Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
Jinarc is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 4 at 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 expertise in managing ADPKD and a full understanding of the risks of tolvaptan therapy including hepatic toxicity 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 or 90 mg + 30 mg. The morning dose is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food. According to these split dose regimens the total daily doses are 60 mg, 90 mg, or 120 mg.
The initial dose is 60 mg tolvaptan per day as a split-dose regimen of 45 mg + 15 mg (45 mg taken upon waking and prior the morning meal and 15 mg taken 8 hours later). The initial dose is to be titrated upward 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 intervals between titrations. Dose titration has to be performed cautiously to ensure that high doses are not poorly tolerated through overly rapid up-titration. Patients may down-titrate to lower doses based on tolerability. 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 and constantly 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 body weight should be considered to monitor the risk of dehydration secondary to the aquaretic effects of tolvaptan in case of patient’s insufficient water intake.
The safety and efficacy of Jinarc in CKD stage 5 have not been explored and therefore tolvaptan treatment 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 (see section 4.4).
Tolvaptan must not be taken with grapefruit juice (see section 4.5). Patients must be instructed to drink sufficient amounts of water or other aqueous fluids (see section 4.4).
In patients taking strong CYP3A inhibitors (see section 4.5), tolvaptan doses have to be reduced as follows:
| 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 |
In patients taking moderate CYP3A inhibitors, tolvaptan doses have to be reduced as follows:
| Tolvaptan daily split-dose | Reduced split-dose |
|---|---|
| 90 mg + 30 mg | 45 mg + 15 mg |
| 60 mg + 30 mg | 30 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 and effectiveness 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 patients undergoing dialysis have been conducted. The risk of hepatic damage in patients with severely reduced renal function (i.e. estimated glomerular filtration rate [eGFR] <20) may be increased; these patients should be carefully monitored for hepatic toxicity. Data for patients in CKD early stage 4 are more limited than for patients in stage 1, 2 or 3 (see section 5.1). No data are available for patients with CKD late stage 4 (eGFR <25 mL/min/1.73 m²) and stage 5. Tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5 (see section 4.4).
In patients with severe hepatic impairment the benefits and risks of treatment with Jinarc must be evaluated 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 liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (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 data are available. Tolvaptan is not recommended in the paediatric age group.
Oral use.
Tablets must be swallowed without chewing and with a glass of water.
Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/hypovolemia.
No mortality was observed in rats or dogs following single oral doses of 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.
In patients with suspected tolvaptan overdose, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Appropriate replacement of water and/or electrolytes must continue until aquaresis abates. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>98%).
4 years.
Store in the original package in order to protect from light and moisture.
Jinarc 15 mg tablets:
7 or 28 tablets in PVC/aluminium foil blister
Jinarc 30 mg tablets:
7 or 28 tablets in PVC/aluminium foil blister
Jinarc 15 mg tablets + Jinarc 45 mg tablets:
14 tablets in 1 PVC/aluminium foil blister with 7 × 15 mg and 7 × 45 mg tablets
28 tablets in 2 PVC/aluminium foil blisters with 7 × 15 mg and 7 × 45 mg tablets
56 tablets in 4 PVC/aluminium foil blisters with 7 × 15 mg and 7 × 45 mg tablets
14 tablets in 1 PVC/aluminium foil blister in wallet card with 7 × 15 mg and 7 × 45 mg tablets
28 tablets in 2 PVC/aluminium foil blisters in wallet card with 7 × 15 mg and 7 × 45 mg tablets
56 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 tablets:
14 tablets in 1 PVC/aluminium foil blister with 7 × 30 mg and 7 × 60 mg tablets
28 tablets in 2 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 60 mg tablets
56 tablets in 4 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 60 mg tablets
14 tablets in 1 PVC/aluminium foil blister in wallet card with 7 × 30 mg and 7 × 60 mg tablets
28 tablets in 2 PVC/aluminium foil blisters in wallet card with 7 × 30 mg and 7 × 60 mg tablets
56 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 tablets:
14 tablets in 1 PVC/aluminium foil blister with 7 × 30 mg and 7 × 90 mg tablets
28 tablets in 2 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 90 mg tablets
56 tablets in 4 PVC/aluminium foil blisters with 7 × 30 mg and 7 × 90 mg tablets
14 tablets in 1 PVC/aluminium foil blister in wallet card with 7 × 30 mg and 7 × 90 mg tablets
28 tablets in 2 PVC/aluminium foil blisters in wallet card with 7 × 30 mg and 7 × 90 mg tablets
56 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 local requirements.
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