JINARC 30mg+JINARC 90mg tablets medication leaflet

Jinarc 15 mg tablets

Jinarc 30 mg tablets

Jinarc 45 mg tablets

Jinarc 60 mg tablets

Jinarc 90 mg tablets

Jinarc 15 mg tablets

Each tablet contains 15 mg of tolvaptan.

Each 15 mg tablet contains approximately 35 mg lactose (as monohydrate).

Jinarc 30 mg tablets

Each tablet contains 30 mg of tolvaptan.

Each 30 mg tablet contains approximately 70 mg lactose (as monohydrate).

Jinarc 45 mg tablets

Each tablet contains 45 mg of tolvaptan.

Each 45 mg tablet contains approximately 12 mg lactose (as monohydrate).

Jinarc 60 mg tablets

Each tablet contains 60 mg of tolvaptan.

Each 60 mg tablet contains approximately 16 mg lactose (as monohydrate).

Jinarc 90 mg tablets

Each tablet contains 90 mg of tolvaptan.

Each 90 mg tablet contains approximately 24 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Tablet

Jinarc 15 mg tablets

Blue, triangular (major axis: 6.58 mm, minor axis: 6.20 mm), shallow-convex, debossed with“OTSUKA” and “15” on one side.

Jinarc 30 mg tablets

Blue, round (diameter: 8 mm), shallow-convex, debossed with “OTSUKA” and “30” on one side.

Jinarc 45 mg tablets

Blue, square (6.8 mm on a side, major axis 8.2 mm), shallow-convex, debossed with “OTSUKA” and“45” on one side

Jinarc 60 mg tablets

Blue, modified rectangular (major axis 9.9 mm, minor axis 5.6 mm), shallow-convex, debossed with“OTSUKA” and “60” on one side

Jinarc 90 mg tablets

Blue, pentagonal (major axis 9.7 mm, minor axis 9.5 mm), shallow-convex, debossed with “OTSUKA”and “90” on one side

Jinarc is indicated to slow the progression of cyst development and renal insufficiency of autosomaldominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 4at initiation of treatment with evidence of rapidly progressing disease (see section 5.1).

Tolvaptan treatment must be initiated and monitored under the supervision of physicians with expertisein managing ADPKD and a full understanding of the risks of tolvaptan therapy including hepatictoxicity and monitoring requirements (see section 4.4).

Jinarc is to be administered twice daily in split dose regimens of 45 mg + 15 mg, 60 mg + 30 mg or90 mg + 30 mg. The morning dose is to be taken at least 30 minutes before the morning meal. Thesecond daily dose can be taken with or without food. According to these split dose regimens the totaldaily doses are 60 mg, 90 mg, or 120 mg.

Dose titration

The initial dose is 60 mg tolvaptan per day as a split-dose regimen of 45 mg + 15 mg (45 mg taken uponwaking and prior the morning meal and 15 mg taken 8 hours later). The initial dose is to be titratedupward to a split-dose regimen of 90 mg tolvaptan (60 mg + 30 mg) per day and then to a target split-dose regimen of 120 mg tolvaptan (90 mg + 30 mg) per day, if tolerated, with at least weekly intervalsbetween titrations. Dose titration has to be performed cautiously to ensure that high doses are not poorlytolerated through overly rapid up-titration. Patients may down-titrate to lower doses based ontolerability. Patients have to be maintained on the highest tolerable tolvaptan dose.

The aim of dose titration is to block activity of vasopressin at the renal V2 receptor as completely andconstantly as possible, while maintaining acceptable fluid balance (see section 4.4).

Measurements of urine osmolality are recommended to monitor the adequacy of vasopressin inhibition.

Periodic monitoring of plasma osmolality or serum sodium (to calculate plasma osmolarity) and/or bodyweight should be considered to monitor the risk of dehydration secondary to the aquaretic effects oftolvaptan in case of patient’s insufficient water intake.

The safety and efficacy of Jinarc in CKD stage 5 have not been explored and therefore tolvaptantreatment should be discontinued if renal insufficiency progresses to CKD stage 5 (see section 4.4).

Therapy must be interrupted if the ability to drink or the accessibility to water is limited (seesection 4.4).

Tolvaptan must not be taken with grapefruit juice (see section 4.5). Patients must be instructed to drinksufficient amounts of water or other aqueous fluids (see section 4.4).

Dose adjustment for patients taking strong CYP3A inhibitors

In patients taking strong CYP3A inhibitors (see section 4.5), tolvaptan doses have to be reduced asfollows:

Tolvaptan daily split-dose Reduced dose (once daily)90 mg + 30 mg 30 mg (further reduction to 15 mg if 30 mg are not well tolerated)60 mg + 30 mg 30 mg (further reduction to 15 mg if 30 mg are not well tolerated)45 mg + 15 mg 15 mg

Dose adjustment for patients taking moderate CYP3A inhibitors

In patients taking moderate CYP3A inhibitors, tolvaptan doses have to be reduced as follows:

Tolvaptan daily split-dose Reduced split-dose90 mg + 30 mg 45 mg + 15 mg60 mg + 30 mg 30 mg + 15 mg45 mg + 15 mg 15 mg + 15 mg

Further reductions have to be considered if patients cannot tolerate the reduced tolvaptan doses.

Increasing age has no effect on tolvaptan plasma concentrations. Limited data on the safety andeffectiveness of tolvaptan in ADPKD patients aged over 55 are available (see section 5.1).

Tolvaptan is contraindicated in anuric patients (see section 4.3).

Dose adjustment is not required in patients with renal impairment.

No clinical trials in subjects with indices of glomerular filtration rate < 10 mL/min or in patientsundergoing dialysis have been conducted. The risk of hepatic damage in patients with severely reducedrenal function (i.e. estimated glomerular filtration rate [eGFR] < 20) may be increased; these patientsshould be carefully monitored for hepatic toxicity. Data for patients in CKD early stage 4 are morelimited than for patients in stage 1, 2 or 3 (see section 5.1). Limited data are available for patients with

CKD late stage 4 (eGFR < 25 mL/min/1.73 m2). No data are available for patients with CKD stage 5.

Tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5 (seesection 4.4).

In patients with severe hepatic impairment the benefits and risks of treatment with Jinarc must beevaluated carefully. Patients must be managed carefully and liver enzymes must be monitored regularly(see section 4.4).

Jinarc is contraindicated in patients with elevated liver enzymes and/or signs or symptoms of liverinjury prior to initiation of treatment that meet the requirements for permanent discontinuation oftolvaptan (see sections 4.3 and 4.4).

No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh classes

A and B).

The safety and efficacy of tolvaptan in children and adolescents has not yet been established. No dataare available. Tolvaptan is not recommended in the paediatric age group.

Oral use.

Tablets must be swallowed without chewing and with a glass of water.

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or tobenzazepine or benzazepine derivatives (see section 4.4)

* Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatmentthat meet the requirements for permanent discontinuation of tolvaptan (see section 4.4)

* Anuria

* Volume depletion

* Hypernatraemia

* Patients who cannot perceive or respond to thirst

* Pregnancy (see section 4.6)

* Breast-feeding (see section 4.6)

Idiosyncratic hepatic toxicity

Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartateaminotransferases (ALT and AST) with infrequent cases of concomitant elevations in bilirubin-total(BT).

In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring livertransplantation has been reported.

In a double-blind, placebo-controlled trial in patients with ADPKD, the period of onset of hepatocellularinjury (by ALT elevations > 3 × ULN) was within 3 to 14 months after initiating treatment and theseincreases were reversible, with ALT returning to < 3 × ULN within 1 to 4 months. While theseconcomitant elevations were reversible with prompt discontinuation of tolvaptan, they represent apotential for significant liver injury. Similar changes with other medicinal products have been associatedwith the potential to cause irreversible and potentially life-threatening liver injury (see section 4.8).

Prescribing physicians must comply fully with the safety measures required below.

To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminasesand bilirubin is required prior to initiation of Jinarc, continuing monthly for 18 months and at regular 3-monthly intervals thereafter. Concurrent monitoring for symptoms that may indicate liver injury (suchas fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, darkurine or jaundice) is recommended.

If a patient shows abnormal ALT, AST or BT levels prior to initiation of treatment which fulfil thecriteria for permanent discontinuation (see below), the use of tolvaptan is contraindicated (seesection 4.3). In case of abnormal baseline levels below the limits for permanent discontinuationtreatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liverfunction testing must continue at increased time frequency. The advice of a hepatologist isrecommended.

During the first 18 months of treatment, Jinarc can only be supplied to patients whose physician hasdetermined that liver function supports continued therapy.

At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal

ALT or AST increases are detected during treatment, Jinarc administration must be immediatelyinterrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained assoon as possible (ideally within 48 hours to 72 hours). Testing must continue at increased timefrequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point Jinarc maybe re-initiated.

Current clinical practice suggests that Jinarc therapy is to be interrupted upon confirmation of sustainedor increasing transaminase levels and permanently discontinued if significant increases and/or clinicalsymptoms 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 (BT > 2-times ULN or International Normalised Ratio[INR] > 1.5)

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

If ALT and AST levels remain below 3-times the ULN, Jinarc therapy may be cautiously re-started,with frequent monitoring at the same or lower doses, as transaminase levels appear to stabilise duringcontinued therapy in some patients.

Access to water

Tolvaptan may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, andpollakiuria (see section 4.8). Therefore, patients must have access to water (or other aqueous fluids) andbe able to drink sufficient amounts of these fluids (see section 4.2). Patients have to be instructed todrink water or other aqueous fluids at the first sign of thirst in order to avoid excessive thirst ordehydration.

Additionally, patients have to drink 1 to 2 glasses of fluid before bedtime regardless of perceived thirstand replenish fluids overnight with each episode of nocturia.

Volume status must be monitored in patients taking tolvaptan because treatment with tolvaptan mayresult in severe dehydration which constitutes a risk factor for renal dysfunction. Accurate monitoring ofbody weight is recommended. A progressive reduction in body weight could be an early sign ofprogressive dehydration. If dehydration becomes evident, take appropriate action, which may includethe need to interrupt or reduce the dose of tolvaptan and increase fluid intake. Special care must betaken in patients having diseases that impair appropriate fluid intake or who are at an increased risk ofwater loss e.g. in case of vomiting or diarrhoea.

Urinary outflow obstruction

Urinary output must be secured. Patients with partial obstruction of urinary outflow, for examplepatients with prostatic hypertrophy or impairment of micturition, have an increased risk of developingacute retention.

Fluid and electrolyte balance

Fluid and electrolyte status must be monitored in all patients. Administration of tolvaptan inducescopious aquaresis and may cause dehydration and increases in serum sodium (see section 4.8) and iscontraindicated in hypernatraemic patients (see section 4.3). Therefore, serum creatinine, electrolytesand symptoms of electrolyte imbalances (e.g. dizziness, fainting, palpitations, confusion, weakness, gaitinstability, hyper-reflexia, seizures, coma) have to be assessed prior to and after starting tolvaptan tomonitor for dehydration.

During long-term treatment, electrolytes have to be monitored at least every three months.

Serum sodium abnormalities

Pre-treatment sodium abnormalities (hyponatraemia or hypernatraemia) must be corrected prior toinitiation with tolvaptan therapy.

Anaphylaxis

In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalised) has beenreported very rarely following administration of tolvaptan. This type of reaction occurred after the firstadministration of tolvaptan. Patients have to be carefully monitored during treatment. Patients withknown hypersensitivity reactions to benzazepines or benzazepine derivatives (e.g. benazepril,conivaptan, fenoldopam mesylate or mirtazapine) may be at risk for hypersensitivity reaction totolvaptan (see section 4.3).

If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan must bediscontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication(see section 4.3) treatment must never be restarted after an anaphylactic reaction or other serious allergicreactions.

Diabetes mellitus

Diabetic patients with an elevated glucose concentration (e.g. in excess of 300 mg/dL) may present withpseudo-hyponatraemia. This condition must be excluded prior and during treatment with tolvaptan.

Tolvaptan may cause hyperglycaemia (see section 4.8). Therefore, diabetic patients treated withtolvaptan must be managed cautiously. In particular this applies to patients with inadequately controlledtype II diabetes.

Uric acid increases

Decreased uric acid clearance by the kidney is a known effect of tolvaptan. In a double-blind, placebo-controlled trial of patients with ADPKD, potentially clinically significant increased uric acid (greaterthan 10 mg/dL) was reported at a higher rate in tolvaptan-patients (6.2 %) compared to placebo-treatedpatients (1.7 %). Adverse reactions of gout were reported more frequently in tolvaptan-treated patients(28/961, 2.9 %) than in patients receiving placebo (7/483, 1.4 %). In addition, increased use ofallopurinol and other medicinal products used to manage gout were observed in the double-blind,placebo-controlled trial. Effects on serum uric acid are attributable to the reversible renal hemodynamicchanges that occur in response to tolvaptan effects on urine osmolality and may be clinically relevant.

However, events of increased uric acid and/or gout were not serious and did not cause discontinuationof therapy in the double-blind, placebo-controlled trial. Uric acid concentrations are to be evaluatedprior to initiation of Jinarc therapy, and as indicated during treatment based on symptoms.

Effect of tolvaptan on glomerular filtration rate (GFR)

A reversible reduction in GFR has been observed in ADPKD trials at the initiation of tolvaptantreatment.

Chronic Kidney Disease

Limited safety and efficacy data are available for Jinarc in patients with CKD late stage 4(eGFR< 25 mL/min/1.73 m2). There are no data in patients with CKD stage 5. Tolvaptan treatmentshould be discontinued if renal insufficiency progresses to CKD stage 5.

Jinarc contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effect of other medicinal products on the pharmacokinetics of tolvaptan

Concomitant use of medicinal products that are moderate CYP3A inhibitors (e.g. amprenavir,aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin,fluconazole, fosamprenavir, imatinib, verapamil) or strong CYP3A inhibitors (e.g. itraconazole,ketoconazole, ritonavir, clarithromycin) increase tolvaptan exposure.

Co-administration of tolvaptan and ketoconazole resulted in a 440 % increase in area under time-concentration curve (AUC) and 248 % increase in maximum observed plasma concentration (Cmax) fortolvaptan.

Co-administration of tolvaptan and fluconazole, a moderate CYP3A inhibitor, produced a 200 % and80 % increase in tolvaptan AUC and Cmax, respectively.

Co-administration of tolvaptan with grapefruit juice, a moderate to strong CYP3A inhibitor, produced adoubling of peak tolvaptan concentrations (Cmax).

Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3Ainhibitors (see section 4.2). Patients taking moderate or strong CYP3A inhibitors must be managedcautiously, in particular if the inhibitors are taken more frequently than once a day.

Concomitant use of medicinal products that are potent CYP3A inducers (e.g. rifampicin) will decreasetolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces Cmax and AUCfor tolvaptan by about 85 %. Therefore, concomitant administration of tolvaptan with potent CYP3Ainducers (e.g. rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, and St. John’s Wort) is to beavoided.

Co-administration with medicinal products that increase serum sodium concentration

There is no experience from controlled clinical trials with concomitant use of tolvaptan and hypertonicsodium chloride solution, oral sodium formulations, and medicinal products that increase serum sodiumconcentration. Medicinal products with high sodium content such as effervescent analgesic preparationsand certain sodium containing treatments for dyspepsia may also increase serum sodium concentration.

Concomitant use of tolvaptan with medicinal products that increase serum sodium concentration mayresult in a higher risk for developing hypernatraemia (see section 4.4) and is therefore notrecommended.

Tolvaptan has not been extensively studied in ADPKD in combination with diuretics. While there doesnot appear to be a synergistic or additive effect of concomitant use of tolvaptan with loop and thiazidediuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a riskfactor for renal dysfunction. If dehydration or renal dysfunction becomes evident, appropriate actionmust be taken which may include the need to interrupt or reduce doses of tolvaptan and/or diuretics andincreased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated andaddressed.

Effect of tolvaptan on the pharmacokinetics of other products

In healthy subjects, tolvaptan, a CYP3A substrate, had no effect on the plasma concentrations of someother CYP3A substrates (e.g. warfarin or amiodarone). Tolvaptan increased plasma levels of lovastatinby 1.3-to 1.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan canpotentially increase exposure to CYP3A4 substrates.

P-glycoprotein substrates: In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitorof P-glycoprotein (P-gp). Steady state digoxin concentrations were increased (1.3-fold in maximumobserved plasma concentration [Cmax] and 1.2-fold in area under the plasma concentration-time curveover the dosing interval [AUCτ]) when co-administered with multiple once daily 60 mg doses oftolvaptan. Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g. dabigatran) musttherefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan.

OATP1B1/OAT3/BCRP and OCT1: In-vitro studies indicate that tolvaptan or its oxobutyric metabolitemay have the potential to inhibit OATP1B1, OAT3, BCRP and OCT1 transporters. Co-administrationof tolvaptan (90 mg) with rosuvastatin (5 mg), a BCRP substrate, increased rosuvastatin Cmax and AUCtof 54 % and 69 %, respectively. If BCRP substrates (e.g. sulfasalazine) are co-administered withtolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinalproducts.

Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthysubjects with elevated oxobutyric acid metabolite (inhibitor of OATP1B1 and OAT3) plasmaconcentrations did not meaningfully alter the pharmacokinetics of rosuvastatin or furosemide. Statinscommonly used in the tolvaptan phase 3 pivotal trial (e.g. rosuvastatin and pitavastatin) are OATP1B1or OATP1B3 substrates, however no difference in adverse events profile was observed during thephase 3 pivotal trial for tolvaptan in ADPKD.

If OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managedcautiously and evaluated for excessive effects of these medicinal products.

Diuretics or non-diuretic anti-hypertensive medicinal product(s)

Standing blood pressure was not routinely measured in ADPKD trials. Therefore, a risk oforthostatic/postural hypotension due to a pharmacodynamic interaction with tolvaptan cannot beexcluded.

Co-administration with vasopressin analogues

In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V2receptors involved in the release of coagulation factors (e.g. von Willebrand factor) from endothelialcells. Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated in patientsusing such analogues to prevent or control bleeding when co-administered with tolvaptan. It is notrecommended to administer Jinarc with vasopressin analogues.

Smoking and alcohol

Data related to smoking or alcohol history in ADPKD trials are too limited to determine possibleinteractions of smoking or alcohol with efficacy and safety of ADPKD treatment with tolvaptan.

There are no or limited amount of data from the use of tolvaptan in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). Jinarc is not recommended in women ofchildbearing potential not using contraception.

Jinarc is contraindicated during pregnancy (see section 4.3).

It is unknown whether tolvaptan is excreted in human breast milk. Studies in rats have shown excretionof tolvaptan in milk. A risk for the newborns/infants cannot be excluded. Jinarc is contraindicatedduring breast-feeding (see section 4.3).

Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans isunknown.

Jinarc has minor influence on the ability to drive or use machines. When driving vehicles or usingmachines it has to be taken into account that occasionally dizziness, asthenia or fatigue may occur.

The pharmacodynamically predictable and most commonly reported adverse reactions are thirst,polyuria, nocturia, and pollakiuria occurring in approximately 55 %, 38 %, 29 % and 23 % of patients,respectively. Furthermore, tolvaptan has been associated with idiosyncratic elevations of blood alanineaminotransferase (ALT; 4.4 %) and aspartate aminotransferases (AST; 3.1 %) with infrequent cases ofconcomitant elevations in bilirubin-total (BT; 0.2 %).

The incidences of the adverse drug reactions (ADRs) associated with tolvaptan therapy are tabulatedbelow. The table is based on adverse reactions reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) andnot known (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they arederived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as'not known'.

Very common Common Uncommon Not known

Immune system Anaphylacticdisorders shock,

Generalised rash

Metabolism and Polydipsia Dehydration,nutrition Hypernatraemia,disorders Decreased appetite,

Hyperuricaemia,

Hyperglycaemia,

Gout

Psychiatric Insomniadisorders

Nervous system Headache, Dysgeusia,disorders Dizziness Syncope

Cardiac Palpitationsdisorders

Very common Common Uncommon Not known

Respiratory, Dyspnoeathoracic andmediastinaldisorders

Gastrointestinal Diarrhoea, Abdominal pain,disorders Dry mouth Abdominal distension,

Constipation,

Dyspepsia,

Gastroesophageal refluxdisease

Hepatobiliary Abnormal hepatic function Acute hepaticdisorders failure1

Skin and Dry skin,subcutaneous Rash,tissue disorders Pruritus,

Urticaria

Musculoskeletal Arthralgia,and connective Muscle spasms,tissue disorders Myalgia

Renal and Nocturia,urinary Pollakiuria,disorders Polyuria

General Fatigue, Astheniadisorders and Thirstadministrationsite conditions

Investigations Alanine aminotransferase Bilirubinincreased, increased

Aspartateaminotransferaseincreased,

Weight decreased,

Weight increased1 observed in post-marketing with tolvaptan in ADPKD. Liver transplantation was necessary.

Laboratory results

Elevation (> 3 × upper limit of normal [ULN]) of ALT was observed in 4.4 % (42/958) of patients ontolvaptan and 1.0 % (5/484) of patients on placebo, while elevation (> 3 × ULN) of AST was observedin 3.1 % (30/958) of patients on tolvaptan and 0.8 % (4/484) patients on placebo in a double-blind,placebo-controlled trial in patients with ADPKD. 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 × ULN) with concomitant elevations in BT (> 2 × ULN).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system listedin Appendix V.

Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses upto 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is nospecific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can beanticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration,polyuria, thirst and dehydration/hypovolemia.

No mortality was observed in rats or dogs following single oral doses of 2,000 mg/kg (maximumfeasible dose). A single oral dose of 2,000 mg/kg was lethal in mice and symptoms of toxicity inaffected mice included decreased locomotor activity, staggering gait, tremor and hypothermia.

In patients with suspected tolvaptan overdose, assessment of vital signs, electrolyte concentrations, ECGand fluid status is recommended. Appropriate replacement of water and/or electrolytes must continueuntil aquaresis abates. Dialysis may not be effective in removing tolvaptan because of its high bindingaffinity for human plasma protein (> 98 %).

Pharmacotherapeutic group: Diuretics, vasopressin antagonists, ATC code: C03XA01.

Tolvaptan is a vasopressin antagonist that specifically blocks the binding of arginine vasopressin (AVP)at the V2 receptors of the distal portions of the nephron. Tolvaptan affinity for the human V2 receptor is1.8 times that of native AVP.

The pharmacodynamic effects of tolvaptan have been determined in healthy subjects and subjects with

ADPKD across CKD stages 1 to 4. Effects on free water clearance and urine volume are evident acrossall CKD stages with smaller absolute effects observed at later stages, consistent with the decliningnumber of fully functioning nephrons. Acute reductions in mean total kidney volume were alsoobserved following 3 weeks of therapy in all CKD stages, ranging from −4.6 % for CKD stage 1 to−1.9 % for CKD stage 4.

The primary focus of the clinical program for development of tolvaptan tablets for the treatment of

ADPKD is a single pivotal, multi-national, phase 3, randomised, placebo-controlled trial in which thelong-term safety and efficacy of oral split dose tolvaptan regimens (titrated between 60 mg/day and120 mg/day) were compared with placebo in 1,445 adult subjects with ADPKD.

In total, 14 clinical trials involving tolvaptan have been completed worldwide in support of the ADPKDindication, including 8 trials in the US, 1 in the Netherlands, 3 in Japan, 1 in Korea, and themultinational phase 3 pivotal trial.

The phase 3 pivotal trial (TEMPO 3:4, 156-04-251) included subjects from 129 centres in the Americas,

Japan, Europe and other countries. The primary objective of this trial was to evaluate the long-termefficacy of tolvaptan in ADPKD through rate of total kidney volume (TKV) change (normalised aspercentage; %) for tolvaptan-treated compared with placebo-treated subjects. In this trial a total of 1,445adult patients (age 18 years to 50 years) with evidence of rapidly-progressing, early ADPKD (meetingmodified Ravine criteria, TKV ≥ 750 mL, estimated creatinine clearance ≥ 60 mL/min) wererandomised 2:1 to treatment with tolvaptan or placebo. Patients were treated for up to 3 years.

Tolvaptan (n = 961) and placebo (n = 484) groups were well matched in terms of gender with anaverage age of 39 years. The inclusion criteria identified patients who at baseline had evidence of earlydisease progression. At baseline, patients had average estimated glomerular filtration rate (eGFR) of82 mL/min/1.73 m2 (Chronic Kidney Disease-Epidemiology Collaboration; CKD-EPI) with 79 %having hypertension and a mean TKV of 1,692 mL (height adjusted 972 mL/m). Approximately 35 % ofsubjects were CKD stage 1, 48 % CKD stage 2, and 17 % CKD stage 3 (eGFRCKD-EPI). While thesecriteria were useful in enriching the study population with patients who were rapidly progressing,subgroup analyses based on stratification criteria (age, TKV, GFR, Albuminuria, Hypertension)indicated the presence of such risk factors at younger ages predicts more rapid disease progression.

The results of the primary endpoint, the rate of change in TKV for subjects randomised to tolvaptan(normalised as percentage, %) to the rate of change for subjects on placebo, were highly statisticallysignificant. The rate of TKV increase over 3 years was significantly less for tolvaptan-treated subjectsthan for subjects receiving placebo: 2.80 % per year versus 5.51 % per year, respectively (ratio ofgeometric mean 0.974; 95 % CI 0.969 to 0.980; p < 0.0001).

Pre-specified secondary endpoints were tested sequentially. The key secondary composite endpoint(ADPKD progression) was time to multiple clinical progression events of:1) Worsening kidney function (defined as a persistent [reproduced over at least 2 weeks] 25 %reduction in reciprocal serum creatinine during treatment [from end of titration to last on-medicinal product visit])2) Medically significant kidney pain (defined as requiring prescribed leave, last-resort analgesics,narcotic and anti-nociceptive, radiologic or surgical interventions)3) Worsening hypertension4) Worsening albuminuria

The relative rate of ADPKD-related events was decreased by 13.5 % in tolvaptan-treated patients,(hazard ratio, 0.87; 95 % CI, 0.78 to 0.97; p = 0.0095).

The result of the key secondary composite endpoint is primarily attributed to effects on worseningkidney function and medically significant kidney pain. The renal function events were 61.4 % less likelyfor tolvaptan compared with placebo (hazard ratio, 0.39; 95 % CI, 0.26 to 0.57; nominal p < 0.0001),while renal pain events were 35.8 % less likely in tolvaptan-treated patients (hazard ratio, 0.64; 95 %

CI, 0.47 to 0.89; nominal p = 0.007). In contrast, there was no effect of tolvaptan on either progressionof hypertension or albuminuria.

TEMPO 4:4 is an open-label extension study that included 871 subjects that completed TEMPO3:4 from 106 centres across 13 countries. This trial evaluated the effects of tolvaptan on safety, TKVand eGFR in subjects receiving active treatment for 5 years (early-treated), compared with subjectstreated with placebo for 3 years, then switched to active treatment for 2 years (delayed-treated).

The primary end point for TKV did not distinguish a difference in change (−1.7 %) over the 5-yeartreatment between early- and delayed-treated subjects at the pre-specified threshold of statisticalsignificance (p = 0.3580). Both groups’ TKV growth trajectory was slowed, relative to placebo in thefirst 3 years, suggesting both early- and delayed- tolvaptan treated subjects benefitted to a similardegree.

A secondary endpoint testing the persistence of positive effects on renal function indicated that thepreservation of eGFR observed by the end of the TEMPO 3:4 pivotal trial (3.01 to 3.34 mL/min/1.73 m2at follow-up visits 1 and 2) could be preserved during open-label treatment. This difference wasmaintained in the pre-specified mixed effect model repeat measurement (MMRM) analysis(3.15 mL/min/1.73 m2, 95 %CI 1.462 to 4.836, p = 0.0003) and with sensitivity analyses where baselineeGFR data were carried forward (2.64 mL/min/1.73 m2, 95 % CI 0.672 to 4.603, p = 0.0086). Thesedata suggest that tolvaptan can slow the rate of renal function decline, and that these benefits persistover the duration of therapy.

Longer term data are not currently available to show whether long-term therapy with tolvaptancontinues to slow the rate of renal function decline and affect clinical outcomes of ADPKD, includingdelay in the onset of end-stage renal disease.

Genotyping for PKD1 and PKD2 genes was conducted in a majority of patients entering the open-labelextension study (TEMPO 4:4) but the results are not yet known.

Following an additional 2 years of tolvaptan treatment, resulting in a total of 5 years on tolvaptantherapy no new safety signals were identified.

The phase 3, multi-centre, international, randomised-withdrawal, placebo-controlled, double-blind trial156-13-210 compared the efficacy and safety of tolvaptan (45 mg/day to 120 mg/day) to placebo inpatients able to tolerate tolvaptan during a five-week titration and run-in period on tolvaptan. The trialutilised a randomised withdrawal design, to enrich for patients that were able to tolerate tolvaptan for a5-week, single-blind pre-randomisation period consisting of a 2-week titration period and 3-week run-inperiod. The design was used to minimise the impact of early discontinuation and missing data on trialendpoints.

A total of 1,370 patients (age 18 years to 65 years) with CKD with an eGFR between 25 and65 mL/min/1.73 m2 if younger than age 56 years; or eGFR between 25 and 44 mL/min/1.73 m2, pluseGFR decline >2.0 mL/min/1.73 m2/year if between age 56 years to 65 years were randomised to eithertolvaptan (n = 683) or placebo (n = 687) and were treated for a period of 12 months.

For subjects randomised, the baseline, average eGFR was 41 mL/min/1.73 m2 (CKD-EPI) and historical

TKV, available in 318 (23 %) of subjects, averaged 2,026 mL. Approximately 5 %, 75 % and 20 % hadan eGFR 60 mL/min/1.73 m2 or greater (CKD stage 2), or less than 60 and greater than30 mL/min/1.73 m2 (CKD stage 3) or less than 30 but greater than 15 mL/min/1.73 m2 (CKD stage 4),respectively. The CKD stage 3 can be subdivided further to stage 3a 30 %, (eGFR 45 mL/min/1.73 m2to less than 60 mL/min/1.73 m2) and stage 3b 45 %, (eGFR between 30 and 45 mL/min/1.73 m2).

The primary endpoint of the trial was the change in eGFR from pre-treatment baseline levels to post-treatment assessment. In patients treated with tolvaptan the reduction in eGFR was significantly lessthan in patients treated with placebo (p < 0.0001). The treatment difference in eGFR change observed inthis trial is 1.27 mL/min/1.73 m2, representing a 35 % reduction in the LS means of change in eGFR of−2.34 mL/min/1.73 m2 in tolvaptan group relative to a −3.61 mL/min/1.73 m2 in placebo groupobserved over the course of one year. The key secondary endpoint was a comparison of the efficacy oftolvaptan treatment versus placebo in reducing the decline of annualised eGFR slope across allmeasured time points in the trial. These data also showed significant benefit from tolvaptan versusplacebo (p < 0.0001).

Subgroup analysis of the primary and secondary endpoints by CKD stage found similar, consistenttreatment effects relative to placebo for subjects in stages 2, 3a, 3b and early stage 4 (eGFR 25 to29 mL/min/1.73 m2) at baseline.

A pre-specified subgroup analysis suggested that tolvaptan had less of an effect in patients older than55 years of age, a small subgroup with a notably slower rate of eGFR decline.

The European Medicines Agency has deferred the obligation to submit the results of studies withtolvaptan in one or more subsets of the paediatric population in polycystic kidney disease (seesection 4.2 for information on paediatric use).

After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurringabout 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56 %. Co-administration oftolvaptan with a high-fat meal increased peak concentrations of tolvaptan up to 2-fold but left AUCunchanged. Even though the clinical relevance of this finding is not known, the morning dose should betaken under fasted conditions to minimise the unnecessary risk of increasing the maximal exposure (seesection 4.2).

Following single oral doses of ≥ 300 mg, peak plasma concentrations appear to plateau, possibly due tosaturation of absorption. Tolvaptan binds reversibly (98 %) to plasma proteins.

Tolvaptan is extensively metabolised in the liver almost exclusively by CYP3A. Tolvaptan is a weak

CYP3A4 substrate and does not appear to have any inhibitory activity. In vitro studies indicated thattolvaptan has no inhibitory activity for CYP3A. Fourteen metabolites have been identified in plasma,urine and faeces; all but one were also metabolised by CYP3A. Only the oxobutyric acid metabolite ispresent at greater than 10 % of total plasma radioactivity; all others are present at lower concentrationsthan tolvaptan. Tolvaptan metabolites have little to no contribution to the pharmacological effect oftolvaptan; all metabolites have no or weak antagonist activity for human V2 receptors when comparedwith tolvaptan. The terminal elimination half-life is about 8 hours and steady-state concentrations oftolvaptan are obtained after the first dose.

Less than 1 % of intact active substance is excreted unchanged in the urine. Radio labelled tolvaptanexperiments showed that 40 % of the radioactivity was recovered in the urine and 59 % was recoveredin the faeces, where unchanged tolvaptan accounted for 32 % of radioactivity. Tolvaptan is only a minorcomponent in plasma (3 %).

Following single oral doses, Cmax values show less than dose proportional increases from 30 mg to240 mg and then a plateau at doses from 240 mg to 480 mg. AUC increases linearly.

Following multiple once daily dosing of 300 mg, tolvaptan exposure was only increased 6.4-fold whencompared to a 30 mg dose. For split-dose regimens of 30 mg/day, 60 mg/day and 120 mg/day in

ADPKD patients, tolvaptan exposure (AUC) increases linearly.

Clearance of tolvaptan is not significantly affected by age.

The effect of mildly or moderately impaired hepatic function (Child-Pugh classes A and B) on thepharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. Noclinically significant changes have been seen in clearance for doses ranging from 5 mg to 60 mg. Verylimited information is available in patients with severe hepatic impairment (Child-Pugh class C).

In a population pharmacokinetic analysis in patients with hepatic oedema, AUC of tolvaptan in severely(Child-Pugh class C) and mildly or moderately (Child-Pugh classes A and B) hepatic impaired patientswere 3.1-times and 2.3-times higher than that in healthy subjects.

In a population pharmacokinetic analysis for patients with ADPKD, tolvaptan concentrations wereincreased, compared to healthy subjects, as renal function decreased below eGFR of60 mL/min/1.73 m2. An eGFRCKD-EPI decrease from 72.2 to 9.79 (mL/min/1.73 m2) was associated witha 32 % reduction in total body clearance.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Teratogenicity was noted in rabbits given 1,000 mg/kg/day (2.6-times the exposure at the maximumhuman recommended dose of 120 mg/day). No teratogenic effects were seen in rabbits at300 mg/kg/day (1.2-times the exposure at the maximum human recommended dose of 120 mg/day).

In a peri- and post-natal study in rats, delayed ossification and reduced pup bodyweight were seen at thehigh dose of 1,000 mg/kg/day.

Two fertility studies in rats showed effects on the parental generation (decreased food consumption andbody weight gain, salivation), but tolvaptan did not affect reproductive performance in males and therewere no effects on the foetuses. In females, abnormal oestrus cycles were seen in both studies.

The no observed adverse effect level (NOAEL) for reproduction in females (100 mg/kg/day) was about4.4-times the exposure at the maximum human recommended dose of 120 mg/day.

Maize starch

Hydroxypropylcellulose

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose

Indigo carmine aluminium lake

Not applicable.

4 years

Store in the original package in order to protect from light and moisture.

Jinarc 15 mg tablets7 or 28 tablets in PVC/aluminium foil blister

Jinarc 30 mg tablets7 or 28 tablets in PVC/aluminium foil blister

Jinarc 15 mg tablets + Jinarc 45 mg tablets14 tablets in 1 PVC/aluminium foil blister with 7 × 15 mg and 7 × 45 mg tablets28 tablets in 2 PVC/aluminium foil blisters with 7 × 15 mg and 7 × 45 mg tablets56 tablets in 4 PVC/aluminium foil blisters with 7 × 15 mg and 7 × 45 mg tablets14 tablets in 1 PVC/aluminium foil blister in wallet card with 7 × 15 mg and 7 × 45 mg tablets28 tablets in 2 PVC/aluminium foil blisters in wallet card with 7 × 15 mg and 7 × 45 mg tablets56 tablets in 4 PVC/aluminium foil blisters in wallet card with 7 × 15 mg and 7 × 45 mg tablets

Jinarc 30 mg tablets + Jinarc 60 mg tablets14 tablets in 1 PVC/aluminium foil blister with 7 × 30 mg and 7 × 60 mg tablets28 tablets in 2 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 60 mg tablets56 tablets in 4 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 60 mg tablets14 tablets in 1 PVC/aluminium foil blister in wallet card with 7 × 30 mg and 7 × 60 mg tablets28 tablets in 2 PVC/aluminium foil blisters in wallet card with 7 × 30 mg and 7 × 60 mg tablets56 tablets in 4 PVC/aluminium foil blisters in wallet card with 7 × 30 mg and 7 × 60 mg tablets

Jinarc 30 mg tablets + Jinarc 90 mg tablets14 tablets in 1 PVC/aluminium foil blister with 7 × 30 mg and 7 × 90 mg tablets28 tablets in 2 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 90 mg tablets56 tablets in 4 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 90 mg tablets14 tablets in 1 PVC/aluminium foil blister in wallet card with 7 × 30 mg and 7 × 90 mg tablets28 tablets in 2 PVC/aluminium foil blisters in wallet card with 7 × 30 mg and 7 × 90 mg tablets56 tablets in 4 PVC/aluminium foil blisters in wallet card with 7 × 30 mg and 7 × 90 mg tablets

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Otsuka Pharmaceutical Netherlands B.V.

Herikerbergweg 2921101 CT, Amsterdam

Netherlands

Jinarc 15 mg tablets

EU/1/15/1000/001-002 (blister)

Jinarc 30 mg tablets

EU/1/15/1000/003-004 (blister)

Jinarc 15 mg tablets + Jinarc 45 mg tablets

EU/1/15/1000/005-007 (blister)

EU/1/15/1000/014-016 (blister in wallet card)

Jinarc 30 mg tablets + Jinarc 60 mg tablets

EU/1/15/1000/008-010 (blister)

EU/1/15/1000/017-019 (blister in wallet card)

Jinarc 30 mg tablets + Jinarc 90 mg tablets

EU/1/15/1000/011-013 (blister)

EU/1/15/1000/020-022 (blister in wallet card)

Date of first authorisation: 27 May 2015

Date of latest renewal: 3 April 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.