JINARC TABLET

Canada - English - Health Canada

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Active ingredient:
TOLVAPTAN; TOLVAPTAN
Available from:
OTSUKA PHARMACEUTICAL CO LTD
ATC code:
C03XA01
INN (International Name):
TOLVAPTAN
Dosage:
15MG; 15MG
Pharmaceutical form:
TABLET
Composition:
TOLVAPTAN 15MG; TOLVAPTAN 15MG
Administration route:
ORAL
Units in package:
1ML/5ML
Prescription type:
Prescription
Therapeutic area:
VASOPRESSIN ANTAGONISTS
Product summary:
Active ingredient group (AIG) number: 0256610004; AHFS: 40:28.28
Authorization status:
APPROVED
Authorization number:
02491575
Authorization date:
2019-08-16

Documents in other languages

JINARC

Product Monograph

Page 1 of 43

PRODUCT MONOGRAPH

JINARC

(tolvaptan)

Tablets, 15 mg, 30 mg, 45 mg, 60 mg and 90 mg

Vasopressin V

-receptor Antagonist

Otsuka Pharmaceutical Co., Ltd.

Tokyo, Japan 101-8535

Imported and distributed by

Otsuka Canada Pharmaceutical Inc.

Saint-Laurent, Quebec

H4S 2C9

Date of Preparation:

February 23, 2015

Date of Revision:

October 23, 2019

Submission Control No: 228294

JINARC

Product Monograph

Page 2 of 43

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................ 3

SUMMARY PRODUCT INFORMATION ....................................................................... 3

INDICATIONS AND CLINICAL USE ............................................................................. 3

CONTRAINDICATIONS .................................................................................................. 4

WARNINGS AND PRECAUTIONS ................................................................................. 5

ADVERSE REACTIONS ................................................................................................... 9

DRUG INTERACTIONS ................................................................................................. 15

DOSAGE AND ADMINISTRATION ............................................................................. 17

OVERDOSAGE ................................................................................................................ 20

ACTION AND CLINICAL PHARMACOLOGY ........................................................... 22

STORAGE AND STABILITY ......................................................................................... 25

DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................ 25

PART II: SCIENTIFIC INFORMATION .............................................................................. 26

PHARMACEUTICAL INFORMATION ......................................................................... 26

CLINICAL TRIALS ......................................................................................................... 27

DETAILED PHARMACOLOGY .................................................................................... 35

TOXICOLOGY ................................................................................................................ 35

REFERENCES .................................................................................................................. 38

PART III: CONSUMER INFORMATION ............................................................................. 40

JINARC

Product Monograph

Page 3 of 43

JINARC

(tolvaptan tablets)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Non-medicinal Ingredients

Oral

Tablets, 15 mg, 30 mg

45 mg, 60 mg and 90

Corn starch, hydroxypropyl cellulose, lactose

monohydrate, low-substituted hydroxypropyl

cellulose, magnesium stearate,

microcrystalline cellulose, and FD&C Blue

No. 2 Aluminum Lake as colorant

INDICATIONS AND CLINICAL USE

JINARC (tolvaptan) is indicated to slow the progression of kidney enlargement and kidney function decline

in patients with autosomal dominant polycystic kidney disease (ADPKD). In ADPKD, kidney enlargement

reflects renal cyst burden.

In order to select patients who might best benefit from the effects of JINARC, clinical trials evaluated

ADPKD patients having a total kidney volume (TKV) ≥ 750 mL, and/or renal function corresponding to a

CKD-EPI eGFR ≥25 mL/min/1.73m

, at the time of initiation of treatment.

JINARC treatment should be initiated and monitored under the supervision of a nephrologist or specialist

with expertise in the management of patients with ADPKD and a full understanding of the benefits and

risks of tolvaptan therapy including hepatic toxicity and monitoring requirements.

Careful consideration and discussion of the appropriateness of JINARC treatment should be undertaken

between the prescriber and patient before initiation of therapy, taking into account the potential benefits

and risks of treatment. Upon mutual agreement to undertake treatment with JINARC, a signed, duly-

documented, manufacturer and product-specific patient-prescriber agreement (PPAF) is required outlining

relevant patient selection criteria to be considered, expected benefits and risks of treatment, and the need

for mandatory hepatic function monitoring (see WARNINGS AND PRECAUTIONS, Hepatotoxicity, and

DOSAGE AND ADMINISTRATION).

JINARC Controlled Hepatic Safety Monitoring and Distribution Programme

JINARC (tolvaptan) is available for treatment of patients with ADPKD only through a manufacturer and

product-specific controlled hepatic safety monitoring and distribution (HSMD) programme conducted and

maintained by, or for, the market authorisation holder of JINARC. A duly signed manufacturer and

product-specific PPAF is required for enrollment in the HSMD programme. For more information on the

programme, please call 1-844-254-6272.

Geriatrics (> 65 years of age): The safety and effectiveness of JINARC in geriatric patients has not been

established.

JINARC

Product Monograph

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Pediatrics (< 18 years of age): JINARC has not been studied in pediatric patients with ADPKD. Its use is

not recommended in this patient population.

CONTRAINDICATIONS

JINARC (tolvaptan) is contraindicated in:

Patients who have been asked to permanently discontinue tolvaptan in the past

Patients with known or suspected hypersensitivity to tolvaptan, benzazepine or benzazepine

derivatives (e.g. mirtazapine) or to any of the excipients. For a complete listing, see DOSAGE

FORMS, COMPOSITION AND PACKAGING.

Patients with hypovolemia

Patients with hypernatremia

Patients with anuria (see WARNINGS AND PRECAUTIONS, Renal Impairment)

Patients who do not have access to fluids or who cannot respond to the physiologic sensation of

thirst

Patients with a history, signs or symptoms of significant liver impairment or injury, excluding

uncomplicated polycystic liver disease (see WARNINGS AND PRECAUTIONS, Hepatotoxicity,

and/or Hepatic Impairment, and DOSAGE AND ADMINISTRATION, Dosing Considerations,

Hepatic Impairment)

Concomitant use of strong CYP3A inhibitors, e.g., ketoconazole, itraconazole, clarithromycin,

telithromycin, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone (see DRUG

INTERACTIONS, Drug-Drug Interactions)

Pregnancy (See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women)

Nursing women (See WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women)

Patients with one of the following rare hereditary diseases: Galactose intolerance, Lapp lactase

deficiency or Glucose-galactose malabsorption because lactose is a non-medicinal ingredient in

JINARC.

JINARC

Product Monograph

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WARNINGS AND PRECAUTIONS

Dehydration

Due to a prominent aquaretic effect, treatment with tolvaptan may result in dehydration which constitutes a

risk factor for renal dysfunction. If dehydration becomes evident, take appropriate action which may

include the need to interrupt or reduce the dose of tolvaptan and increase fluid intake. Special care should

be taken in patients having diseases that impair appropriate fluid intake or who are at an increased risk of

water loss, e.g. in case of vomiting or diarrhea. JINARC should not be prescribed to patients who cannot

perceive or respond to thirst (see CONTRAINDICATIONS).

Tolvaptan may cause undesirable effects related to water loss such as thirst, polyuria, nocturia, and

pollakiuria. Therefore, it is imperative that patients should have access to water (or other aqueous fluids)

and be able to drink sufficient amounts of these fluids. Patients should be instructed to drink water or other

aqueous fluids at the first sign of thirst in order to avoid excessive thirst or dehydration (see DOSAGE

AND ADMINISTRATION).

Patients should be generally encouraged to drink water while taking JINARC to avoid development of

dehydration or hypernatremia, and to improve tolerability of tolvaptan.

Drugs metabolised by CYP-3A or transported by P-gp

JINARC is a substrate of CYP-3A and co-administration with CYP-3A inhibitors or CYP-3A inducers may

lead to a change in exposure. Patient response should be monitored and the dose adjusted accordingly, as

appropriate.

CYP-3A Inhibitors

CYP3A4 is the predominant enzyme involved in tolvaptan metabolism. Concomitant use with strong

CYP3A4 inhibitors is contraindicated as this may lead to a significant increase in tolvaptan exposure.

In an interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, significantly

inhibited the metabolism of tolvaptan, increasing mean tolvaptan exposure up to 5.4-fold (as determined by

AUC∞). (see CONTRAINIDICATIONS).

Concomitant use with moderate CYP-3A inhibitors, i.e., verapamil, fluconazole and erythromycin, requires

lowered dosing of JINARC (see DRUG INTERACTIONS, and DOSAGE AND ADMINISTRATION,

CYP-3A Inhibitors).

WARNING: IDIOSYNCRATIC HEPATIC TOXICITY

JINARC (tolvaptan) use has led to idiosyncratic elevations of blood alanine and aspartate

aminotransferases (ALT & AST), rarely associated with concomitant elevations of total bilirubin

(see Hepatotoxicity, below). To help mitigate the risk of liver injury, blood testing for hepatic

transaminases and total bilirubin is required prior to initiation of JINARC, then hepatic

transaminases continuing monthly for 18 months, every 3 months for the next 12 months, and then

every 3-6 months thereafter during treatment with JINARC (see DOSAGE AND

ADMINISTRATION, Dosing Considerations; See WARNINGS AND PRECAUTIONS,

Hepatotoxicity). Therefore, JINARC is available for treatment of patients with ADPKD only

through a controlled hepatic safety monitoring and distribution (HSMD) programme conducted and

maintained by, or for, the market authorization holder of JINARC.

JINARC

Product Monograph

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JINARC should not be taken with grapefruit juice.

CYP-3A Inducers

Concomitant use of JINARC with strong CYP-3A inducers should be avoided, e.g. rifampin, phenytoin,

carbamazepine, St. John’s Wort (see DRUG INTERACTIONS, and DOSAGE AND ADMINISTRATION,

CYP-3A Inducers).

P-gp Inhibitors

Reduction in the dose of JINARC may be required in patients concomitantly treated with P-glycoprotein

(P-gp) inhibitors, such as cyclosporine and quinidine, based on clinical response (see DRUG

INTERACTIONS, and DOSAGE AND ADMINISTRATION, P-gp Inhibitors). However, concomitant use

with those P-gp inhibitors that also act as strong CYP-3A inhibitors (e.g., ketoconazole, clarithromycin,

ritonavir, saquinavir), is contraindicated (see CONTRAINDICATIONS).

Hepatotoxicity

Tolvaptan has been associated with idiosyncratic drug-induced hepatocellular injury, as seen by elevations

of serum alanine and aspartate aminotransferases (ALT and AST), rarely associated with concomitant

elevations of total bilirubin (BT).

In a double-blind, placebo-controlled trial called TEMPO 3:4 completed in patients with ADPKD,

elevation (>3 x upper limit of normal [ULN]) of ALT was observed in 4.4% (42/958) of patients on

tolvaptan, and 1.0% (5/484) of patients on placebo, while elevation (>3 x ULN) of AST was observed in

3.1% (30/958) of patients on tolvaptan and 0.8% (4/484) patients on placebo when monitoring for liver

enzymes elevation was every 3-4 months (also, see ADVERSE REACTIONS, Hepatic Injury). Two

(2/957, 0.2%) of these tolvaptan treated-patients, as well as a third patient from an extension open-label

trial, exhibited increases in hepatic enzymes (>3 x ULN) with concomitant elevations in total bilirubin

(>2 x ULN). The period of onset of hepatocellular injury, as reflected by ALT elevations >3 x ULN, was

within 3 to 14 months after initiating treatment, and these increases were reversible, with ALT returning to

<3 x ULN within 1 to 4 months. While these concomitant elevations were gradually reversible with prompt

discontinuation of tolvaptan, they represent a potential for significant liver injury. Similar changes with

other drugs have been associated with the potential to cause irreversible and potentially life-threatening

liver injury. The incidence of hepatotoxicity does not appear to be dose related. To date, there is no

evidence of hepatocellular injury with tolvaptan when used in patients not treated for ADPKD.

In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation

has been reported.

In another double-blind placebo-controlled trial (called REPRISE) including patients with later stages of

ADPKD, all patients were monitored monthly for liver enzymes elevation. In the single-blind tolvaptan

run-in phase, elevations (>3 x ULN) of ALT and AST were observed in 0.2% (3/1,478) and 0.2% (3/1,477)

of patients on tolvaptan, respectively. Relative to the first double-blind, placebo-controlled trial, similar

elevations (>3 x ULN) of ALT (5.6% (38/681) of patients on tolvaptan and 1.2% (8/685) of patients on

placebo) and AST (3.5% (24/681) of patients on tolvaptan and 0.9% (6/685) of patients on placebo) were

observed in the double-blind phase. Overall, all patients recovered and no subject met Hy’s laboratory

criteria relative to laboratory values of potential clinical relevance, i.e. increases in hepatic enzymes

(>3 x ULN) with concomitant elevations in total bilirubin (>2 x ULN) (see ADVERSE REACTIONS,

Hepatic Injury). Data suggest that monthly liver function monitoring during treatment helps detect liver

enzymes elevation early on.

JINARC

Product Monograph

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To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases

and total bilirubin is required prior to initiation of JINARC, then hepatic transaminases continuing monthly

for 18 months, every 3 months for the next 12 months, and then at 3-6 month intervals thereafter during

treatment with JINARC (see DOSING AND ADMINISTRATION, Dosing Considerations). Concurrent

monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper

abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) is also warranted.

At the onset of symptoms or signs consistent with hepatic injury, or if abnormal ALT or AST increases are

detected, JINARC administration must be immediately interrupted and repeat liver tests, i.e., ALT, AST,

total bilirubin, alkaline phosphatase, must be obtained as soon as possible, ideally within 48-72 hours (see

DOSING AND ADMINISTRATION, Dosing Considerations). Testing should continue at an increased

frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point cautious re-

initiation of JINARC may be considered.

Permanent discontinuation from receiving tolvaptan is a contraindication and so once a patient has been

permanently discontinued from receiving tolvaptan, treatment must never be restarted. The permanent

discontinuation status of patients should be verified prior to initiation with tolvaptan.

Anaphylaxis

In post-marketing experience, anaphylaxis (including anaphylactic shock and generalised rash) has been

reported very rarely following administration of JINARC. This type of reaction occurred after the first

administration of tolvaptan. Patients have to be carefully monitored during treatment. If an anaphylactic

reaction or other serious allergic reactions occur, administration of JINARC must be discontinued

immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication, treatment must

never be restarted after an anaphylactic reaction or other serious allergic reactions.

Patients with known hypersensitivity reactions to benzazepines or benzazepine derivatives (e.g. benazepril,

conivaptan, fenoldopam mesylate or mirtazapine) may be at risk for hypersensitivity reaction to tolvaptan.

If a hypersensitivity reaction is suspected, tolvaptan should be discontinued.(see

CONTRAINDICATIONS).

Hypernatremia

During treatment initiation, patients must be frequently monitored for serum sodium and volume status. If

serum sodium increases above the normal range, tolvaptan treatment must be down-titrated or discontinued

promptly, with serum sodium carefully monitored and appropriate clinical measures taken, as necessary

(see ADVERSE REACTIONS, Increases in Serum Sodium). Concomitant use with hypertonic saline

solutions or drugs that may increase serum sodium concentrations should be avoided.

Hyperkalemia

Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which

could result in increased serum potassium. Serum potassium levels should be monitored carefully after

initiation of tolvaptan, especially in those who are receiving drugs known to increase serum potassium

levels, e.g. spironolactone.

Hyperuricemia

Treatment with tolvaptan may lead to increases in serum uric acid and clinical gout (see ADVERSE

REACTIONS, Increases in Serum Uric Acid, and ACTION AND CLINICAL PHARMACOLOGY,

Pharmacodynamics). Uric acid concentrations should be evaluated prior to initiation of JINARC therapy,

and as indicated during treatment (see DOSAGE AND ADMINISTRATION, Increases in Serum Uric

JINARC

Product Monograph

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Acid).

Hypotension-related adverse events

In patients taking anti-hypertensive agents concomitantly with JINARC, an increased incidence of

hypotension-related adverse events was observed (see ADVERSE REACTIONS, Co-administration with

Anti-Hypertensive Medications), including dizziness and syncope. These findings were not seen in patients

not taking anti-hypertensive drugs.

Serum sodium abnormalities

Serum sodium abnormalities, i.e., hyponatremia or hypernatremia, must be corrected prior to initiation of

JINARC

therapy (also, see CONTRAINDICATIONS).

Vasopressin analogues

In addition to V

receptor mediated renal aquaretic effects, tolvaptan blocks vascular vasopressin V

receptors involved in the release of coagulation factors (e.g., von Willebrand factor) from endothelial cells.

Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated in patients using

these therapies concomitantly with tolvaptan. Accordingly, it is not recommended to administer JINARC

together with vasopressin analogues.

Special Populations

Pregnant Women:

There are no adequate, well-controlled trials of JINARC in pregnant women. In animal trials with

tolvaptan, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight,

delayed fetal ossification, and embryo-fetal death occurred. JINARC use is contraindicated in pregnant

women.

Women of childbearing potential must have effective contraceptive measures in place prior to and during

JINARC use.

Nursing Women:

It is not known whether JINARC is secreted into human milk. The presence of tolvaptan has been observed

in the milk of lactating rats. Because many drugs are secreted into human milk and because of the potential

for serious adverse reactions in nursing infants, treatment with JINARC is contraindicated in nursing

women.

Pediatrics (< 18 years of age):

JINARC has not been studied in pediatric patients with ADPKD. Its use is not recommended in this patient

population.

Geriatrics (> 65 years of age):

Safety and effectiveness in geriatric patients has not been studied.

Hepatic Impairment:

In hyponatremia studies, moderate or severe hepatic impairment was found to decrease the clearance and

increase the volume of distribution of tolvaptan (see CONTRAINDICATIONS, DOSAGE AND

ADMINISTRATION, Dosing Considerations, Hepatic Impairment, and ACTION AND CLINICAL

PHARMACOLOGY, Hepatic Insufficiency). The effects of such changes have not been studied in

ADPKD patients, since these patients generally have normal liver function even in the presence of

polycystic liver disease. JINARC is contraindicated in patients with clinically relevant impairment of

JINARC

Product Monograph

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hepatic function.

Renal Impairment:

JINARC is contraindicated in anuric patients, since it is not expected that tolvaptan would offer benefit in

these patients. Further, no clinical trial data are available in ADPKD patients on chronic dialysis or with a

creatinine clearance < 10 mL/min or with severe renal insufficiency (e.g. CKD-EPI eGFR <25

mL/min/1.73m

), including those unable to make urine (see DOSAGE AND ADMINISTRATION, Dosing

Considerations, Renal Impairment).

Potential for Cognitive and Motor Impairment

There are no controlled trials of the effects of tolvaptan on driving performance. When driving vehicles or

using machines, it should be taken into account that occasionally dizziness, asthenia and syncope may

occur.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The adverse reaction profile of JINARC (tolvaptan) is mainly based on three phase III clinical trials

(TEMPO 3:4, TEMPO 4:4 and REPRISE) which are briefly described in the CLINICAL TRIALS section.

In TEMPO 3:4, JINARC, total daily dose of 60-120 mg, has been evaluated for safety in 961 adult ADPKD

patients, with approximately 2,335 patient-years of exposure to tolvaptan. A total of 836 patients were

treated with tolvaptan for at least 1 year and 742 patients treated with tolvaptan had at least 3 years of

exposure.

In TEMPO 4:4, an open-label extension of TEMPO 3:4, JINARC was evaluated for safety in 1,083 adult

patients at a total daily dose of 60-120 mg, with approximately 3,281 patient-years of exposure to

tolvaptan. A total of 698 and 509 patients were treated with tolvaptan for at least 1 year and at least 3 years,

respectively.

In the REPRISE study, JINARC was evaluated for safety in 683 adult patients with approximately 612

patient-years of exposure to tolvaptan at a daily divided dose of up to 90 mg/30 mg. A total of 577 patients

were treated with tolvaptan for at least 1 year.

The total clinical safety database for tolvaptan is comprised of approximately 3,226 adult patients who

participated in single and multiple-dose trials in ADPKD and who had approximately 8,430 patient-years of

exposure to tolvaptan.

TEMPO 3:4

In a double-blind, placebo-controlled trial known as TEMPO 3:4, the most commonly reported adverse

reactions, consistent with the pharmacologic activity of tolvaptan, are thirst, polyuria, nocturia, and

pollakiuria occurring in approximately 55%, 38%, 29% and 23% of patients, respectively. The most

commonly reported serious adverse events (SAE) that occurred more frequently in tolvaptan patients

compared to placebo patients, with ≥0.5% difference, included increased ALT (0.9% vs. 0.4%), increased

AST (0.9% vs. 0.4%), chest pain (0.8% vs. 0.4%) and headache (0.5% vs. 0%).

Adverse events that led to discontinuation of tolvaptan were reported for 15.0% of patients, compared to

4.3% of placebo-treated patients, and included polyuria, pollakiuria, nocturia, thirst, abnormal hepatic

function, and fatigue.

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REPRISE

In REPRISE, patients who successfully completed the single-blind tolvaptan run-in period were

randomized to a double-blind phase. If an adverse event continued from the single- to double-blind period,

it was considered treatment emergent in the double-blind treatment period only if the adverse event

worsened, became more severe or serious, or led to discontinuation. In the single-blind tolvaptan run-in

phase the most frequently reported adverse reactions were: polyuria (31.4%), thirst (28.2%), and nocturia

(20.3%). In the single-blind tolvaptan run-in phase, the most frequently reported serious adverse events

(SAE) were alanine aminotransferase increased (0.3%), polyuria (0.3%), and nocturia (0.2%). In the

double-blind phase, the most frequently reported adverse reactions were (tolvaptan vs placebo): polyuria

(5.3% vs. 1.3%), nocturia (4.7% vs. 1.6%), blood creatinine increased (4.6% vs. 4.8%), thirst (3.8% vs.

1.9%), fatigue (3.5% vs. 0.6%), headache (2.3% vs. 1.6%), ALT increased (3.2% vs. 0.9%), and AST

increased (2.2% vs. 1.2%) and the most commonly reported SAE that occurred more frequently in

tolvaptan patients compared to placebo patients, with ≥0.5% difference, included hepatic enzyme increased

(1.6% vs 0.1%) and alanine aminotransferase increased (1.2% vs 0.0%).

In the single-blind tolvaptan run-in phase, 6.8% of patients discontinued tolvaptan due to an adverse event

which included polyuria, nocturia, thirst, fatigue and pollakiuria. In the double-blind phase, adverse events

that led to discontinuation of tolvaptan were reported for 9.5% of patients, compared to 2.2% of placebo-

treated patients, and included hepatic enzyme increased, ALT increased, AST increased, liver function test

increased, and pollakiuria.

Idiosyncratic elevations of hepatic aminotransferases, i.e., ALT and AST, have been observed in ADPKD

patients treated with JINARC, rarely associated with concomitant elevations in total bilirubin (see Clinical

Trial Adverse Drug Reactions, Hepatic Injury, below, and WARNINGS AND PRECAUTIONS,

Hepatotoxicity).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information from

clinical trials is useful for identifying drug-related adverse events and for approximating rates.

TEMPO 3:4

Table 1 below presents the incidence of treatment emergent adverse drug reactions occurring at a rate of

3% or greater and greater than placebo in TEMPO 3:4.

Table 1 Incidence of Treatment-Emergent Adverse Drug Reactions in at Least

3% of Tolvaptan Subjects and Greater than Placebo in TEMPO 3:4

System Organ Class

Preferred Term

Tolvaptan

(N = 961)

n (%)

Placebo

(N = 483)

n (%)

Cardiac disorders

Palpitations

34 (3.5)

6 (1.2)

Gastrointestinal disorders

Abdominal Distension

47 (4.9)

16 (3.3)

Constipation

81 (8.4)

12 (2.5)

Diarrhea

128 (13.3)

53 (11.0)

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Table 1 Incidence of Treatment-Emergent Adverse Drug Reactions in at Least

3% of Tolvaptan Subjects and Greater than Placebo in TEMPO 3:4

System Organ Class

Preferred Term

Tolvaptan

(N = 961)

n (%)

Placebo

(N = 483)

n (%)

Dry Mouth

154 (16.0)

60 (12.4)

Dyspepsia

76 (7.9)

16 (3.3)

Gastroesophageal Reflux Disease

43 (4.5)

16 (3.3)

General disorders and administration site conditions

Asthenia

57 (5.9)

27 (5.6)

Fatigue

131 (13.6)

47 (9.7)

Thirst

531 (55.3)

99 (20.5)

Metabolism and nutrition disorders

Decreased Appetite

69 (7.2)

5 (1.0)

Hyperuricemia

37 (3.9)

9 (1.9)

Polydipsia

100 (10.4)

17 (3.5)

Musculoskeletal and connective tissue disorders

Muscle Spasms

35 (3.6)

17 (3.5)

Nervous system disorders

Dizziness

109 (11.3)

42 (8.7)

Headache

241 (25.1)

121 (25.1)

Psychiatric disorders

Insomnia

55 (5.7)

21 (4.3)

Renal and urinary disorders

Nocturia

280 (29.1)

63 (13.0)

Pollakiuria

223 (23.2)

26 (5.4)

Polyuria

368 (38.3)

83 (17.2)

Skin and subcutaneous tissue disorders

Pruritus

33 (3.4)

13 (2.7)

Rash

40 (4.2)

9 (1.9)

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REPRISE

The incidence of treatment emergent adverse drug reactions occurring at a rate of 3% or greater and greater

than placebo in the REPRISE trial are presented in Table 2 below.

Table 2 Incidence of Treatment-Emergent Adverse Drug Reactions in at Least

3% of Tolvaptan Subjects and Greater than Placebo in REPRISE

Single-blind Treatment Period (≥3% only)

System Organ Class

Preferred Term

Tolvaptan

(N = 1,491)

n (%)

Gastrointestinal Disorders

Dry Mouth

132 (8.9)

General Disorders and Administration Site Conditions

Fatigue

64 (4.3)

Thirst

430 (28.8)

Infections and Infestations

Viral Upper Respiratory Tract

Infection

47 (3.2)

Metabolism and Nutrition Disorders

Polydipsia

146 (9.8)

Nervous System Disorders

Headache

63 (4.2)

Renal and Urinary Disorders

Nocturia

308 (20.7)

Pollakiuria

70 (4.7)

Polyuria

475 (31.9)

Double-blind Treatment Period (≥3% and greater than placebo)

System Organ Class

Preferred Term

Tolvaptan

(N = 681)

n (%)

Placebo

(N = 685)

n (%)

Gastrointestinal Disorders

Abdominal Pain

25 (3.7)

15 (2.2)

Constipation

22 (3.2)

18 (2.6)

Diarrhea

47 (6.9)

23 (3.4)

General Disorders and Administration Site Conditions

Fatigue

46 (6.8)

24 (3.5)

Thirst

27 (4.0)

13 (1.9)

Investigations

Alanine Aminotransferase Increased

25 (3.7)

9 (1.3)

Metabolism and Nutrition Disorders

Gout

21 (3.1)

20 (2.9)

Nervous System Disorders

Dizziness

25 (3.7)

19 (2.8)

Renal and Urinary Disorders

Nocturia

32 (4.7)

12 (1.8)

Polyuria

36 (5.3)

11 (1.6)

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Hepatic Injury

TEMPO 3:4

Elevations (>3 x ULN) of ALT were observed in 4.4% (42/958) of patients on tolvaptan, and 1.0% (5/484)

of patients on placebo in TEMPO 3:4, while elevation (>3 x ULN) of AST was observed in 3.1% (30/958)

of patients on tolvaptan and 0.8% (4/484) patients on placebo when monitoring for liver enzymes elevation

was every 3-4 months (see WARNINGS AND PRECAUTIONS, Hepatotoxicity). Elevations (>5 x ULN)

of ALT were observed in 2.3% (22/958) of patients on tolvaptan, and 0.4% (2/484) of placebo-treated

patients, while similar elevations of AST were observed in 1.9% (18/958), and 0.4% (2/484), respectively.

Elevations (>10 x ULN) of ALT were observed in 1.3% (12/958) of tolvaptan-treated patients, and (>20 x

ULN) in 0.6% (6/958), with none in placebo-treated patients. Elevations (>10 x ULN) of AST were

observed in 1.0% (10/958) of tolvaptan-treated patients, and (>20 x ULN) in 0.3% (3/958), with none in

placebo. Two (2/957, 0.2%) of these tolvaptan treated-patients, as well as a third patient from an extension

open-label trial (TEMPO 4:4), exhibited increases in hepatic enzymes (>3 x ULN) with concomitant

elevations in total bilirubin (>2 x ULN). In this pivotal trial, no cases of clinically-apparent hepatic failure

were reported.

REPRISE

In the single-blind tolvaptan run-in phase of REPRISE, elevations (>3 x ULN) of ALT and AST were

observed in 0.2% (3/1,478) and 0.2% (3/1,477) of patients on tolvaptan, respectively. Elevation of

(>5 x ULN) of ALT was observed in 0.1% (1/1,478) of patients on tolvaptan; no patients experienced ALT

elevations of (>10 x ULN) or (>20 x ULN). No AST elevations of (>5 x ULN), (>10 x ULN) or

(>20 x ULN) were observed.

In the double-blind phase, all patients were monitored monthly for liver enzymes elevations. Elevations (>3

x ULN) of ALT were observed in 5.6% (38/681) of patients on tolvaptan, and 1.2% (8/685) of patients on

placebo in REPRISE, while elevation (>3 x ULN) of AST were observed in 3.5% (24/681) of patients on

tolvaptan, and 0.9% (6/685) of patients on placebo. Elevations of (>5 x ULN) of ALT were observed in

3.4% (23/681) of patients on tolvaptan, and 0.7% (5/685) of patients on placebo, while similar elevations of

AST were observed in 1.8% (12/681), and 0.6% (4/685), respectively. Elevations (>10 x ULN) of ALT or

AST were observed in 1.2% (8/681) of tolvaptan-treated patients, and 0.6% (4/685) of patients on placebo.

Elevations (>20 x ULN) of ALT or AST were observed in 0.1% (1/681 and 1/685, respectively) of patients

on tolvaptan and placebo. For the 29 subjects in the tolvaptan group who discontinued tolvaptan after

reporting a potential clinically significant increased ALT (> 3 x ULN), the values returned toward normal

after tolvaptan was discontinued. For the 9 subjects in the tolvaptan group who did not discontinue the

investigational medicinal product after reporting a potential clinically significant increased ALT (> 3 x

ULN), the ALT values returned to normal for all except for 1 subject; that subject had 4 serious TEAEs of

liver function test increased, the last of which resulted in discontinuation of tolvaptan; values returned to

normal upon treatment discontinuation. Overall, no subject met the criteria for Hy’s laboratory criteria

relative to laboratory values of potential clinical relevance, i.e. increases in hepatic enzymes (>3 x ULN)

with concomitant elevations in total bilirubin (>2 x ULN). Data suggest that monthly liver function

monitoring during treatment helps detect liver enzymes elevation early on and mitigate the risk for drug-

induced liver injury.

Co-administration with Anti-Hypertensive Medications

Among ADPKD patients taking anti-hypertensive medications, a higher incidence of dizziness,

presyncope, and syncope was observed in patients treated with tolvaptan, compared to those treated with

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placebo as shown in Table 3(also, see WARNINGS AND PRECAUTIONS, Hypotension-related adverse

events).

Table 3

Incidence of Adverse Events Associated with Decreased Blood Pressure in TEMPO

3:4

System organ

class

Adverse Event

No anti−hypertensives

Anti−hypertensives

Tolvaptan

(N=129)

Placebo

(N=64)

Tolvaptan

(N=832)

Placebo

(N=419)

Nervous system

disorders

Dizziness

8 (6.2%)

5 (7.8%)

101 (12.1%)

37 (8.8%)

Dizziness exertional

0 (0.0%)

0 (0.0%)

1 (0.1%)

0 (0.0%)

Dizziness postural

0 (0.0%)

0 (0.0%)

6 (0.7%)

0 (0.0%)

Presyncope

0 (0.0%)

0 (0.0%)

3 (0.4%)

0 (0.0%)

Syncope

3 (2.3%)

0 (0.0%)

13 (1.6%)

3 (0.7%)

Total

11 (8.5%)

5 (7.8%)

116 (13.9%)

39 (9.3%)

Adverse events are counted only once for multiple occurrences of an event

.

Increases in Serum Sodium

TEMPO 3:4

The overall incidence of hypernatremia, reported as an adverse event, in TEMPO 3:4 was 2.8% in patients

treated with tolvaptan, compared to 1.0% in placebo-treated patients. The incidence of serum sodium >

150 mEq/L was 4.0%, and 1.4%, respectively. None of these events led to discontinuation of tolvaptan.

Mean trough sodium levels were observed to be 1-3 mEq/L higher than placebo.

REPRISE

In the single-blind period, no incidence of hypernatremia was reported. In the double-blind treatment

period of REPRISE, 0.4% of hypernatremia were reported in the tolvaptan group and 0% in the placebo

group. None of these events lead to tolvaptan discontinuation.

Increases in Serum Uric Acid

TEMPO 3:4

Decreased uric acid clearance by the kidney is a known effect of tolvaptan. Gout was observed in 2.9%

(20/961) of patients on tolvaptan and 1.4% (7/483) patients on placebo in TEMPO 3:4, with a higher

incidence of the use of allopurinol (8.2% vs. 5.8%), benzbromarone (0.4% vs. 0.2%), and colchicine-

containing medications (2.3% vs. 0.8%) to manage gout

in patients on tolvaptan, compared to patients on

placebo, respectively. Similarly, there was a higher incidence of increased blood uric acid (greater than 10

mg/dL), at 6.2% vs. 1.7%, reported in patients on tolvaptan compared to patients on placebo, respectively

(see DOSAGE AND ADMINISTRATION, Increases in Serum Uric Acid). Mean serum uric acid levels

increased about 0.9 mg/dL from baseline in patients treated with tolvaptan (see ACTION AND CLINICAL

PHARMACOLOGY, Pharmacodynamics).

REPRISE

In the single-blind period, gout was reported in 0.5% (7/1,491). Gout was observed in 3.1% (21/681) of

patients on tolvaptan and 2.9% (20/685) of patients on placebo in the double-blind placebo-controlled trial

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in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD).

Less Common Clinical Trial Adverse Drug Reactions <3%

The following adverse reactions occurred in <3% of ADPKD patients treated with tolvaptan and at a rate

greater than placebo in the double-blind, placebo-controlled trial (n = 961 tolvaptan; n = 483 placebo), and

are not mentioned elsewhere in the labeling:

Metabolism and Nutrition Disorders: dehydration, hyperglycemia

Respiratory, Thoracic and Mediastinal Disorders: dyspnea

Post-Market Adverse Drug Reactions

Angioedema, anaphylactic shock, and generalized rash, have been reported very rarely following

administration of tolvaptan for indications not related to ADPKD.

DRUG INTERACTIONS

Overview

Tolvaptan is a substrate of CYP-3A, and thus co-administration with CYP-3A inhibitors or CYP-3A

inducers may lead to a change in tolvaptan exposure. Patient response should be monitored and the dose

adjusted accordingly, as appropriate (see DOSAGE AND ADMINISTRATION). Tolvaptan does not

inhibit or induce its own metabolism.

Non-clinical studies indicate that tolvaptan is a substrate and competitive inhibitor of p-glycoprotein; other

transporters have not been studied.

There have been no trials performed to determine the potential interaction of tolvaptan with alcohol.

Drug-Drug Interactions

Effects of Other Drugs on Tolvaptan

CYP-3A Inhibitors

CYP3A4 is the predominant enzyme involved in tolvaptan metabolism. Concomitant use of tolvaptan with

strong CYP3A4 inhibitors is contraindicated as this may lead to a significant increase in tolvaptan

exposure. In an interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4,

significantly inhibited the metabolism of tolvaptan, increasing mean tolvaptan exposure up to 5.4-fold (as

determined by AUC

). Co-administration of a 30 mg single dose of tolvaptan with 200 mg QD

ketoconazole resulted in a 440% increase in AUC and 248% increase in C

for tolvaptan (see

CONTRAINDICATIONS).

CYP-3A Inducers

Co-administration of a single oral dose of 240 mg of tolvaptan with 600 mg QD of rifampicin, a strong

CYP-3A4 inducer, at steady state decreased tolvaptan C

and AUC

by approximately 85% (see

WARNINGS AND PRECAUTIONS, CYP-3A Inducers).

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P-gp Inhibitors

Co-administration of tolvaptan with P-gp inhibitors has not been studied in dedicated clinical studies (see

WARNINGS AND PRECAUTIONS, P-gp Inhibitors). Concomitant use with those P-gp inhibitors that

also act as strong CYP-3A inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, saquinavir), is

contraindicated (see CONTRAINDICATIONS)

Effects of Tolvaptan on Other Drugs

CYP-3A substrates

In healthy subjects, tolvaptan, a CYP-3A substrate, had no effect on the plasma concentrations of some

other CYP-3A substrates, e.g., warfarin or amiodarone. However, tolvaptan increased plasma levels of

lovastatin by 1.3- to 1.4-fold, indicating a potential effect on weak substrates of CYP-3A substrates.

Digoxin

Steady-state digoxin concentrations were statistically significantly increased (approximately 30% increase

as determined by C

and 20% increase as determined by AUC

), when digoxin was co-administered with

multiple 60 mg doses (QD) of tolvaptan; in vitro studies indicate that tolvaptan is a substrate and

competitive inhibitor of p-glycoprotein. Patients receiving digoxin should be evaluated for excessive

digoxin effects after adding tolvaptan.

Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide

Co-administration of tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide,

hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant

degree.

Vasopressin Analogues

In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V

receptors

involved in the release of coagulation factors (e.g., von Willebrand’s factor) from endothelial cells.

Therefore, the effect of vasopressin analogs such as desmopressin may be attenuated in patients using such

analogs to prevent or control bleeding when co-administered with tolvaptan. Administering JINARC with

vasopressin analogues is not recommended.

Drug-Food Interactions

Grapefruit Juice

Co-administration of tolvaptan with 240 mL of grapefruit juice produced a doubling of peak tolvaptan

concentrations (C

) but had no effect on tolvaptan elimination half-life (see WARNINGS AND

PRECAUTIONS, CYP-3A Inhibitors). JINARC should not be taken with grapefruit juice (see

WARNINGS & PRECAUTIONS; Drugs metabolised by CYP-3A or transported by P-gp).

Drug-Herb Interactions

Interactions with herbal products have not been established; however, St John’s Wort should be avoided

while taking JINARC.

Pharmacodynamic Interactions

Concomitant Diuretic Use

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Tolvaptan use alone produces a greater 24-hour urine volume than does furosemide or hydrochlorothiazide

alone. However, concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in

a 24-hour volume that is similar to that after tolvaptan administration alone.

Furosemide co-administered with tolvaptan produces a similar maximal rate of urine excretion compared to

furosemide alone, and 70% higher than tolvaptan alone. HCTZ co-administered with tolvaptan produces a

slightly higher maximal excretion rate compared to tolvaptan alone, and 66% higher compared to HCTZ

alone.

DOSAGE AND ADMINISTRATION

JINARC (tolvaptan) treatment should be initiated and monitored by a physician experienced in the

diagnosis and treatment of autosomal dominant polycystic kidney disease (ADPKD; see INDICATIONS

AND CLINICAL USE).

Upon mutual agreement to undertake treatment with JINARC, a

signed, duly-documented, manufacturer

and product-specific patient-prescriber agreement (PPAF) is required for all patients before initiation of

JINARC (see INDICATIONS AND CLINICAL USE). This written agreement should be kept in good

standing as long as JINARC treatment is continued.

JINARC (tolvaptan) is available for treatment of patients with ADPKD only through a manufacturer and

product-specific controlled hepatic safety monitoring and distribution (HSMD) programme conducted and

maintained by, or for, the market authorisation holder of JINARC. A duly signed manufacturer and

product-specific PPAF is required for enrollment in the HSMD programme. For more information on the

programme, please call 1-844-254-6272.

Prior to initiation of treatment with JINARC, it is important to determine whether expected benefit-risk is

deemed to be favourable for the individual patient to be treated. Based on TEMPO 3:4, patients most likely

to benefit from JINARC appear to be those with rapidly progressive ADPKD, or at a stage of incipient

rapid progression, but before widespread destruction of renal architecture has occurred. Factors associated

with rapid progression of ADPKD include, large total renal cyst mass for a given age, as measured by total

kidney volume (TKV), CKD Stage 2-3, rapid deterioration of renal function, presence of systemic

hypertension or albuminuria (also see, Dosing Considerations, below). Conversely, ADPKD patients

without evidence of hypertension, and especially those at an early stage of disease with excellent renal

function, e.g., estimated creatinine clearance (eCrCL) ≥ 120 mL/min, consistent with renal glomerular

(compensatory) hyperfiltration, appear to show little near-term benefit in terms of TKV progression or

diminution of renal function decline. From REPRISE, patients most likely to benefit from JINARC appear

to be those at high risk of progressive eGFR decline based on renal function for age (18 to 65 years of age

with baseline eGFR between 25 and 65 mL/min/1.73m

All patients need to be apprised of the risk of idiosyncratic drug-induced liver injury associated with

tolvaptan use in ADPKD (see WARNINGS AND PRECAUTIONS, Hepatotoxicity), and the need for

ongoing monitoring of hepatic function during JINARC treatment.

In order to enhance the continuous evaluation of the long-term effects of tolvaptan in ADPKD, all patients

to be initiated on JINARC should be offered participation in the manufacturer and product-specific

Canadian JINARC patient outcomes registry. For more information on the registry, please call 1-877-341-

9245 or go to www.clinicaltrials.gov, study ID NCT02925221.

Once JINARC treatment is instituted, all patients should be encouraged to drink water liberally on an

ongoing basis in order to match increased urine output, to reduce the likelihood of dehydration and

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hypernatremia from the aquaretic effects of tolvaptan (see WARNINGS AND PRECAUTIONS,

Dehydration).

Recommended Dose and Dosage Adjustment

JINARC is to be administered twice daily in split tolvaptan dose regimens of 45+15 mg, 60+30 mg, or

90+30 mg. According to these split-dose regimens, the total daily tolvaptan doses are 60, 90, or 120 mg,

respectively.

The initial dosage for JINARC is generally 60 mg tolvaptan per day, as a split-dose regimen of 45+15 mg,

with 45 mg taken upon waking, and 15 mg taken approximately 8 hours later. The initial dose should be

titrated upward to a split-dose regimen of 90 mg tolvaptan (60+30 mg) per day, and then to a target split-

dose regimen of 120 mg tolvaptan (90+30 mg) per day, if tolerated, with at least weekly intervals between

titrations. Dose titration should be performed judiciously to ensure that high doses are not poorly tolerated

through overly rapid up-titration. Physicians may down-titrate to lower doses based on patient tolerability,

and up-titrate again when appropriate. Patients should normally be maintained on the highest tolerated

dose of tolvaptan.

The aim of dose titration is to block activity of vasopressin at the renal V

receptor as completely and

constantly as possible, while maintaining acceptable fluid balance, in order to achieve optimal effects on

TKV progression or diminution of renal function decline. The adequacy of vasopressin suppression at a

given dose of JINARC can be monitored through measurement of urine osmolality and may be used to

optimise the clinical benefit of JINARC in ADPKD patients. Treatment with JINARC is more likely to

achieve a better clinical response in patients with greater mean changes from baseline urine osmolality (see

CLINICAL TRIALS, Figures 4 and 5). A target of a decrease of at least 300 mOsm/kg from baseline may

be considered ideal in most cases, although a decrease of at least 200 mOsm/kg from baseline may be

appropriate in those at moderate risk of disease progression and relatively early in their disease course, but

still eligible for JINARC treatment. If possible, an absolute urine osmolality of less than 300 mOsm/kg

should be maintained at all times (see CLINICAL TRIALS).

Measurement of urine concentrating ability prior to initiation of JINARC will help determine the

subsequent level of vasopressin blockade obtained with a particular dosage regimen of tolvaptan. Such

subsequent measurements may then be useful in guiding dose titration with tolvaptan, particularly in

patients in whom tolerability is dose limiting. Initial assessment of urine concentrating ability before

initiation of JINARC should be carried out following complete overnight fluid restriction of 10-14 hours,

using urine osmolality or specific gravity. During treatment with JINARC, measurement of urine

osmolality or specific gravity should be carried out at trough before the morning dose, to determine the

change in urine osmolality from baseline. However, patients then taking tolvaptan should not be restricted

in their usual fluid intake overnight. Although not specifically evaluated, a urine specific gravity in the

range of 1.005 generally corresponds to a Uosm < 300 mOsm/kg, although use of specific gravity

measurement is considered less accurate than direct measurement of urine osmolality.

Patients should be told that unnecessary treatment interruption should be avoided, and that daily adherence

to the recommended dosing regimen of JINARC is important in order to achieve best outcomes in terms of

diminution of renal cyst progression and preservation of renal function (see ACTION AND CLINICAL

PHARMACOLOGY, Pharmacodynamics).

JINARC may be taken with or without meals.

Therapy should be interrupted if the ability to drink or accessibility to water is limited.

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Dosing Considerations

Liver testing must be performed, including total bilirubin, prior to initiating treatment with JINARC to

establish baseline liver function. JINARC is contraindicated in patients with clinically relevant impairment of

hepatic function (also, see WARNINGS AND PRECAUTIONS, Hepatotoxicity, and/or Hepatic Impairment).

Treatment with JINARC should not normally be initiated in patients with AST/ALT >3 x ULN. However,

substantial hepatic cyst burden, without advanced impairment of hepatic function, should not serve as an

impediment to initiation of JINARC treatment for ADPKD. If, at any time during treatment with tolvaptan, a

patient shows abnormal ALT, AST or total bilirubin (BT) levels that fulfil the criteria for permanent

discontinuation, tolvaptan treatment should not be reinitiated. In case of abnormal baseline levels below the

limits for permanent discontinuation, pre-existing liver disease is likely, and treatment should only be initiated

if the potential benefits of treatment outweigh the potential risks and liver function testing must continue at

increased frequency. The advice of a hepatologist is recommended or ADPKD specialist.

To mitigate the risk of significant and/or irreversible liver injury, regular and ongoing blood testing

for hepatic transaminases is required

during JINARC treatment, on a monthly basis for the first 18

months, then every 3 months for 12 months, and thereafter at 3-6 month intervals during treatment

with JINARC.

At the onset of symptoms or signs consistent with hepatic injury, or if abnormal ALT, or AST increases are

detected, JINARC administration must be immediately interrupted and repeat liver tests, i.e., ALT, AST,

total bilirubin, alkaline phosphatase, must be obtained as soon as possible, ideally within 48-72 hours.

Testing should continue at an increased frequency until symptoms/signs/laboratory abnormalities stabilise

or resolve, at which point cautious re-initiation of JINARC may be considered.

Current clinical practice suggests that JINARC therapy should be interrupted upon confirmation of

sustained or increasing transaminase levels, and permanently discontinued if significant increases and/or

clinical symptoms of hepatic injury persist. Recommended guidelines for permanent discontinuation

include:

ALT or AST >8-times ULN

ALT or AST >5-times ULN, for more than 2 weeks

ALT or AST >3-times ULN, and total bilirubin > 2 x ULN or INR > 1.5

ALT or AST >3-times ULN, with persistent symptoms of hepatic injury as noted above.

If ALT and AST levels remain <3 x ULN, JINARC therapy may be cautiously continued with frequent

monitoring, as transaminase levels appear to stabilise during continued therapy in some patients without

increases in other liver function tests.

Hepatic Impairment

The effect of hepatic impairment on tolvaptan concentrations in treatment of ADPKD has not been studied.

These patients should be managed cautiously and liver enzymes should be monitored regularly.

Due to its potential to induce hepatocellular injury, patients with clinically relevant impairment of hepatic

function should not be treated with tolvaptan (see CONTRAINDICATIONS, and WARNINGS AND

PRECAUTIONS, Hepatotoxicity).

Renal Impairment

Patients who are anuric, or at, or approaching end-stage-renal disease (ESRD), would not be expected to

benefit from tolvaptan treatment (see WARNINGS AND PRECAUTIONS, Renal Impairment, and

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ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency). Treatment should be avoided in

these patients.

Increases in Serum Uric Acid

Tolvaptan use may lead to increases in serum uric acid and gout (see WARNINGS AND PRECAUTIONS,

Hyperuricemia, ADVERSE REACTIONS, Increases in Serum Uric Acid, and ACTION AND CLINICAL

PHARMACOLOGY, Pharmacodynamics). Uric acid concentrations should be evaluated prior to initiation

of JINARC therapy, and as indicated during treatment.

CYP-3A Inhibitors

Concomitant use of JINARC with strong CYP-3A inhibitors is contraindicated (see

CONTRAINDICATIONS, DRUG INTERACTIONS).

For patients taking moderate inhibitors of CYP-3A concomitantly (see WARNINGS AND

PRECAUTIONS, CYP-3A Inhibitors), split-dose regimens should be down-adjusted by half, e.g., split

dose regimens of 90+30 mg per day should be down-adjusted to 45+15 mg per day; 45 mg/15 mg per day

should be adjusted to 15 mg/15 mg per day; 60 mg/30 mg per day should be adjusted to 30 mg/15 mg per

day. Further reductions should be considered if patients cannot tolerate the reduced tolvaptan doses. With

such down-adjustments, the second daytime dose should be maintained at 15 mg, and the first daily dose

down-adjusted, as required.

CYP-3A Inducers

Concomitant use of JINARC with strong CYP-3A inducers should be avoided (see WARNINGS AND

PRECAUTIONS, Drugs metabolised by CYP-3A or transported by P-gp, and DRUG INTERACTIONS).

Missed Dose

If a patient misses a dose of JINARC, the patient should take their next dose at its scheduled time and

prescribed dose level.

Administration

Tolvaptan can be taken without regard to food or the timing of food. It should not be taken with grapefruit

juice, or after eating grapefruit, as this may cause a significant increase in tolvaptan concentrations.

OVERDOSAGE

In healthy subjects, single oral doses of JINARC (tolvaptan) of up to 480 mg, and multiple doses up to 300

mg once daily for 5 days have been well tolerated in trials. 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, that is, a rise in serum sodium concentration, polyuria, thirst, and

dehydration/hypovolemia.

No mortality was observed in rats or dogs following single oral doses of 2,000 mg/kg (maximum feasible

dose). A single oral dose of 2,000 mg/kg was lethal in mice and symptoms of toxicity in affected mice

included decreased locomotor activity, staggering gait, tremor and hypothermia.

If overdose occurs, estimation of the severity of poisoning is an important first step. A thorough history and

details of overdose should be obtained, and a physical examination should be performed. The possibility of

multiple drug involvement must be considered.

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Treatment should involve symptomatic and supportive care, with respiratory, ECG and blood pressure

monitoring, and water/electrolyte supplements as needed. A profuse and prolonged aquaresis should be

anticipated, which, if not matched by oral fluid ingestion, should be replaced with intravenous hypotonic

fluids, while closely monitoring electrolytes and fluid balance.

ECG monitoring should begin immediately and continue until ECG parameters are within normal ranges.

Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma

protein (> 98%). Close medical supervision and monitoring should continue until the patient recovers.

For management of suspected drug overdose, consult the regional Poison Control Centre.

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ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

JINARC (tolvaptan) is a selective vasopressin V

-receptor antagonist with an affinity for the V

-receptor

that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V

-receptor is 29

times greater than for the V

-receptor. When taken orally, tolvaptan inhibits the binding of vasopressin at

the V

-receptor in the kidney. The decreased binding of vasopressin to the V

-receptor lowers adenylate

cyclase activity resulting in a decrease in intracellular adenosine 3′, 5′-cyclic monophosphate (cAMP)

concentrations. 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. Inhibition of the V

-receptor in the kidney epithelial cells also

prevents aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn results in an

increase in free water clearance, i.e., aquaresis, and a decrease in urine osmolality.

Tolvaptan metabolites have no or weak antagonist activity for human V

-receptors, compared with

tolvaptan. In vitro studies have found both enantiomers of tolvaptan to be equally potent at the V

receptor.

Pharmacodynamics

With the recommended split-dose regimens in patients with autosomal dominant polycystic kidney disease

(ADPKD), tolvaptan inhibits vasopressin from binding to the V

-receptor in the kidney for the entire day,

as indicated by increased urine output and decreased urine osmolality by about 250-300 mOsm/kg from

baseline, or to below 300 mOsm/kg. Higher doses, e.g., 90+30 mg/day, reduced urine osmolality to below

300 mOsm/kg in a greater proportion of patients than the lower doses.

In healthy subjects or patients with CKD Stage 1 to 4 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 and 90 mg

produce a peak effect of about 9 mL/min increase in urine excretion rate that 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. The offset of tolvaptan action is rapid with urine excretion rate

returning to baseline within 24 hours following a 90 mg dose.

Increases in daily urine output in response to tolvaptan treatment are positively correlated with baseline

renal function. Following a 90+30 mg split-dose regimen in patients with CKD Stage 1 or 2, the change in

mean daily urine volume was about 4 L for a mean total daily volume of about 7 L. In Stage 4 patients, the

mean change in daily urine volume was about 2 L for a total daily urine volume of about 5 L. Urine

osmolality appears to be maximally suppressed at a urine excretion rate of about 4 mL/min or about 5

L/day.

The increase in free water excretion can result in an increase in serum sodium concentration unless fluid

intake is increased to match urine output. Following a 90+30 mg split-dose regimen of tolvaptan in patients

with CKD Stage 1 to 4, mean serum sodium concentrations were increased about 2 mEq/L.

Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan treatment and return to

baseline levels when treatment is stopped.

With tolvaptan treatment, small decreases in glomerular filtration rate, as measured by iothalamate

clearance, in the order of 6-10% are observed soon after JINARC initiation, and are independent of

baseline renal function. It is noted that percent changes in renal plasma flow are highly correlated to

percent changes in GFR, with these changes reversible upon discontinuation of tolvaptan. It is believed

these changes may occur in response to the observed decrease in urine osmolality caused by tolvaptan.

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Serum concentrations of creatinine and cystatin C are slightly increased in patients with CKD Stage 1 to 3,

with creatinine changes 2-fold larger in patients with CKD Stage 4.

Uric acid clearance is decreased about 20%-25% in patients with eGFR

MDRD

>30 mL/min/1.73m

. Mean uric

acid values observed at baseline in the pivotal registration trial were 5.6 mg/dL (n= 948), increased to 6.4

mg/dL (n= 907) following 3 weeks of tolvaptan titration, and were 6.5 mg/dL (n= 721) following 36 months

of treatment with tolvaptan (see WARNINGS AND PRECAUTIONS, Hyperuricemia). With placebo, mean

uric acid values observed at baseline were 5.5 mg/dL (n= 482), increased to 5.6 mg/dL (n= 474) following 3

weeks of treatment, and were 5.9 mg/dL (n= 406) following 36 months of treatment.

After 3 weeks of tolvaptan treatment at doses from 90 to 120 mg/day, ADPKD patients demonstrated a

total kidney volume (TKV) reduction of approximately 3.7%, p<0.0001 (see CLINICAL TRIALS, Figure

1). Treatment with tolvaptan appears more likely to achieve a greater response in patients with the greatest

mean changes from baseline in urine osmolality (see CLINICAL TRIALS, Figures 4 and 5). Repeated

“breakthrough” from inhibition, as indicated by a urine osmolality greater than plasma osmolality, i.e., >

300 mOsm/kg, may provide a stimulus for cyst cell division and progression of the disease.

In healthy subjects, no prolongation of the QT interval was observed with tolvaptan following multiple

doses of 300 mg/day for 5 days.

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 examined. For single doses, area under the curve (AUC) increases

proportionally with dose. After administration of doses ≥ 60 mg, however, C

increases less than

proportionally with dose. For multiple administration of 300 mg doses compared to 30 mg doses, C

AUC were only 4.2- and 6.4-fold higher. The pharmacokinetic properties of tolvaptan are stereospecific,

with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3.

Following oral administration of tolvaptan, peak concentrations are observed between 2 and 4 hours post-

dose.

Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the

volume of distribution of tolvaptan.

Absorption:

The absolute bioavailability of tolvaptan is 56% (range 42-80%). In vitro data indicate that tolvaptan is a

substrate and inhibitor of P-gp.

Ingestion of a single dose of 90 mg of tolvaptan with a high-fat meal increased tolvaptan C

1.96-fold,

with no increase in AUC. Similar intake of 60 mg and 30 mg increased tolvaptan C

1.4- and 1.2-fold,

respectively, with no significant increase in AUC.

Distribution:

Tolvaptan is highly plasma protein bound (98%).

Metabolism:

Tolvaptan is extensively metabolized with less than 1% of the dose excreted unchanged in the urine.

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Tolvaptan is a CYP-3A substrate and does not appear to have clinically meaningful inhibitory activity. In

vitro trials indicated that tolvaptan was extensively metabolized by the cytochrome P450 isoenzyme CYP-

3A4/5 and formed many metabolites, with fourteen identified in plasma, urine and feces. The metabolism

of most tolvaptan metabolites was also mediated by CYP-3A4/5.

Excretion:

Tolvaptan is eliminated entirely by non-renal routes, with 19% of a radioactive dose excreted as unchanged

tolvaptan in the feces. The rest is metabolised mainly, if not exclusively, by CYP-3A. After oral dosing,

clearance is about 4 mL/min/kg and the terminal phase half-life is about 9 hours. The accumulation factor

of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to ≤ 16% of the peak

concentrations, suggesting a dominant half-life somewhat shorter than 9 hours. There is marked inter-

subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging

between 30 and 60%.

Special Populations and Conditions

Pediatrics:

The pharmacokinetics of tolvaptan in patients under the age of 18 years have not been studied.

Geriatrics:

Age did not substantially influence the pharmacokinetic characteristics of tolvaptan following single-dose

or multiple-dose administration of 60 mg tablets.

Gender:

Gender was found to have no significant effect on tolvaptan pharmacokinetics.

Race:

In an open-label crossover trial, 24 Japanese and 25 Caucasian men were administered a single 30 mg oral

dose of tolvaptan. The mean tolvaptan C

and AUC

values were only 5-15% higher in Japanese subjects

compared to Caucasian subjects.

Hepatic Insufficiency:

In a population pharmacokinetic analysis of hyponatremia patients, moderate hepatic impairment was

associated with a 19% decrease in tolvaptan clearance and severe hepatic impairment was associated with a

24% decrease in clearance and a 50% increase in volume of distribution. The effects of such changes have

not been studied in ADPKD patients who typically have normal hepatic function despite having variable

degrees of polycystic liver disease.

Renal Insufficiency:

Tolvaptan has been studied in subjects with varying degrees of renal function following a single 60-mg

dose. Tolvaptan AUC

in subjects with CrCL<30 mL/min was approximately 1.9 times higher than that in

subjects with CrCL>60 mL/min, but there was no correlation between tolvaptan AUC

and changes in

pharmacodynamic endpoints (urine volume, fluid intake, creatinine and free water clearances, urinary

excretions of creatinine, Na+ and K+). Tolvaptan increased free water clearance and suppressed urine

osmolality to below 300 mOsm/kg in all subjects studied. Increases in urine output were positively

correlated with baseline renal function and were significantly lower in patients with CKD Stage 4, i.e.,

GFR <30 mL/min.

No clinical trial data is available for tolvaptan in patients with a creatinine clearance <10 mL/min or in

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patients on chronic dialysis.

STORAGE AND STABILITY

Store JINARC at 15

C to 30

DOSAGE FORMS, COMPOSITION AND PACKAGING

JINARC (tolvaptan) is available in weekly combination blister packs of 15+15 mg, 30+15 mg, 45+15 mg,

60+30 mg, and 90+30 mg tablets. Each blister pack will contain a total of 14 tablets, 7 tablets of each

strength, with one tablet from the row of the higher dose to be taken each morning and one tablet from the

row of the lower dose to be taken each evening.

JINARC 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with “otsuka” and “15”

on one side.

JINARC 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with “otsuka” and “30” on

one side.

JINARC 45 mg tablets are non-scored, blue, square, shallow-convex, debossed with “otsuka” and “45” on

one side.

JINARC 60 mg tablets are non-scored, blue, modified rectangular, shallow-convex, debossed with “otsuka”

and “60” on one side.

JINARC 90 mg tablets are non-scored, blue, pentagonal, shallow-convex, debossed with “otsuka” and “90”

on one side.

Inactive Ingredients: Corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted

hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and FD&C Blue No. 2 Aluminum

Lake as colorant.

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name:

Tolvaptan

Chemical name:

(±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)

carbonyl]-o-tolu-m-toluidide

Molecular formula and molecular mass: C

448.94

Structural formula:

Physicochemical properties: Tolvaptan is a white crystalline powder. It is practically insoluble in

water (0.00005 w/v% at 25

C), and no pH dependence of solubility

was observed. Tolvaptan is stable to light.

and enantiomer

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CLINICAL TRIALS

The efficacy of JINARC in slowing the progression of kidney enlargement (reflecting cyst growth) and

kidney function decline is based on randomized, double-blind, placebo-controlled trials in early to late

stage of ADPKD.

TEMPO 3:4

In the pivotal double-blind, 36-month, placebo-controlled, multi-center trial, called TEMPO 3:4, a total of

1,445 adult patients (age 18-50 years) with early, rapidly-progressing ADPKD (meeting modified Ravine

criteria, total kidney volume (TKV) ≥750 mL, and estimated creatinine clearance ≥60 mL/min) were

randomised 2:1 to treatment with JINARC (tolvaptan) or placebo, respectively. A total of 1.444 patients

were treated for up to 3 years, then followed for 14-42 days after treatment withdrawal. Randomisation was

stratified based on several predictors of more rapid progression, namely baseline hypertension status,

kidney volume and renal function. All patients remained on standard concomitant medications. Patients

were evaluated at screening, baseline, during weekly titration steps and at intervals of at least 4 months for

outcome, laboratory and safety assessments. At baseline and yearly visits, magnetic resonance imaging

(MRI) of TKV and pharmacokinetic assessments were also performed. Patients who completed the study

terminated treatment at 3 years, and were followed for a further period of 2-6 weeks to assess off-drug

effects.

Tolvaptan (N=961) and placebo (N=484) groups were well matched, with an average age of 39 years, 52%

being male, 84% Caucasian, 13% Asian and 3% other races. At baseline, 79% had hypertension, average

estimated glomerular filtration rate (eGFR) was 82 mL/min/1.73 m

calculated by CKD-EPI, and mean

TKV was 1,692 mL, with height-adjusted TKV 972 mL/m. Using eGFR

CKD-EPI

, the distribution of

tolvaptan and placebo patients at baseline across CKD stages was as follows: CKD Stage 1 (35%), 2 (48%),

and 3 (17%). Within the study population receiving placebo, stratification factors successfully predicted

more rapid progression in those who had larger kidneys, lower eGFR, or hypertension at baseline. All

patients were encouraged to drink adequate water to avoid thirst or dehydration and at night before retiring.

The primary endpoint was the difference of the rate of change of TKV, normalised as a percentage. TKV

increased in the tolvaptan group at a rate of 2.8% per year (95% CI, 2.5% to 3.1%), compared with 5.5%

per year (95% CI, 5.1% to 6.0%) for placebo, representing a 49.2% reduction in growth rate averaged over

3 years (p<0.0001).

Analysis also indicated that the effect of treatment on TKV growth was greatest in the first year and

included negative cyst growth for the tolvaptan group (−1.7%), compared with positive cyst growth in the

placebo group (4.6%), for a treatment effect of −6.3%, a statistically significant difference between groups

(p < 0.0001). However, tolvaptan has a short-term, so-called “secretory” effect on TKV, presumably due to

its aquaretic effect, leading to a diminution of renal cyst fluid, which appears largely reversible upon

discontinuation of tolvaptan (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

This phenomenon will thus apparently overstate the effect of tolvaptan on renal cyst proliferation in the

first year when measured by TKV, see Figure 1 below. During the second and third years, kidney

enlargement progressed in both groups. Further absolute reductions in TKV growth (relative to placebo) of

1.92% per year (95%CI 2.81 to 1.03%) and 1.78% per year (95%CI 2.77 to 0.78%) were observed at Year

2 and Year 3 of therapy, respectively.

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Figure 1: Model of Tolvaptan’s Effects on Total Kidney Volume

This Figure represents analysis of percent change in TKV over time for tolvaptan-treated patients (intention-to-treat dataset)

from TEMPO 3:4, overlaid with 3-week data from a Phase 2 pharmacodynamic study.

Pre-specified secondary end-points were tested sequentially. The key secondary composite outcome

endpoint, reflecting ADPKD progression, was evaluated using a time-to-event analysis, consisting of:

worsening kidney function, defined as a persistent 25% reduction, i.e., reproduced over at least two

weeks, in reciprocal serum creatinine during treatment (equivalent to a 33% increase in serum

creatinine), from end of titration to last on-drug visit;

medically significant kidney pain, defined as requiring prescribed leave, last-resort analgesics,

narcotic or anti-nociceptive, radiologic or surgical interventions;

worsening hypertension, defined as a persistent increase in blood pressure category, or an increase

in anti-hypertensive medication(s); or

worsening albuminuria, defined as a persistent increase in albumin/creatinine ratio category (seen at

2 of 3 successive assessments).

The rate of ADPKD-related events, as assessed by the key secondary composite outcome endpoint, was

decreased by 13.5% in tolvaptan-treated patients, compared to placebo-treated patients (44 vs. 50 events;

HR 0.87; 95% CI, 0.78 to 0.97; p=0.0095), see Figure 2, below.

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Figure 2: Key Secondary Composite Endpoint of Clinical Progression Events in TEMPO 3:4

The result of the key secondary composite outcome endpoint is primarily attributed to effects on worsening

kidney function and medically significant kidney pain. The renal function events were seen to occur 61.4%

less often for tolvaptan compared with placebo (HR 0.39; 95% CI, 0.26 to 0.57; nominal p <0.0001), and

renal pain events occurred 35.8% less often in tolvaptan-treated patients (HR 0.64; 95% CI, 0.47 to 0.89;

nominal p=0.007), see Figure 2, above. In contrast, there was no effect of tolvaptan on either progression of

hypertension or albuminuria. It should be noted, however, that 79% of patients were already hypertensive

at baseline in both groups.

The next sequentially ordered secondary endpoint was the slope of kidney function decline, assessed as

change in estimated glomerular filtration rate (eGFR

CKD-EPI

) during treatment from end of titration to last

on-drug visit. The tolvaptan-treated patients had a 26.4% reduction in the rate of renal function decline,

compared to placebo, -2.7 versus -3.6 mL/min/1.73m

/year, respectively, p <0.0001. Note that initiation of

tolvaptan is associated with a generally reversible, prompt decline in GFR, likely due to hemodynamic

factors (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

Preliminary analyses for urine osmolality (Uosm) suggest that the greatest degree of efficacy, as related to

outcomes of events of worsening renal function or renal pain, is seen when Uosm was suppressed by at least

-300 mOsm/kg. A lesser degree of efficacy (when compared with other groups of Uosm suppression) is seen

for the group between -105 and -300 mOsm/kg, see Figure 3 below.

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Figure 3: Time to Events of Worsening Renal Function or Kidney Pain, derived from the Key Secondary

Composite Endpoint, in TEMPO 3:4

Change of urine osmolality from End of Titration/Week 3 to Baseline; -- --- -- (-1119 to -300 mOsm/kg), ---- (-300 to -105

mOsm/kg), ─ ─ (-105 to 0 mOsm/kg), and ─── (0 to + 545 mOsm/kg)

Patients treated with tolvaptan demonstrating greater changes in urine osmolality from baseline appeared to

have better responses in terms of slowing progression of TKV and renal function decline, see Figures 4 and

5, respectively, below. Note that best responses are represented by the lightest coloured bars to the left, and

worst responses in darkest coloured bars presented to the right, for both endpoints of TKV and renal

function decline in all tolvaptan and placebo panels. Although a threshold effect seems to have been

reached for TKV with any tolvaptan treatment, with all quartiles achieving a mean change in urine

osmolality from baseline of at least 200 mOsm/kg and no apparent correlation of relative changes of urine

osmolality on TKV growth, there is an apparent correlation of change of urine osmolality from baseline and

attenuation of renal function decline, see Figure 5, below. Placebo shows no such effect.

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Figure 4: Mean Change from Baseline in Urine Osmolality in TEMPO 3:4, by Quartile of TKV Growth Rate

Quartiles of TKV Growth Rates, ranging from < -0.3 %/year growth to ≥ 6.2 %/year growth for tolvaptan, and from < 3.0 %/year

growth to ≥ 8.6 %/year for placebo.

Figure 5: Mean Change from Baseline in Urine Osmolality in TEMPO 3:4, by Quartile of Renal Function

Decline, as Measured by Slope of eGFR

CKD-EPI

Quartiles of Renal Function Decline, ranging from < 0.6 mL/min/1.73m

/year to > 4.5 mL/min/1.73m

/year of renal function

decline for tolvaptan, and from < 1.3 mL/min/1.73m

/year to > 5.8 mL/min/1.73m

/year of renal function decline for placebo

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TEMPO 4:4

Following completion of TEMPO 3:4, and after a washout period, most placebo-treated and tolvaptan-

treated patients were offered ongoing tolvaptan treatment in TEMPO 4:4, an open-label extension study.

This trial evaluated the effects of tolvaptan on safety, TKV and eGFR in subjects receiving active treatment

for 5 years (early-treated), compared with subjects treated with placebo for 3 years, then switched to active

treatment for 2 years (delayed-treated). Analysis of TKV progression and eGFR decline for the completed

trial are presented below in Figures 6 and 7, respectively.

Figure 6: Percent Change in Total Kidney Volume (TKV) from Baseline, from TEMPO 3:4 AND TEMPO 4:4

Figure 6: Percent Change in Total Kidney Volume (TKV) from Baseline, from TEMPO 3:4 and TEMPO 4:4

Trial Duration (Months)

Total Kidney Volume Growth

(% of Baseline)

Early Tolvaptan (covariate correction)

Early Tolvaptan

Placebo (covariate correction)

Delayed Tolvaptan (covariate correction)

Placebo

Delayed Tolvaptan

TEMPO 3:4

TEMPO 4:4

** p < 0.01

p = 0.04

Average TKV change from baseline for patients receiving tolvaptan (solid circles) or placebo (open triangles) during the three

years of placebo-controlled TEMPO 3:4 are shown, followed by a washout period post-treatment (open circles or triangles), and

then, for the previously tolvaptan-treated patients, two further years of treatment with tolvaptan in the open-label extension

study, TEMPO 4:4 (solid circles for early-treated patients, solid triangles for delayed-treated patients).

The primary endpoint for TKV did not distinguish a difference in change (-1.7%) over the 5-year treatment

between early- and delayed-treated subjects at the pre-specified threshold of statistical significance

(p=0.3580). Both groups’ TKV growth trajectory was slowed, relative to placebo in the first 3 years,

suggesting both early- and delayed- tolvaptan treated subjects benefitted to a similar degree.

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Figure 7: Change in Renal Function from Baseline, from TEMPO 3:4 (at the left of the Off-Treatment period)

and TEMPO 4:4 (at the right of the Off-Treatment period)

Figure 7: Change in Renal Function from Baseline from TEMPO 3:4 (at the left of the Off-treatment period) and TEMPO 4:4 (at the right of the Off-Treatment period)

Trial Duration (Months)

Change in eGFR (mL/min/1.73m

Early Tolvaptan

Early Tolvaptan (Follow-up TEMPO 3:4)

Placebo

Placebo (Follow-up TEMPO 3:4)

Delayed Tolvaptan

Off-treatment

Double-blind Placebo-controlled RCT

Open-label Tolvaptan

TEMPO 3:4

TEMPO 4:4

p < 0.05

p < 0.005

Average eGFR change from baseline for patients receiving tolvaptan (solid circles) or placebo (open triangles) during the three

years of placebo-controlled TEMPO 3:4 are shown, followed by off-treatment measurements for approximately 3 months post-

treatment (open circles or triangles), and then, for the patients previously treated with tolvaptan in TEMPO 3:4, two further years

of treatment with tolvaptan in the open-label extension study, TEMPO 4:4 (solid circles for early-treated patients, solid triangles

for delayed-treated patients).

The early-treated subjects experienced a greater overall benefit in renal function than the delayed-treated

subjects based on eGFR change over the 5-year treatment period (p=0.0003).

A secondary endpoint testing the persistence of positive effects on renal function indicated that the

preservation of eGFR observed by the end of the TEMPO 3:4 pivotal trial (3.01 to 3.34 mL/min/1.73m

follow-up visits 1 and 2) could be preserved during open-label treatment. This difference was maintained in

the pre-specified MMRM analysis (3.15 mL/min/1.73m

, 95%CI 1.462 to 4.836, p=0.0003) and with

sensitivity analyses where baseline eGFR data were carried forward (2.64 mL/min/1.73m

, 95%CI 0.672 to

4.603, p=0.0086). This trial yielded data which supported the long-term effects of tolvaptan on both renal

function and TKV, including a demonstrable, incremental renal function benefit for those receiving

treatment earlier. These data suggest that JINARC can slow the rate of renal function decline, and that these

benefits persist over the duration of therapy.

Following an additional 2 years of tolvaptan treatment, resulting in a total of 5 years on tolvaptan therapy,

the safety and tolerability were supportive of the results observed in the double-blind, placebo-controlled

study.

REPRISE

The pivotal double-blind, placebo-controlled, multi-center trial, called REPRISE, included a total of 1,519

adult patients (age 18-65) with chronic kidney disease (CKD) from late stage 2 to early stage 4 (eGFR

between 25 and 65 mL/min/1.73m

if younger than age 56; or eGFR between 25 and 44 mL/min/1.73m

plus eGFR decline >2.0 mL/min/1.73m

/year if between age 56-65). They entered an 8-week single-blind

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pre-randomization phases (screening, placebo run-in, tolvaptan titration and tolvaptan run-in). Tolvaptan

was initiated during the single-blind pre-randomization phase and up-titrated every 3-4 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) were

randomized 1:1 to treatment with tolvaptan or placebo. A total of 1,370 patients were randomized and

treated during the 12-month double-blind period. After completion of treatment the patients entered a 3-

week follow-up period.

Randomization was stratified by patients’ baseline characteristics of eGFR, age, and TKV (if available) and

all patients remained on standard concomitant medications. 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. Patients were evaluated weekly during the pre-randomization phases and monthly during

randomized treatment for efficacy and safety assessments.

Patients were assigned to tolvaptan (N=683) or placebo (N=687) and were distributed across CKD stages

as follows: Stage 2 (5.2%), Stage 3a (30%), Stage 3b (45.1%) and Stage 4 (19.5%). The average age was

47 years.

The primary endpoint (eGFR change) 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. Decline in renal function was 35% slower with tolvaptan compared to placebo (p < 0.0001); the

change of eGFR from pretreatment baseline to post-treatment follow-up was -2.34 mL/min/1.73 m

/year

with tolvaptan vs -3.61 mL/min/1.73 m

/year with placebo, with a treatment effect of 1.271 mL/min/1.73

/year, see as illustrated in Figure 8. The key secondary endpoint (eGFR slope) and all sensitivity

analyses were significant (at p ≤ 0.0005).

Figure 8: Annualized Change in eGFR (CKD-EPI) from Pre-treatment Baseline to Post-treatment Follow-up

in REPRISE

Subgroup analysis for the primary and key secondary endpoints demonstrated consistent treatment effects

of tolvaptan for subjects in CKD Stages 2, 3a, 3b, and 4.

LS Mean Annualized Change in eGFR (± SE)

(CKD-EPI) mL/min/1.73m

Tolvaptan

Placebo

Difference: 1.271 mL/min/1.73m

/yr (35%)

p-value: <0.0001

-2.34

-3.61

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The results of REPRISE, therefore, supplement the earlier finding that JINARC reduces the progression of

the enlargement of kidney volume and show that JINARC also reduces the rate of regression of renal

function.

DETAILED PHARMACOLOGY

Arginine vasopressin (AVP) is a neuropeptide hormone which causes vasoconstriction via V

-receptors

and promotes water reabsorption in the kidneys via V

-receptors, both of which are G-protein-coupled

transmembrane receptors. The V

-receptors are primarily responsible for the anti-diuretic effects of AVP.

Patients with various disorders, including congestive heart failure, liver cirrhosis, and syndrome of

inappropriate secretion of anti-diuretic hormone (SIADH), are at risk of experiencing excess water

retention or inadequate water disposal due to increased vasopressin secretion. JINARC (tolvaptan) is a

competitive, non-peptide vasopressin antagonist drug that blocks the binding of arginine vasopressin at the

-receptors of the distal nephron, thereby inducing water diuresis (aquaresis), but notably without the

depletion of electrolytes.

Pharmacodynamics

In vitro antagonistic effects of tolvaptan were investigated in binding experiments using a human

endocervical carcinoma cell line (HeLa cells) expressing human AVP receptor subtypes (V

, and V

Tolvaptan inhibited [

H]AVP binding to the V

-receptors in a concentration-dependent manner, with an

inhibition constant (K

) of 0.43

0.06 nM, which was approximately 1.8 times higher than that of AVP (K

= 0.78

0.08 nM). Tolvaptan also inhibited [

H]AVP binding to the V

-receptors with a K

of 12.3

nM, but the affinity is approximately 29 times weaker than that for V

-receptors. On the other hand,

tolvaptan did not inhibit [

H]AVP binding to the V

-receptors even at 100 nM.

The affinities of tolvaptan for rat and canine AVP receptors were investigated by measuring the inhibition

of [

H]AVP binding to membrane preparations prepared from rat liver (V

), canine platelet (V

), and rat

and canine kidney (V

). Tolvaptan concentration-dependently inhibited [

H]AVP binding to rat AVP V

and V

-receptors with K

of 345

54 nM and 1.33

0.26 nM, and to canine AVP V

- and V

-receptors

with K

of 40.3

12.0 nM and 0.66

0.09 nM, respectively. Thus, tolvaptan was approximately 259- and

61-times more selective for V

-receptors than for V

-receptors in rats and dogs.

TOXICOLOGY

Single-Dose Toxicity

Single-dose toxicity trials of tolvaptan were conducted by the oral route at doses of up to 2,000 mg/kg in

Sprague-Dawley rats and Beagle dogs. No mortality or clinical signs indicative of toxicity were observed in

rats or dogs. The minimum lethal dose was not determined in the single-dose trials in rats or dogs. There

were no apparent gender differences in sensitivity to the acute effects of tolvaptan in either rats or dogs.

There was no macroscopic evidence of target organ toxicity at any dose level.

Repeat-Dose Toxicity

Repeat-dose oral toxicity trials were conducted in Sprague-Dawley rats and Beagle dogs for up to 26 weeks

and 52 weeks, respectively. In rats, the No Observed Adverse Effect Level (NOAEL) was 1,000 mg/kg/day

in both sexes in the 4-week and 13-week repeated oral dose toxicity trials. In the 26-week trial at doses of

30, 100 and 1,000 mg/kg/day, the results showed neither overt toxicity nor target organ toxicity even at

1,000 mg/kg/day. However, 3 females given 1,000 mg/kg/day were euthanized in a moribund state

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(dehydration). Therefore, the NOAEL in this trial was estimated to be 1,000 mg/kg/day in the males and

100 mg/kg/day in the females (serum drug concentration at the fourth week of administration: C

1.37 and 3.42

g/mL and AUC

0-24h

was 12.72 and 20.76

h/mL in the males and females, respectively).

In dogs, the NOAEL was 1,000 mg/kg/day in both sexes in the 4-week and 13-week administration. In the

52-week administration trial at doses of 30, 100 and 1,000 mg/kg/day, the results showed no notable target

organ toxicity even at 1000 mg/kg/day. However, one male and 2 females given 1,000 mg/kg/day were

sacrificed in a moribund state because of decreases in body weight and food consumption. Therefore, the

NOAEL in this trial was estimated to be 100 mg/kg/day in both sexes (serum drug concentration at 52nd

week of administration: C

was 5.46 and 6.05

g/mL and AUC

0-24h

was 31.45 and 42.35

h/mL in the

males and females, respectively).

Genotoxicity

The genotoxic potential of JINARC (tolvaptan) was assessed in a battery of in vitro and in vivo test

systems. Tolvaptan exhibited no genotoxic potential at concentrations up to 5,000

g/plate in the bacterial

(Salmonella typhimurium and Escherichia coli) reverse-mutation test, up to 200

g/mL in the forward gene

mutation test in mouse lymphoma cells, following pulse treatment at up to 100

g/mL (in the presence or

absence of metabolic activation) or with continuous treatment at up to 40

g/mL (in the presence or

absence of metabolic activation) in the chromosomal aberration test using Chinese hamster lung fibroblast

cell line (CHL) or at doses up to 2,000 mg/kg in rat micronucleus test using bone marrow cells from male

and female rats administered tolvaptan.

Carcinogenicity

The carcinogenic potential of tolvaptan was evaluated in one 104-week oral carcinogenicity trial in mice

and one 104-week oral carcinogenicity trial in rats. Dose levels for the mouse carcinogenicity trial were 0,

10, 30 and 60 mg/kg/day in males and 0, 10, 30 and 100 mg/kg/day in females. The dose levels for the rat

carcinogenicity trial were 0, 100, 300 and 1000 mg/kg/day in males and 0, 30, 100, 300 and 1,000

mg/kg/day in females. Oral (gavage) administration of tolvaptan to B6C3F

mice or Sprague-Dawley rats

for 104 weeks was not associated with a decrease in survival or an increase in the incidence of neoplastic or

non-neoplastic drug-related findings in males or females. The highest doses tested in mice resulted in

exposures (AUC

0-24h

) that were just below (females; 4.3317

h/mL) and below (males; 2.8595

h/mL)

the exposure in humans at the MRHD.(120 mg). The highest dose tested in rats resulted in exposures

(AUC

0-24h

) that were approximately 2-times (males; 12.716

h/mL) and 5-times (females; 33.449

h/mL) greater than the exposure in humans at steady state at the MRHD of 120 mg.

Reproductive and Developmental Toxicity Trials

In trials of effects on fertility and reproductive performance in Sprague-Dawley rats, tolvaptan did not

impair reproductive performance at doses up to 1,000 mg/kg/day in males and 100 mg/kg/day in females

(approximately 81- and 8-times the MRHD on a mg/m

basis, respectively). Fertility was not affected at

1,000 mg/kg/day in males and females. The drug-related effect of altered estrous cycles due to prolongation

of diestrus was observed in females given 300 and 1,000 mg/kg/day. The NOAEL was less than 100

mg/kg/day for general toxicologic effects in males and females, 100 mg/kg/day for reproductive

performance in females and 1,000 mg/kg/day for reproductive performance in males and for fetal

development.

In trials of embryo-fetal development, tolvaptan did not cause any developmental toxicity in rats at

maternal doses up to 100 mg/kg/day (8-times the MRHD on a mg/m

basis) or in New Zealand White

rabbits at maternal doses up to 300 mg/kg/day (49-times the MRHD on a mg/m

basis). Dose-dependent

maternal toxicity was evident in rats at 100 mg/kg/day and higher and in rabbits at 30 mg/kg/day and

JINARC

Product Monograph

Page 37 of 43

higher. The NOAEL in rats was 10 mg/kg/day for general toxicologic effects in the parental generation (F

dams, 1,000 mg/kg/day for reproductive performance in F

dams and 100 mg/kg/day for embryo-fetal

development in first generation (F

) fetuses. Maternal toxicity in female rats consisted of decreased food

consumption and body weight (100 mg/kg/day and higher) and developmental toxicity of the F

fetuses

consisted of decreased body weight and delayed ossification (1,000 mg/kg/day).

In rabbits, the NOAEL was 10 mg/kg/day for general toxicologic effects in F

dams, and 100 mg/kg/day for

reproductive performance in F

dams and 300 mg/kg/day for embryo-fetal development in F

fetuses.

Maternal toxicity in female rabbits consisted of decreased food consumption and body weight (30 mg/kg

and higher). In addition, maternal changes in physiology were examined in dams given 1,000 mg/kg and

the changes included increased urine volume, decreased urine osmolality, increased water consumption and

increased plasma sodium and chloride concentration as well as plasma osmolality and plasma AVP levels.

Maternal reproductive performance, as assessed by the ability to maintain pregnancy, was altered at dose

levels of 300 mg/kg and higher where a dose-dependent incidence of abortion was observed. There was

also evidence of developmental toxicity in rabbits at the maternally toxic dose of 1,000 mg/kg (162-times

the MRHD on a mg/m

basis). This developmental toxicity consisted of increased incidences of embryo-

fetal death, microphthalmia, open eyelids, cleft palate, brachymelia (zygopodium malformations) and fused

phalanx.

Teratogenicity of tolvaptan was further investigated in rabbits. The sensitive period of teratogenicity was

during gestation Days 6 to 11, and the maximum sensitivity was shown to be during gestation Days 9 to 11.

A toxicokinetics trial in pregnant rabbits showed that 13-day repetitive administration of tolvaptan caused a

decrease in exposure level (AUC) of unchanged compound to approximately 1/10 of that at the first

administration.

In the prenatal and postnatal trial in pregnant rats, tolvaptan had no effect on offspring development at

doses up to 100 mg/kg/day following oral administration to pregnant rats from gestation Day 7 through

lactation Day 21. Increased perinatal death and decreased body weight of F

generation animals during the

lactation period and after weaning were observed in the 1,000 mg/kg/day group. The NOAEL was less than

10 mg/kg/day for general toxicologic effects in F

dams, and 1,000 mg/kg/day for reproductive

performance in F

dams and 100 mg/kg/day in terms of effects on offspring development.

JINARC

Product Monograph

Page 38 of 43

REFERENCES

Braun WE. Autosominal dominant polycystic kidney disease: emerging concepts of pathogenesis.

Cleve Clin J Med. 2009;76(2):97-104

Devuyst D, Torres VE. Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant

polycystic kidney disease. Curr Opin Nephrol Hyperten. 2013; 22:459-470.

Grantham JJ. Clinical Practice. Autosomal dominant polycystic kidney disease. N Engl J Med.

2008;395(14):1477-1485

Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet.

2007;369:1287-1301

Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor

antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat.

J Am Soc Nephrol. 2005 Apr;16(4):846-51.

Shoaf SE, Bramer SL, Bricmont P, Zimmer CA. Pharmacokinetic and pharmacodynamic

interaction between tolvaptan, a non-peptide AVP antagonist, and furosemide or

hydrochlorothiazide. J Cardiovasc Pharmacol 2007, 50(2):213-222.

Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, Wetzel LH,

Baumgarten DA, Kenney PJ, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers CM, Zhang

X, Zhu F, Miller JP. Volume progression in polycystic kidney disease. N Engl J Med.

2006;354(20):2122-2130

Kistler AD, Poster D, Krauer F, Weishaupt D, Raina S, Senn O, Binet I, Spanaus K, Wüthrich RP,

Serra AL. Increases in kidney volume in autosomal dominant polycystic kidney disease can be

detected within 6 months. Kidney Int. 2009;75(2):235-241

Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic

kidney disease: the major factor in determining clinical outcomes. Clin J Amer Soc Nephrol. 2006

Jan;1(1):148-57.

Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten BA, et al.

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium

for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003

Sep;64(3):1035-45.

Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, et al. Tolvaptan in

autosomal dominant polycystic kidney disease: three years' experience. Clin J Am Soc Nephrol.

2011 Oct;6(10):2499-507

Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly regulates cyst growth in

polycystic kidney disease. J Am Soc Nephrol. 2008;19(1):102-108

JINARC

Product Monograph

Page 39 of 43

Meijer E, Boertien WE, Zietse R, Gansevoort RT. Potential deleterious effects of vasopressin in

chronic kidney disease and particularly autosomal dominant polycystic kidney disease. Kidney

Blood Press Res. 2011;34(4):235-244

Torres VE. Vasopressin antagonists in polycystic kidney disease. Semin

Nephrol.2008;28(3):306-317.

Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP. Tolvaptan inhibits ERK-

dependent cell proliferation, Cl- secretion, and in vitro cyst growth of human ADPKD cells

stimulated by vasopressin. Amer J Physiol Renal Physiol. 2011 Nov;301(5):F1005-13.

Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development

and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003 Oct;9(10):1232-6

Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic

kidney disease. Nat Rev Nephrol. 2011 Aug 23;7(10):556-66

Chapman AB, Bost JE, Torres VE, Guay-Woodford L, Bae KT, Landsittel D, Li J, et al. Kidney

volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc

Nephrol. 2012 Mar;7(3):479-86.

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JG, Higashihara E, Perrone RD,

Krasa HB, Ouyang J, Czerwiec FS, for TEMPO 3:4 Trial Investigators. Tolvaptan in Patients with

Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2012: 367:2407-2418.

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J,

Czerwiec FS, Blais JD, for TEMPO 4:4 Trial Investigators. Multicenter, open-label, extension trial

to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in

autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant.

2017 Jul 1;32(7):1262.

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade

RD, Blais JD, Czerwiec FS, Sergeyeva O, for REPRISE Trial Investigators. Tolvaptan in Later-

Stage Autosomal Dominant Polycystic Kidney Disease. N. Engl. J. Med. 2017 Nov

16;377(20):1930-42.

IMPORTANT: PLEASE READ

JINARC

Product Monograph

Page 40 of 43

PART III: CONSUMER INFORMATION

Pr

JINARC

Tolvaptan Tablets

This leaflet is part III of a three-part "Product

Monograph" published when JINARC was approved for

sale in Canada and is designed specifically for

Consumers. This leaflet is a summary and will not tell you

everything about JINARC. Contact your doctor, nurse or

pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

JINARC is used in adults to treat autosomal dominant

polycystic kidney disease (ADPKD).

ADPKD is a genetic disorder which leads to the growth of

multiple cysts (sacs filled with fluid) on the kidneys. Over

time, the cysts grow in size, which can damage the way your

kidneys work, and may ultimately lead to kidney failure.

JINARC should only be prescribed by a doctor experienced

in the diagnosis and treatment of ADPKD.

What it does:

JINARC works by blocking the effects of a hormone called

vasopressin, which promotes cyst growth in the kidneys in

patients with ADPKD. By blocking the effects of the

hormone, JINARC is able to reduce the growth of the cysts in

the kidneys and slow the decline of kidney function. This

should help protect your kidneys from damage and failure.

Because of the way that JINARC works, you will produce

more urine causing you to urinate more frequently during the

day and at night. This may become less pronounced over

time.

Before starting this medication:

Before taking JINARC you should discuss carefully with

your doctor if this medication is suitable for you, taking into

consideration the potential benefits and risks involved. Once

you and your doctor have agreed that JINARC is suitable for

you, your doctor will ask that you sign a patient-prescriber

agreement form (PPAF), stating that you understand the

benefits and risks of treatment and that you agree to take

blood tests as prescribed by your doctor to start and remain

on treatment. For more information on JINARC controlled

hepatic safety monitoring and distribution programme, please

call 1-844-254-6272. In order to gather information on the

long-term clinical outcomes with JINARC, your doctor may

discuss with you the possibility to participate in the Canadian

JINARC patient outcomes registry. For more information on

the study, please call 1-877-341-9245 or go to

www.clinicaltrials.gov, study ID NCT02925221.

When it should not be used:

Do not take JINARC if:

you have been asked to permanently discontinue

tolvaptan in the past

you are allergic to tolvaptan, benzazepine or

benzazepine derivatives

(e.g. REMERON®)

, or any

non-medicinal ingredients in the formulation.

you can not replace fluids by drinking or you can

not feel if you are thirsty

you have elevated sodium (salt) in your blood

you have a condition associated with a low blood

volume

your liver is not functioning properly and in a way

that is of concern to your doctor. The presence of

hepatic cysts in and of themselves should not be an

impediment to initiation of JINARC treatment.

you are pregnant or plan to become pregnant. It is

not known if JINARC will harm your unborn baby.

you are breast-feeding. It is not known if JINARC

passes into your breast milk. You and your

healthcare provider should decide if you will take

JINARC or breast-feed. You should not do both.

your body is not able to make any urine. JINARC

will not help your condition.

you take certain medicines. These medicines could

cause you to have too much JINARC in your blood:

the antibiotic medicines, clarithromycin or

telithromycin

the antifungal medicines, ketoconazole or

itraconazole

the anti-HIV medicines, ritonavir,

indinavir, nelfinavir, and saquinavir

the antidepressant medicine, nefazodone

you have one of the following rare hereditary

diseases:

Galactose intolerance

Lapp lactase deficiency

Glucose-galactose malabsorption

because lactose is a non-medicinal ingredient in

JINARC.

What the medicinal ingredient is:

tolvaptan

What the non-medicinal ingredients are:

Corn starch, hydroxypropyl cellulose, lactose monohydrate,

low-substituted hydroxypropyl cellulose, magnesium

stearate, microcrystalline cellulose, and FD&C Blue No. 2

Aluminum Lake as colorant.

What dosage forms it comes in:

Weekly combination blister packs of 15+15 mg, 30+15 mg,

45+15 mg, 60+30 mg, and 90+30 mg tablets.

IMPORTANT: PLEASE READ

JINARC

Product Monograph

Page 41 of 43

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions – Liver damage

Your doctor will arrange blood tests before you start

treatment with JINARC and then at regular intervals

during treatment to check for changes in your liver

function.

To prevent pregnancy while on JINARC treatment, women

of childbearing potential must have effective contraceptive

measures in place before and during treatment.

BEFORE you use JINARC talk to your doctor, nurse or

pharmacist if you:

have difficulty urinating or have an enlarged

prostate

are dehydrated or suffer from excessive vomiting,

diarrhea or sweating

have low levels of sodium in your blood

have high potassium levels in your blood

have high levels of uric acid in your blood or gout

are taking medication to treat high blood pressure

are less than 18 years old

have been asked to permanently discontinue

tolvaptan in the past

Driving and using machines: Before doing tasks which

require special attention, wait until you know how you

respond to JINARC. Dizziness, weakness and fainting can

occur.

INTERACTIONS WITH THIS MEDICATION

As with most medicines, interactions with other drugs are

possible. Tell your doctor, nurse, or pharmacist about all the

medicines you take, including drugs prescribed by other

doctors, vitamins, minerals, natural supplements, or

alternative medicines.

The following may interact with JINARC: clarithromycin,

ketoconazole, ritonavir, saquinavir, rifampicin, phenytoin,

carbamazepine, St. John’s Wort, cyclosporin, quinidine,

verapamil, erythromycin, fluconazole, hypertonic saline

solutions, drugs that increase serum sodium concentrations,

drugs known to increase serum potassium levels (such as

spironolactone), digoxin, consuming grapefruit juice, or

vasopressin drugs, such as desmopressin, used to control

bleeding.

PROPER USE OF THIS MEDICATION

Always take JINARC exactly as your doctor has prescribed.

Check with your doctor, nurse or pharmacist if you are not

sure.

You can take JINARC with or without food.

While taking JINARC you will produce more urine, urinate

more frequently, and urinate at night. If this causes you

concern, consult your doctor, nurse or pharmacist. This side-

effect should become less pronounced with time.

To prevent becoming dehydrated, have water available to

drink at all times while taking JINARC. Unless your doctor

tells you otherwise, drink plenty of water during the day and

one or two glasses before going to bed. If you suffer from

vomiting, diarrhea or any other condition that might cause

you to become dehydrated while taking JINARC call your

doctor.

Blood tests:

During treatment with JINARC, your doctor will arrange

blood tests to check for changes in your liver function, as

follows:

before starting treatment with JINARC

every month for the first 18 months, then

every 3 months thereafter during treatment for the next

12 months, and every 3-6 months thereafter during treatment

Usual adult dose:

JINARC is to be taken twice a day in two different

doses. There are three possible dose combinations

that your doctor may prescribe:

45+15 mg, for a total daily dose of 60 mg,

or

60+30 mg, for a total daily dose of 90 mg,

or

90+30 mg, for a total daily dose of 120 mg.

Take one tablet of the higher dose (45 mg, 60 mg or

90 mg) in the morning.

8 hours later take one tablet of the lower dose (15

mg or 30 mg).

This schedule was designed to give you the best

balance between the amount of medicine in your

body and possible side effects (especially night time

urination).

Do not drink grapefruit juice during treatment with

JINARC. This could cause you to have too great of

a drug effect, while taking JINARC.

Adjusted dose if you are taking certain medicines:

Your doctor will tell you to reduce your usual dose of

JINARC if you take certain medicines as these medicines

could cause you to have too much JINARC in your blood.

Your doctor may reduce your dose to the following:

IMPORTANT: PLEASE READ

JINARC

Product Monograph

Page 42 of 43

15 mg + 15 mg, for a total daily dose of 30

30 mg +15 mg, for a total daily dose of 45

Overdose: If you think you have taken too much JINARC

contact your doctor, nurse, pharmacist, hospital emergency

department or regional Poison Control Centre

immediately, even if there are no symptoms.

Missed Dose:

Do not miss or skip doses of JINARC. If you miss a dose,

take your next dose at the scheduled time and prescribed

level. Do not take 2 doses at the same time.

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

Side effects may include:

Thirst

Increased amount of urine

Increased frequency of urination during the day and

at night

Headache

Constipation, diarrhea, dry mouth, indigestion,

decreased appetite

Fatigue, weakness, dizziness

Trouble sleeping

Muscle spasms

Rash, itching

Abdominal pain

If any of these affects you severely, tell your doctor, nurse

or pharmacist.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor, nurse or

pharmacist

Stop

taking

drug and

seek

immediate

medical

help

Only if

severe

In all

cases

Common

Increased

levels of

potassium in

the blood:

irregular heart

beats, muscle

weakness and

generally

feeling unwell

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor, nurse or

pharmacist

Stop

taking

drug and

seek

immediate

medical

help

Only if

severe

In all

cases

Common

Increased

levels of uric

acid in the

blood/Gout:

joint pain,

commonly in

the big toe,

followed by

redness,

swelling,

warmth

Uncommon

Dehydration:

increased

thirst, dry

mouth and/or

skin, fatigue,

decreased

amount of

urine,

headache,

dizziness,

irregular heart

beats

Rare or

Uncommon

Liver

Disorder:

yellowing of

the skin or

eyes, dark

urine,

abdominal

pain, nausea,

vomiting, loss

of appetite

IMPORTANT: PLEASE READ

JINARC

Product Monograph

Page 43 of 43

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor, nurse or

pharmacist

Stop

taking

drug and

seek

immediate

medical

help

Only if

severe

In all

cases

Rare or

Uncommon

Angioedema

and Severe

Allergic

Reactions:

swelling of

the face, eyes,

or tongue,

difficulty

swallowing,

wheezing,

hives and

generalized

itching, rash,

fever,

abdominal

cramps, chest

discomfort or

tightness,

difficulty

breathing,

unconsciousn

ess.

This is not a complete list of side effects. For any

unexpected effects while taking JINARC contact your

doctor, nurse or pharmacist.

HOW TO STORE IT

Store JINARC between 15

C to 30

Keep JINARC out of sight and reach of children.

REPORTING SIDE EFFECTS

You can report any suspected side effects associated with

the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (http://www.hc-sc.gc.ca/dhp-

mps/medeff/report-declaration/index-eng.php)

for information on how to report online, by mail

or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical

advice.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found at:

www.otsukacanada.com

or by contacting the marketer, Otsuka Canada Pharmaceutical

Inc., at:

1-877-341-9245.

This leaflet was prepared by Otsuka Pharmaceutical Co., Ltd.

Imported by: Otsuka Canada Pharmaceutical Inc.

Last revised: October 23, 2019

JINARC is a trademark of Otsuka Pharmaceutical Co., Ltd.,

used under licence by Otsuka Canada Pharmaceutical Inc.

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