow obstruction
• Anuria
5 WARNINGS AND PRECAUTIONS
5.1 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.

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
JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months
thereafter.

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 At the onset of signs or symptoms consistent with hepatic injury or if ALT, AST, or bilirubin increase to
>2 times ULN, immediately discontinue JYNARQUE, obtain repeat tests as soon as possible (within
48 to 72 hours), and continue testing as appropriate. If laboratory abnormalities stabilize or resolve,
JYNARQUE may be reinitiated with increased frequency of monitoring as long as ALT and AST remain below
3 times ULN.

Do not restart JYNARQUE 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 JYNARQUE REMS Program
JYNARQUE is available only through a restricted distribution program under a Risk Evaluation and Mitigation
Strategy (REMS) called the JYNARQUE REMS Program, because of the risks of liver injury [see Warnings
and Precautions (5.1)].

Notable requirements of the JYNARQUE REMS Program include the following:

• Prescribers must be certified by enrolling in the REMS program.
• Prescribers must inform patients receiving JYNARQUE 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 JYNARQUE.
Further information, including a list of qualified pharmacies/distributors, is available at
www.JYNARQUEREMS.com or by telephone at 1-877-726-7220.
5.3 Hypernatremia, Dehydration and Hypovolemia
JYNARQUE increases 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 4.0% 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 JYNARQUE therapy, if serum sodium increases above normal range or the patient becomes
hypovolemic or dehydrated and fluid intake cannot be increased, then suspend JYNARQUE until serum
sodium, hydration status and volume status is within the normal range.

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 5.4 Co-Administration with Inhibitors of CYP 3A
Concomitant use of JYNARQUE 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 JYNARQUE is 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)]
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. JYNARQUE has been studied in over 3000 patients with
ADPKD. Long-term, placebo-controlled safety information of JYNARQUE 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 JYNARQUE. Of these, 742 (77%) subjects who were treated with
JYNARQUE 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
JYNARQUE group and 5.0% (24/483) of subjects in the placebo group. Aquaretic effects were the most
common reasons for discontinuation of JYNARQUE. These included pollakiuria, polyuria, or nocturia in
63 (6.6%) subjects treated with JYNARQUE 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
JYNARQUE and at least 1.5% more than on placebo.
Table 2: TEMPO 3:4, Treatment Emergent Adverse Reactions in ≥3% of JYNARQUE Treated Subjects
with Risk Difference ≥ 1.5%, Randomized Period
Adverse Reaction Tolvaptan Placebo
(N=961) (N=483)
Number of Proportion Annualized Number of Proportion Annualized
Subjects (%)* Rate† Subjects (%)* Rate†
Increased urination‡ 668 69.5 28.6 135 28.0 10.3
§
Thirst 612 63.7 26.2 113 23.4 8.7
Dry mouth 154 16.0 6.6 60 12.4 4.6
Fatigue 131 13.6 5.6 47 9.7 3.6
5

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 Table 2: TEMPO 3:4, Treatment Emergent Adverse Reactions in ≥3% of JYNARQUE Treated Subjects
with Risk Difference ≥ 1.5%, Randomized Period
Adverse Reaction Tolvaptan Placebo
(N=961) (N=483)
Number of Proportion Annualized Number of Proportion Annualized
Subjects (%)* Rate† Subjects (%)* Rate†
Diarrhea 128 13.3 5.5 53 11.0 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 3.0 5 1.0 0.4
Abdominal distension 47 4.9 2.0 16 3.3 1.2
Dry skin 47 4.9 2.0 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
*100x (Number of subjects with an adverse event/N)
†
100x (Number of subjects with an adverse event/Total subject years of drug exposure)
‡
Increased urination includes micturition urgency, nocturia, pollakiuria, polyuria
§
Thirst includes polydipsia and thirst

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 JYNARQUE prior to the
randomized double-blind period. During the JYNARQUE 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 JYNARQUE 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

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 7 DRUG INTERACTIONS
7.1 CYP 3A Inhibitors and Inducers
CYP 3A Inhibitors
Tolvaptan’s AUC was 5.4 times as large and Cmax was 3.5 times as large after co-administration of tolvaptan
and 200 mg ketoconazole [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. Larger
doses of the strong CYP 3A inhibitor would be expected to produce larger increases in tolvaptan exposure.
Concomitant use of tolvaptan with strong CYP 3A inhibitors is contraindicated [see Contraindications (4)].
Dose reduction of JYNARQUE is recommended for patients while taking moderate CYP 3A inhibitors
[see Dosage and Administration (2.4)]. Patients should avoid grapefruit juice beverages while taking
JYNARQUE.
Strong CYP 3A Inducers
Co-administration of JYNARQUE with strong CYP 3A inducers reduces exposure to JYNARQUE [see
Clinical Pharmacology (12.3)]. Avoid concomitant use of JYNARQUE with strong CYP 3A inducers [see
Dosage and Administration (2.4)].

7.2 V2-Receptor Agonist

As a V2-receptor antagonist, tolvaptan will interfere with the V2-agonist activity of desmopressin (dDAVP).
Avoid concomitant use of JYNARQUE with a V2-agonist.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data with JYNARQUE use in pregnant women are insufficient to determine if there is a drug
associated risk of adverse developmental outcomes. In embryo-fetal development studies, pregnant rats and
rabbits received oral tolvaptan during organogenesis. At maternally non-toxic doses, tolvaptan did not cause any
developmental toxicity in rats or in rabbits at exposures approximately 4- and 1-times, respectively, the human
exposure at the maximum recommended human dose (MRHD) of 90/30 mg. However, effects on embryo-fetal
development occurred in both species at maternally toxic doses. In rats, reduced fetal weights and delayed fetal
ossification occurred at 17-times the human exposure. In rabbits, increased abortions, embryo-fetal death, fetal
microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at approximately
3-times the human exposure (see Data). Advise pregnant women of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated
background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20%
of clinically recognized pregnancies, respectively.
Data
Animal Data
Oral administration of tolvaptan during the period of organogenesis in Sprague-Dawley rats produced no
evidence of teratogenesis at doses up to 100 mg/kg/day. Lower body weights and delayed ossification were seen
at 1000 mg/kg, which is approximately 17-times the exposure in humans at the 90/30 mg dose (AUC24h
6570 h·ng/mL). The fetal effects are likely secondary to maternal toxicity (decreased food intake and low body

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 weights). In a prenatal and postnatal study in rats, tolvaptan had no effect on physical development, reflex
function, learning ability or reproductive performance at doses up to 1000 mg/kg/day.

In New Zealand White rabbits, placental transfer was demonstrated with Cmax values in the yolk sac fluid
approximating 22.7% of the value in maternal rabbit serum. In embryo-fetal studies, teratogenicity
(microphthalmia, embryo-fetal mortality, cleft palate, brachymelia and fused phalanx) was evident in rabbits at
1000 mg/kg (approximately 3 times the exposure at the 90/30 mg dose). Body weights and food consumption
were lower in dams at all doses, equivalent to 0.6 to 3- times the human exposure at the 90/30 mg dose.
8.2 Lactation
Risk Summary
There are no data on the presence of tolvaptan in human milk, the effects on the breastfed infant, or the effects
on milk production. Tolvaptan is present in rat milk. When a drug is present in animal milk, it is possible that
the drug will be present in human milk, but relative levels may vary (see Data). Because of the potential for
serious adverse reactions, including liver toxicity, electrolyte abnormalities (e.g., hypernatremia), hypotension,
and volume depletion in breastfed infants, advise women not to breastfeed during treatment with JYNARQUE.
Data
In lactating rats administration of radiolabeled tolvaptan, lacteal radioactivity concentrations reached the highest
level at 8 hours after administration and then decreased gradually with time with a half-life of 27.3 hours. The
level of activity in milk ranged from 1.5- to 15.8-fold those in blood over the period of 72 hours post-dose. In a
prenatal and postnatal study in rats, maternal toxicity was noted at 100 mg/kg/day or higher (≥4.4 times the
human exposure at the 90/30 mg dose). Increased perinatal death and decreased body weight of the offspring
were observed during the lactation period and after weaning at approximately 17.3 times the human exposure at
the 90/30 mg dose.
8.4 Pediatric Use
Safety and effectiveness of JYNARQUE in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of tolvaptan did not include sufficient numbers of subjects aged 65 years old and over to
determine whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Use in Patients with Hepatic Impairment
Because of the risk of serious liver injury, use is contraindicated in patients with a history, signs or symptoms of
significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver
disease which was present in 60% and 66% of patients in TEMPO 3:4 and REPRISE, respectively. No specific
exclusion for hepatic impairment was implemented in TEMPO 3:4. However, REPRISE excluded patients with
ADPKD who had hepatic impairment or liver function abnormalities other than that expected for ADPKD with
typical cystic liver disease [see Contraindications (4)].
8.7 Use in Patients with Renal Impairment
Efficacy studies included patients with normal and reduced renal function [see Clinical Studies (14)]. TEMPO
3:4 required patients to have an estimated creatinine clearance ≥60 mL/min, while REPRISE included patients
with eGFRCKD-Epi 25 to 65 mL/min/1.73m2.

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 10 OVERDOSAGE
Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to
300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote
for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of
excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and
dehydration/hypovolemia.
No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose).
A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included
decreased locomotor activity, staggering gait, tremor and hypothermia.
In patients with suspected JYNARQUE overdosage, assessment of vital signs, electrolyte concentrations, ECG
and fluid status is recommended. Continue replacement of water and electrolytes until aquaresis abates. Dialysis
may not be effective in removing JYNARQUE because of its high binding affinity for human plasma protein
(>98%).
11 DESCRIPTION
JYNARQUE contains tolvaptan, a selective vasopressin V2-receptor antagonist in immediate release tablets for
oral administration available in 15 mg, 30 mg, 45 mg, 60 mg and 90 mg strengths. Tolvaptan is (±)-4’-[(7-
chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o-tolu-m-toluidide. The empirical
formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:

Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted
hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum
Lake as colorant.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times
that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times that for the V1a-
receptor. Decreased binding of vasopressin to the V2-receptor in the kidney lowers adenylate cyclase activity
resulting in a decrease in intracellular adenosine 3′, 5′-cyclic monophosphate (cAMP) concentrations.
Decreased cAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma
membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance
(aquaresis) and a decrease in urine osmolality. In human ADPKD cyst epithelial cells, tolvaptan inhibited AVP-
stimulated in vitro cyst growth and chloride-dependent fluid secretion into cysts. In animal models, decreased
cAMP concentrations were associated with decreases in the rate of growth of total kidney volume and the rate
of formation and enlargement of kidney cysts. Tolvaptan metabolites have no or weak antagonist activity for
human V2-receptors compared with tolvaptan.

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 12.2 Pharmacodynamics
In healthy subjects or patients with eGFRs as low as 10 mL/min/1.73m2 receiving a single dose of tolvaptan, the
onset of the aquaretic effects occurs within 1 to 2 hours post-dose. In healthy subjects, single doses of 60 mg
and 90 mg produce a peak effect of about a 9 mL/min increase in urine excretion rate is observed between
4 and 8 hours post-dose. Higher doses of tolvaptan do not increase the peak effect in urine excretion rate but
sustain the effect for a longer period of time.
Urine excretion rate returns to baseline within 24 hours following the maximum recommended 90 mg dose of
tolvaptan.
Changes in free water clearance mirror the changes in urine excretion rate. Increased free water clearance
causes an increase in serum sodium concentration unless fluid intake is increased to match urine output.
Increases in urine excretion rate and free water clearance are positively correlated with baseline glomerular
filtration rate with increases in both values observed in patients with creatinine clearance as low as 15 mL/min.
With the recommended split-dose regimens, tolvaptan inhibits vasopressin from binding to the V2-receptor in
the kidney for the entire day, as indicated by increased urine output and decreased urine osmolality. Following a
90/30 mg split-dose regimen in patients with eGFR >60 mL/min/1.73 m2, the change in mean daily urine
volume was about 4 L for a mean total daily volume of about 7 L. In patients with eGFR <30 mL/min/1.73 m2,
the mean change in daily urine volume was about 2 L for a total daily urine volume of about 5 L.
Plasma concentrations of native AVP may increase (avg. 2 to 9 pg/mL) with tolvaptan treatment and return to
baseline levels when treatment is stopped.
During tolvaptan treatment, small changes in renal function are expected and the changes are independent of
baseline renal function. Glomerular filtration rate is decreased about 6% to 10% and uric acid clearance is
decreased about 20% to 25%. Percent changes in renal plasma flow are highly correlated to percent changes in
GFR. These changes are reversed upon discontinuation of tolvaptan.
Cardiac Electrophysiology
No prolongation of the QT interval was observed with tolvaptan following multiple doses of 300 mg/day for
5 days.
12.3 Pharmacokinetics
In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up
to 300 mg once daily have been studied. In ADPKD patients, single doses up to 120 mg and multiple split-doses
up to 90/30 mg have been studied.
Absorption:
In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Peak
concentrations increase less than dose proportionally with doses greater than 240 mg.
The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of
tolvaptan following an oral dose of 30 mg is 56% (range 42 to 80%).
Co-administration of 90 mg JYNARQUE with a high-fat meal (~1000 calories, of which 50% are from fat)
doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or
without food.
Distribution:
Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is >98%; binding is
not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg. The pharmacokinetic
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 properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about
3. When administered as multiple once-daily 300 mg doses to healthy subjects or as split-dose regimens to
patients with ADPKD, tolvaptan’s accumulation factor is <1.2. There is marked inter-subject variation in peak
and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.
Metabolism and Elimination:
Tolvaptan is metabolized almost exclusively by CYP 3A. Fourteen metabolites have been identified in plasma,
urine and feces; all but one were also metabolized by CYP 3A and none are pharmacodynamically active. After
oral administration of radiolabeled tolvaptan, tolvaptan was a minor component in plasma representing 3% of
total plasma radioactivity; the oxobutyric acid metabolite was present at 52.5% of total plasma radioactivity
with all other metabolites present at lower concentrations than tolvaptan. The oxobutyric acid metabolite shows
a plasma half-life of ~180 h. About 40% of radioactivity was recovered in urine (<1% as unchanged tolvaptan)
and 59% in feces (19% as unchanged tolvaptan). Following intravenous infusion, tolvaptan half-life is
approximately 3 hours. Following single oral doses to healthy subjects, the estimated half-life of tolvaptan
increases from 3 hours for a 15 mg dose to approximately 12 hours for 120 mg and higher doses due to more
prolonged absorption of tolvaptan at higher doses; apparent clearance is approximately 4 mL/min/kg and does
not appear to change with increasing dose.
Specific Populations
Age, Gender and Race
Age, gender and race have no effect on tolvaptan pharmacokinetics.
Hepatic Impairment
In studies involving patients with hepatic impairment (Child-Pugh class A-C), but without ADPKD; moderate
(class A, B) or severe (class C) hepatic impairment decreases the clearance and increases the volume of
distribution of tolvaptan.
Renal Impairment
In subjects with creatinine clearances ranging from 10 to 124 mL/min administered a single dose of 60 mg
tolvaptan, the AUC and Cmax of plasma tolvaptan was increased 90% and 10%, respectively, for subjects with
clearances of <30 mL/min compared to subjects with clearances >60 mL/min [see Use in Special Populations
(8.7)].
In ADPKD patients with estimated creatinine clearance >60 mL/min, pharmacokinetics were similar to healthy
subjects.
Drug Interaction Studies:
Impact of Other Drugs on Tolvaptan
Strong CYP 3A Inhibitors
Tolvaptan’s Cmax and AUC were, respectively, 3.5 times and 5.4 times as high following ketoconazole 200 mg
given one day prior to and concomitantly with 30 mg tolvaptan.
Moderate CYP 3A4 Inhibitors
Fluconazole: Fluconazole 400 mg given one day prior and 200 mg given concomitantly produced an
80% and 200% increase in tolvaptan Cmax and AUC, respectively.
Grapefruit Juice: When 60 mg tolvaptan was taken with 240 mL regular strength grapefruit juice, tolvaptan Cmax
and AUC increased 90% and 60%, respectively.
CYP 3A Inducers
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 Rifampin: Rifampin 600 mg once daily for 7 days followed by a single 240 mg dose of tolvaptan decreased
both tolvaptan Cmax and AUC about 85%.
Other Drugs
Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with tolvaptan has no clinically
relevant impact on the exposure to tolvaptan.
Impact of Tolvaptan on Other Drugs
CYP 3A Substrates
Co-administration of lovastatin and tolvaptan increases the AUC of lovastatin and its active metabolite
lovastatin-β hydroxy acid by 40% and 30%, respectively. These are non-clinically significant increases in
exposure.
P-gp Substrates
Digoxin: Digoxin 0.25 mg was administered once daily for 12 days. Tolvaptan 60 mg, was co-administered
once daily on Days 8 to 12. Digoxin Cmax and AUC were increased 30% and 20%, respectively.
Transporter Substrates
Tolvaptan is a substrate of P-gp and an inhibitor of P-gp and BCRP. The oxobutyric acid metabolite of
tolvaptan is an inhibitor of OATP1B1 and OAT3. Co-administration of tolvaptan with rosuvastatin (BCRP
substrate) did not have a clinically significant effect on rosuvastatin exposure. Rosuvastatin Cmax and AUCt
increased 54% and 69%, respectively.
Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthy subjects with
elevated oxobutyric acid metabolite plasma concentrations did not meaningfully alter the pharmacokinetics of
rosuvastatin or furosemide.
Other Drugs
Co-administration of tolvaptan did not meaningfully alter the pharmacokinetics of warfarin, furosemide,
hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of JYNARQUE was assessed in 2-year carcinogenicity studies in mice and rats.
Tolvaptan was not tumorigenic in male or female rats at doses up to 1000 mg/kg/day (1.9 to 5.1 times the
human exposure at the 90/30 mg dose), in male mice at doses up to 60 mg/kg/day (0.4 times the human
exposure at the 90/30 mg dose) and to female mice at doses up to 100 mg/kg/day (0.7 times the human exposure
at the 90/30 mg dose).
Mutagenesis
Tolvaptan was not clastogenic in the in vitro chromosomal aberration test in Chinese hamster lung fibroblast
cells or the in vivo rat micronucleus assay and was not mutagenic in the in vitro bacterial reverse mutation
assay.
Impairment of fertility
In a fertility study in which male and female rats were administered tolvaptan orally at 100, 300 or
1000 mg/kg/day, altered estrous cycles due to prolongation of diestrus were observed in dams given
300 and 1000 mg/kg/day (9.7- and 17.3 times the human exposure at the 90/30 mg dose). Tolvaptan had no
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 effect on copulation or fertility indices. There were also no effects on the incidences of early or late resorption,
dead fetuses, pre- or post-implantation loss, external anomalies, or fetal body weights.
14 CLINICAL STUDIES
JYNARQUE was shown to slow the rate of decline in renal function in patients at risk of rapidly progressing
ADPKD in two trials; TEMPO 3:4 in patients at earlier stages of disease and REPRISE in patients at later
stages. The findings from these trials, when taken together, suggest that JYNARQUE slows the loss of renal
function progressively through the course of the disease.

TEMPO 3:4-NCT00428948: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early,

Rapidly-Progressing ADPKD
In TEMPO 3:4, 1445 adult patients (age >18 years) with early (estimated creatinine clearance [eCrCl]
≥60 mL/min), rapidly-progressing (total kidney volume [TKV] ≥750 mL and age <51 years) ADPKD
(diagnosed by modified Ravine criteria) were randomized 2:1 to treatment with tolvaptan or placebo.
Patients were treated for up to 3 years; patients who discontinued medication prematurely were only
required to attend clinic visits to assess renal function for up to 42 days after treatment withdrawal and to
attend telephone visits at all scheduled visits for up to 36 months. Patients who completed treatment at the
3-year visit had treatment interrupted for 2 to 6 weeks to assess renal function post treatment. Patients
received treatment twice a day (first dose on waking, second dose approximately 9 hours later). Patients
were initiated on 45 mg/15 mg, and up-titrated weekly to 60 mg/30 mg and then to 90 mg/30 mg as
tolerated. Patients were to maintain the highest tolerated dose for 3 years, but could interrupt, decrease
and/or increase as clinical circumstances warranted within the range of titrated doses. All patients were
encouraged to drink adequate water to avoid thirst or dehydration and before bedtime.
The primary endpoint was the intergroup difference for rate of change of TKV normalized as a percentage.
The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression
events of: 1) worsening kidney function (defined as a persistent 25% reduction in reciprocal serum
creatinine during treatment from end of titration to last on-drug visit); 2) medically significant kidney pain
(defined as requiring prescribed leave, last-resort analgesics, narcotic and anti-nociceptive, radiologic or
surgical interventions); 3) worsening hypertension (defined as a persistent increase in blood pressure
category or an increased anti-hypertensive prescription); 4) worsening albuminuria (defined as a persistent
increase in albumin/creatinine ratio category).
At baseline, average estimated glomerular filtration rate (eGFR) was 82 mL/min/1.73 m2 (CKD-
Epidemiology formula) and mean TKV was 1692 mL (height adjusted 972 mL/m). Approximately 35%
had an eGFR of 90 mL/min/1.73 m2 or greater, 48% had an eGFR between 60 to 89 mL/min/1.73 m2, 14%
had an eGFR of 45 to 60 mL/min/1.73 m2, and 3% had an eGFR of <45 mL/min/1.73 m2. The subjects’
mean age was 39 years, 48% were female, 84% were Caucasian, 13% were Asian, and 1.7% were Black or
African-American. Approximately 80% had hypertension and approximately 71% were taking an agent
that acts on the renin-angiotensin system. Of the 770 subjects who submitted to genetic analysis in
TEMPO 3:4’s open-label extension, 749 (97%) had an identifiable mutation in the PKD1 (656 or 88%), or
PKD2 (93 or 12%) gene.
The trial met its prespecified primary endpoint of 3-year change in TKV (p<0.0001). The difference in
TKV between treatment groups mostly developed within the first year, the earliest assessment, with little
further difference in years two and three. In years 4 and 5 during the TEMPO 3:4 extension trial, both
groups received JYNARQUE and the difference between the groups in TKV was not maintained.
Tolvaptan has little effect on kidney size beyond what accrues during the first year of treatment.
The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (44 vs.
50 events per 100 person-years; hazard ratio, 0.87; 95% CI, 0.78 to 0.97; p=0.0095). As shown in the table
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 below, the result of the key secondary composite endpoint was driven by effects on worsening kidney
function and kidney pain events. In contrast, there was no effect of tolvaptan on either progression of
hypertension or albuminuria. Few subjects in either arm required a radiologic or surgical intervention for
kidney pain. Most kidney pain events reflected use of a medication to treat pain such as use of
paracetamol, tricyclic antidepressants, narcotics and other non-narcotic agents.

Event Tolvaptan Placebo Hazard

Ratio,
Total Number Number of Total Number Number of
95% CI
of Events Subjects with of Events Subjects with
(Events per an Event (Events per an Event
100 person- (percentage) 100 person- (percentage)
years) years)
Composite 1049 (43.9) 572 (59.5) 665 (50.0) 341 (70.6) 0.87
(0.78,0.97)
Worsening Kidney 44 (1.9) 42 (4.6) 64 (4.8) 61 (12.8) 0.39
Function (0.26,0.57)
Kidney Pain 113 (4.7) 95 (9.9) 97 (7.3) 78 (16.2) 0.64
(0.47,0.89)
Onset or 734 (30.7) 426 (44.3) 426 (32.1) 244 (50.5) 0.94
progression of (0.81,1.09)
hypertension
Worsening 195 (8.2) 195 (20.3) 103 (7.8) 101 (20.9) 1.04
Albuminuria (0.84,1.28)

The third endpoint (kidney function slope) was assessed as slope of eGFR during treatment (from end of
titration to last on-drug visit). The estimated difference in the annual rate of change in those who contributed to
the analysis was 1.0 mL/min/1.73m2/year with a 95% confidence interval of (0.6, 1.4). Of the subjects enrolled
in the trial, 5% of subjects in the tolvaptan arm and 2% in the placebo arm either had missing baseline data or
discontinued from treatment prior to the end of the titration visit and hence were excluded from the analysis. In
the extension trial, eGFR differences produced by the third year of the TEMPO 3:4 trial were maintained over
the next 2 years of JYNARQUE treatment.

The efficacy profile was generally consistent across subgroups of interest for this indication; few Black or
African-American patients were enrolled in the trial.
REPRISE-NCT02160145: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Withdrawal Trial in
Later-Stage ADPKD
REPRISE was a double-blind, placebo-controlled randomized withdrawal trial in adult patients (age
18 to 65 years) with chronic kidney disease (CKD) with an eGFR between 25 and 65 mL/min/1.73m2 if
younger than age 56 years; or eGFR between 25 and 44 mL/min/1.73m2, plus eGFR decline
>2.0 mL/min/1.73m2/year if between age 56 to 65 years. Subjects were to be treated for 12 months; after
completion of treatment, patients entered a 3-week follow-up period to assess renal function. The primary
endpoint was the treatment difference in the change of eGFR from pre-treatment baseline to post-treatment
follow-up, annualized by dividing by each subject’s treatment duration.
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 Prior to randomization, patients were required to complete sequential single-blind run-in periods during which
they received placebo for 1 week, followed by tolvaptan titration for 2 weeks, and then treatment with tolvaptan
at the highest tolerated dose achieved during titration for 3 weeks. During the titration period, tolvaptan was up-
titrated every 3 to 4 days from a daily oral dose of 30 mg/15 mg to 45 mg/15 mg, 60 mg/30 mg and up to a
maximum dose of 90 mg/30 mg. Only patients who could tolerate the two highest doses of tolvaptan
(60 mg/30 mg or 90 mg/30 mg) for the subsequent 3 weeks were randomized 1:1 to treatment with tolvaptan or
placebo.

Patients were maintained on their highest tolerated dose for a period of 12 months but could interrupt, decrease
and/or increase as clinical circumstances warranted within the range of titrated doses. All patients were
encouraged to start drinking an adequate amount of water at screening and continuing through the end of the
trial to avoid thirst or dehydration.

A total of 1519 subjects were enrolled in the study. Of these, 1370 subjects successfully completed the pre-
randomization period and were randomized and treated during the 12-month double-blind period. Because
57 subjects did not complete the off-treatment follow-up period, 1313 subjects were included in the primary
efficacy analysis.

For subjects randomized, the baseline, average estimated glomerular filtration rate (eGFR) was
41 mL/min/1.73 m2 (CKD-Epidemiology formula) and historical TKV, available in 318 (23%) of subjects,
averaged 2026 mL. Approximately 5%, 75% and 20% had an eGFR 60 mL/min/1.73 m2 or greater, between
30 to 59 mL/min/1.73 m2, and between 25 and 29 mL/min/1.73 m2, respectively. The subjects’ mean age was
47 years, 50% were female, 92% were Caucasian, 4% Black or African-American and 3% were Asian, 93% had
hypertension, and 87% of subjects were taking antihypertensive agents affecting the angiotensin converting
enzyme or receptor. Of the 115 (8%) of subjects who had prior genetic tests, only 54 (47%) knew their results
with 48 (89%) of these having PKD1 and 6 (11%) having PKD2 mutations.

In the randomized period, the change of eGFR from pretreatment baseline to post-treatment follow-up was
−2.3 mL/min/1.73 m2/year with tolvaptan as compared with −3.6 mL/min/1.73 m2/year with placebo,
corresponding to a treatment effect of 1.3 mL/min/1.73 m2/year (p <0.0001). The key secondary endpoint
(eGFR slope in ml/min/1.73 m2/year assessed using a linear mixed effect model of annualized eGFR (CKD-
EPI)) showed a difference between treatment groups of 1.0 ml/min/ m2/year that was also statistically
significant (p < 0.0001).

The efficacy profile was generally consistent across subgroups of interest for this indication; few Black or
African-American patients were enrolled in the trial.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied
JYNARQUE (tolvaptan) is supplied as non-scored, blue, shallow-convex, immediate release tablets, debossed
with “OTSUKA” and the tablet strength (mg) on one side.
JYNARQUE (tolvaptan) 15 mg tablets are triangular, 30 mg tablets are round, 45 mg tablets are square, 60 mg
tablets are rectangular, and 90 mg tablets are pentagonal.
JYNARQUE (tolvaptan) tablets are supplied as:

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 Morning and Afternoon Doses NDC
7-Day Blister Card 28-Day Carton
(Containing 14 Tablets) (4 Blister Cards Containing a
Total of 56 Tablets)

15 mg and 15 mg 59148-079-07 59148-079-28

30 mg and 15 mg 59148-080-07 59148-080-28

45 mg and 15 mg 59148-087-07 59148-087-28

60 mg and 30 mg 59148-088-07 59148-088-28

90 mg and 30 mg 59148-089-07 59148-089-28

30 Count Bottles NDC

15 mg 59148-082-13
30 mg 59148-083-13

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP
controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
As part of patient counseling, healthcare providers must review the JYNARQUE Medication Guide with every
patient [see Medication Guide].
Serious Liver Injury
Advise patients that blood testing is required before starting JYNARQUE, at 2 weeks and 4 weeks after
initiation, then monthly during the first 18 months of therapy and every 3 months thereafter as a requirement to
reduce the risk of serious liver injury [see Boxed Warning and Warnings and Precautions (5.1)].
Advise patients to immediately stop taking JYNARQUE and notify their healthcare provider if they have
symptoms or signs (e.g., abnormal transaminase elevations) of hepatic injury (such as fatigue, anorexia, nausea,
right upper abdominal discomfort or tenderness, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice)
[see Warnings and Precautions (5.1)].
JYNARQUE REMS Program
Advise patients that JYNARQUE is only available through a restricted program called the JYNARQUE REMS
Program [see Warnings and Precautions (5.2)]. Inform the patient of the following notable requirement:
• Patients must enroll in the program and comply with ongoing monitoring requirements [see Warnings
and Precautions (5.1)]
Advise patients that JYNARQUE is only available only through restricted distribution from certified specialty
pharmacies participating in the JYNARQUE REMS program. Therefore, provide patients with the telephone
number and web site for information on how to obtain the product [see Warnings and Precautions (5.2)].

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 Hypernatremia, Dehydration and Hypovolemia
Advise patients to drink water to avoid thirst, throughout the day and night. Patients should stop taking
JYNARQUE and notify their healthcare provider if they have symptoms or signs of sodium imbalance or
dehydration (e.g., dizziness, fainting, weight loss, palpitations, confusion, weakness, gait instability) [see
Warnings and Precautions (5.3)]. Advise the patient that if they cannot drink enough water for any reason (no
access to water, cannot sense thirst, unable to maintain hydration due to vomiting, diarrhea) they should stop
taking JYNARQUE and inform their health care provider right away [see Warnings and Precautions (5.3)].
Pregnancy
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their
prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Lactation
Advise women not to breastfeed during treatment with JYNARQUE [see Use in Specific Populations (8.2)].

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA
JYNARQUE is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
© 2020, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

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 MEDICATION GUIDE
JYNARQUE® (jin-AR-kew)
(tolvaptan)
Tablets
What is the most important information I should know about JYNARQUE?
JYNARQUE can cause serious side effects, including:
• Serious liver problems. JYNARQUE can cause serious liver problems that can lead to the need for a liver transplant
or can lead to death. Stop taking JYNARQUE and call your healthcare provider right away if you get any of the
following symptoms:

o feeling tired o fever

o loss of appetite o rash
o nausea o itching
o right upper stomach (abdomen) pain or tenderness o yellowing of the skin and white part of the eye
(jaundice)
o vomiting o dark urine
To help reduce your risk of liver problems, your healthcare provider will do a blood test to check your liver:

o before you start taking JYNARQUE

o at 2 weeks and 4 weeks after you start treatment with JYNARQUE

o then monthly for 18 months during treatment with JYNARQUE

o and every 3 months from then on

It is important to stay under the care of your healthcare provider during treatment with JYNARQUE.

Because of the risk of serious liver problems JYNARQUE is only available through a restricted distribution
program called the JYNARQUE Risk Evaluation and Mitigation Strategy (REMS) Program.
• Before you start treatment with JYNARQUE, you must enroll in the JYNARQUE REMS Program. Talk to your
healthcare provider about how to enroll in the program.
• JYNARQUE can only be dispensed by a certified pharmacy that participates in the JYNARQUE REMS Program. Your
healthcare provider can give you information on how to find a certified pharmacy.

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 What is JYNARQUE?
JYNARQUE is a prescription medicine used to slow kidney function decline in adults who are at risk of rapidly progressing
autosomal dominant polycystic kidney disease (ADPKD).
It is not known if JYNARQUE is safe and effective in children.
Do not take JYNARQUE if you:
• have a history of liver problems or have signs or symptoms of liver problems, excluding polycystic liver disease.
• cannot feel if you are thirsty or cannot replace fluids by drinking.
• have been told that the amount of sodium (salt) in your blood is too high or too low.
• are dehydrated.
• are allergic to tolvaptan or any of the ingredients in JYNARQUE. See the end of this Medication Guide for a complete
list of ingredients in JYNARQUE.
• are unable to urinate.
Before taking JYNARQUE, tell your healthcare provider about all your medical conditions, including if you:
• have a history of sodium levels that are too low.
• are pregnant or plan to become pregnant. It is not known if tolvaptan will harm your unborn baby. Tell your healthcare
provider if you become pregnant or think that you may be pregnant.
• are breast-feeding or plan to breastfeed. It is not known if tolvaptan passes into your breast milk. Do not breastfeed
during treatment with JYNARQUE. Talk to your healthcare provider about the best way to feed your baby during this
time.
Tell your healthcare provider about all the medicines you take including prescription medicines, over-the-counter
medicines, vitamins and herbal supplements.
• Taking JYNARQUE with certain medicines could cause you to have too much tolvaptan in your blood. JYNARQUE
should not be taken with certain medications. Your healthcare provider can tell you if it is safe to take JYNARQUE
with other medicines.
• Do not start taking a new medicine without talking to your healthcare provider.
• Keep a list of your medicines to show your healthcare provider and pharmacist.

How should I take JYNARQUE?

• Take JYNARQUE exactly as your healthcare provider tells you to.
• Take JYNARQUE orally two times each day. Take the first dose of JYNARQUE when you wake up and take the
second dose 8 hours later.
• Be sure to drink enough water so that you will not get thirsty or become dehydrated.
• If you miss a dose of JYNARQUE, take the next dose at your regular time.
• If you take too much JYNARQUE, call your healthcare provider or go to the nearest hospital emergency room right
away.
What should I avoid while taking JYNARQUE?
• Do not drink grapefruit juice during treatment with JYNARQUE. This could cause you to have too much tolvaptan in
your blood.

What are the possible side effects of JYNARQUE?

JYNARQUE may cause serious side effects, including:
See “What is the most important information I should know about JYNARQUE?”
• Too much sodium in your blood (hypernatremia) and loss of too much body fluid (dehydration). In some cases,
dehydration can lead to extreme loss of body fluid called hypovolemia. You should drink water when you are thirsty
and throughout the day and night. Stop taking JYNARQUE and call your healthcare provider if you cannot drink
enough water for any reason, such as not having access to water, or vomiting or diarrhea. Tell your healthcare provider
if you get any of the following symptoms:
o dizziness
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 o fainting
o weight loss
o a change in the way your heart beats
o feel confused or weak
The most common side effects of JYNARQUE include:
• thirst and drinking more fluid than normal
• making large amounts of urine, urinating often and urinating at night
These are not all the possible side effects of JYNARQUE.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store JYNARQUE?
JYNARQUE comes in a child-resistant package. Store JYNARQUE between 68°F to 77°F (20°C to 25°C).
Keep JYNARQUE and all medicines out of the reach of children.
General information about the safe and effective use of JYNARQUE.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use JYNARQUE
for a condition for which it was not prescribed. Do not give JYNARQUE to other people, even if they have the same
symptoms you have. It may harm them.
What are the ingredients in JYNARQUE?
Active ingredient: tolvaptan
Inactive ingredients: corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose,
magnesium stearate and microcrystalline cellulose, and FD&C Blue no. 2 Aluminum Lake as colorant.
Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA
JYNARQUE is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
© 2020, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
For more information about JYNARQUE, go to www.JYNARQUEREMS.com or call 1-877-726-7220.
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 10/2020

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