IN ADPKD FIND OUT WHY

SEEING IS BELIEVINGADPKD=autosomal dominant polycystic kidney disease.

Patient image and patient case are fictional.

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

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

Please see IMPORTANT SAFETY INFORMATION on pages 9-10.

2

BENEATH THE SURFACEImaging the kidneys to measure total kidney volume (TKV) can help1-3:• Identify rapidly progressing ADPKD• Reveal the extent of disease progression

KIDNEY FUNCTION ALONE MAY NOT REVEAL WHAT’S GOING ON1

Joe, a 25-year-old repairman with ADPKD

SELECT IMPORTANT SAFETY INFORMATION: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® (tolvaptan) or any component of the product

• Uncorrected urinary outflow obstruction• Anuria

Patient image and patient case are fictional.

3Please see IMPORTANT SAFETY INFORMATION on pages 9-10.

JOE’S MEDICAL HISTORY MAY NOT BE TELLING THE FULL STORYIdentifying certain risk factors associated with rapidly progressing ADPKD can start to give you a better understanding of a patient’s disease4

CKD=chronic kidney disease.eGFR=estimated glomerular filtration rate.ESRD=end-stage renal disease.

Vitals• Age: 25• Height: 6 feet, 0 inches (1.8 m)• Weight: 178 lb• BMI: 24• Blood pressure: 110/90 mm Hg

(managed with an antihypertensive)

ADPKD diagnosis• Proactive ultrasound revealed 5

renal cysts on Joe’s right kidney and 7 on his left

Family history• Mother had a kidney transplant at

age 50• Grandmother died of kidney failure

at age 65

Medical history• CKD stage 2• Hypertension (presented with a

blood pressure of 153/95 mm Hg)• Serum creatinine: 1.27 mg/dL• eGFR: 89 mL/min/1.73 m2

Risk factor: Family history

A family history of ESRD before age 58 is a risk factor associated with rapid disease progression.5

Risk factor: Hypertension

Hypertension before age 35 is a risk factor associated with rapid disease progression in ADPKD. In fact, ADPKD is often diagnosed upon the discovery of hypertension.4,6,7

4

SELECT IMPORTANT SAFETY INFORMATION:Serious Liver Injury: JYNARQUE® (tolvaptan) 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.

Risk factor: Urologic events before age 35

Younger patients experiencing flank pain related to cysts, gross hematuria, or cyst infection may be at risk of rapidly progressing ADPKD.6

History of symptoms• Hematuria: No• Abdominal/flank pain: Yes• Kidney stones: Yes• Urinary tract infection: Yes• Liver cysts: No• Kidney cyst infections: No

5Please see IMPORTANT SAFETY INFORMATION on pages 9-10.

Imaging the kidneys to determine TKV can help confirm a risk of rapid progression—and predict future decline of kidney function8

After identifying risk factors associated with rapidly progressing ADPKD, Joe’s nephrologist ordered an abdominal MRI to see the extent of his disease.

IMAGING JOE’S KIDNEYS HELPED REVEAL THE EXTENT OF HIS DISEASE

CT=computed tomography. MRI=magnetic resonance imaging.

Risk factor: TKV greater than expected for age

In ADPKD, cyst growth precedes a decline in kidney function. Calculating TKV can help provide an important predictor of early-stage disease progression and future kidney decline—even before symptoms appear and kidney function begins to drop.1,2,7

When MRI- or CT-calculated TKV is not feasible, ultrasound-measured kidney length has been proposed as a useful surrogate for identifying young ADPKD patients at risk of rapid progression.9,10

Ultrasound bilateral kidney length >16.5 cm has been shown to predict the development of CKD stage 3A within 8 years in patients aged <45 years.5

Imaging results

MRI to evaluate TKV confirmed a high risk of rapidly progressing ADPKD and the potential for future eGFR decline.

6

CALCULATING JOE’S TKVJoe’s TKV can be calculated using MRI measurements of kidney length, width, and depth using the ellipsoid equation11

Hypernatremia, Dehydration and Hypovolemia: JYNARQUE® (tolvaptan) 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.

SELECT IMPORTANT SAFETY INFORMATION:

Width

Depth

LengthLength

DepthWidthHeight-adjusted (ht) TKV3,8

Joe’s htTKV can be used to estimate his future renal declineTKV: 860 mLHeight: 1.8 m Joe’s htTKV: 478 mL/m

L=length; W=width; D=depth.Units for kidney dimensions are in mm. To get kidney volume in mL, multiply by 0.001.

LEFT KIDNEY RIGHT KIDNEY

x (LxWxD)6π TKVx (LxWxD)6

π+ =

hTKV htTKV=

7Please see IMPORTANT SAFETY INFORMATION on pages 9-10.

Plotting htTKV and age predicts the change in eGFR over time in patients with typical* ADPKD8

*Bilateral and diffuse distribution, with mild, moderate, or severe replacement of kidney tissue by cysts, where all cysts contribute similarly to TKV.8

Republished with permission of the American Society of Nephrology, from Imaging classification of autosomal polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-172.

PREDICTING CHANGES IN JOE’S KIDNEY FUNCTION

Patient Age (Years)

HtTK

V (m

L/m

)

200

400

600800

1000

2000

4000

60008000

10000

16000

15 20 25 30 35 40 45 50 55 60 65 70 75 80

Class 1E

Class 1C

Class 1B

Class 1A

Class 1D

Estimated kidney growth rate:

yearly percentage increase

1A

Low risk

<1.5% 3%–4.5%1.5%–3%

Intermediate risk High risk High risk High risk

4.5%–6%

1B 1C 1D 1E

>6%

Class

Risk for eGFR decline

Joe

8

Patient Age (Years)

HtTK

V (m

L/m

)200

400

600800

1000

2000

4000

60008000

10000

16000

15 20 25 30 35 40 45 50 55 60 65 70 75 80

Class 1E

Class 1C

Class 1B

Class 1A

Class 1D

Estimated kidney growth rate:

yearly percentage increase

1A

Low risk

<1.5% 3%–4.5%1.5%–3%

Intermediate risk High risk High risk High risk

4.5%–6%

1B 1C 1D 1E

>6%

Class

Risk for eGFR decline

A patient’s ADPKD imaging classification† can help estimate their disease progression8

SELECT IMPORTANT SAFETY INFORMATION: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.

† Classification only applies to patients with typical morphology of ADPKD as defined by diffuse bilateral cystic involvement of the kidneys.8

In ADPKD

Seeing is BelievingImaging the kidneys can help you identify patients at risk of rapidly progressing ADPKD like Joe, who may benefit from treatment with JYNARQUE® (tolvaptan)1-3

9(Continued on next page)

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

IMPORTANT SAFETY 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

• 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

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.

INDICATION and IMPORTANT SAFETY INFORMATION for JYNARQUE® (tolvaptan)

10

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• OATP1B1/3 and OAT3 Transporter Substrates: Patients who take JYNARQUE should avoid concomitant use with OATP1B1/

B3 and OAT3 substrates (e.g., statins, bosentan, glyburide, nateglinide, repaglinide, methotrexate, furosemide), as the plasma concentrations of these substrates may be increased

• BCRP Transporter Substrates: Tolvaptan is an inhibitor of BCRP. Patients who take JYNARQUE, should avoid concomitant use with BCRP substrates (e.g., rosuvastatin)

• 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.

INDICATION and IMPORTANT SAFETY INFORMATION for JYNARQUE® (tolvaptan) (Cont’d)

Talk to your Otsuka Sales Representative about watching an interactive video featuring

Joe and visit JYNARQUEhcp.com to learn more about why

Seeing is Believing

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.All rights reserved.

©2019 Otsuka America Pharmaceutical, Inc. October 2019 10US19EBP0186

References: 1. Grantham JJ, Chapman AB, Torres VE. Clin J Am Soc Nephrol. 2006;1(1):148-157. 2. Grantham JJ, Torres VE. Nat Rev Nephrol. 2016;12(11):667-677. 3. Chapman AB, Bost JE, Torres VE, et al. Clin J Am Soc Nephrol. 2012;7(3):479-486. 4. Schrier RW, Brosnahan G, Cadnapaphornchai MA, et al. J Am Soc Nephrol. 2014;25(11):2399-2418. doi:10.1681/ASN.2013111184 5. Gansevoort RT, Arici M, Benzing T, et al. Nephrol Dial Transplant. 2016;31(3):337-348. 6. Cornec-Le Gall E, Audrézet MP, Rousseau A, et al. J Am Soc Nephrol. 2016;27(3):942-951. 7. Grantham JJ, Mulamalla S, Swenson-Fields KI. Nat Rev Nephrol. 2011;7(10):556-566. 8. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. J Am Soc Nephrol. 2015;26(1):160-172. 9. Bhutani H, Smith V, Rahbari-Oskoui F, et al; for the CRISP Investigators. Kidney Int. 2015;88(1):146-151. doi:10.1038/ki.2015.71 10. Soroka S, Alam A, Bevilacqua M, et al. Can J Kidney Health Dis. 2017;4:2054358117695784. doi:10.1177/2054358117695784 11. Magistroni R, Corsi C, Martí T, Torra R. Am J Nephrol. 2018;48(1):67-78. doi:10.1159/000491022

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.