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Tablets must be swallowed without chewing and with a glass of water.
Dose titration: 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 Precautions).
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 Tolvaptan (JINARC®) in CKD stage 5 have not been adequately explored and therefore tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5. The morning dose of Tolvaptan (JINARC®) is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food. Therapy must be interrupted if the ability to drink or the accessibility to water is limited (see Precautions).
PRECAUTION: 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 Precautions).
Tolvaptan must not be taken with grapefruit juice (see Interactions). Patients must be instructed to drink sufficient amounts of water or other aqueous fluids (see Precautions)
IMPORTANT PRECAUTION: Dose adjustment for patients taking strong CYP3A inhibitors: In patients taking strong CYP3A inhibitors (see Interactions), tolvaptan doses have to be reduced as follows: See Table 1.
Click on icon to see table/diagram/imageDose adjustment for patients taking moderate CYP3A inhibitors: In patients taking moderate CYP3A inhibitors, tolvaptan doses have to be reduced as follows: See Table 2.
Click on icon to see table/diagram/imageFurther reductions have to be considered if patients cannot tolerate the reduced tolvaptan doses.
Elderly population: Increasing age has no effect on tolvaptan plasma concentrations. However, the safety and effectiveness of tolvaptan in ADPKD patients aged over 50 years has not yet been established.
Renal impairment: Tolvaptan is contraindicated in anuric patients (see Contraindications).
Dose adjustment is not required in patients with renal impairment. No clinical trials in subjects with a creatinine clearance < 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. eGFR < 20) may be increased; these patients should be carefully monitored for hepatic toxicity. Data for patients in CKD stage 3 are more limited than for patients in stage 1 or 2 (see Pharmacology: Pharmacodynamics under Actions).
Hepatic impairment: In patients with severe hepatic impairment the benefits and risks of treatment with Tolvaptan (JINARC®) must be evaluated carefully. Patients must be managed carefully and liver enzymes must be monitored regularly (see Precautions). Tolvaptan (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 Contraindications and Precautions). No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).
Paediatric population: 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.
