Jinarc Special Precautions

Idiosyncratic Hepatic Toxicity: Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (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 liver transplantation has been reported.
In a double-blind, placebo-controlled trial 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. 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 BT (> 2 x ULN). The period of onset of hepatocellular injury (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 reversible with prompt discontinuation of tolvaptan, they represent a potential for significant liver injury. Similar changes with other medicinal products have been associated with the potential to cause irreversible and potentially life-threatening liver injury.
Prescribing physicians must comply fully with the safety measures required as follows.
To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of Tolvaptan (JINARC^®), continuing monthly for 18 months and at regular 3-monthly intervals thereafter. Concurrent monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, dark. urine or jaundice) is recommended.
If a patient shows abnormal ALT, AST or BT levels prior to initiation of treatment which fulfil the criteria for permanent discontinuation (see as follows) the use of tolvaptan is contraindicated (see Contraindications). In case of abnormal baseline levels below the limits for permanent discontinuation treatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liver function testing must continue at increased time frequency. The advice of a hepatologist is recommended.
During the first 18 months of treatment, Tolvaptan (JINARC^®) can only be supplied to patients whose physician has determined 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, Tolvaptan (JINARC^®) administration must be immediately interrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideally within 48-72 hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point Tolvaptan (JINARC^®) may be reinitiated.
Current clinical practice suggests that Tolvaptan (JINARC^®) therapy is to 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 (BT > 2-times ULN or International Normalized Ratio [INR] > 1.5); ALT or AST > 3-times ULN with persistent symptoms of hepatic injury as previously noted.
If ALT and AST levels remain below 3-times the upper limit of normal (ULN), Tolvaptan (JINARC^®) therapy may be cautiously re-started, with frequent monitoring at the same or lower doses, as transaminase levels appear to stabilise during continued therapy in some patients.
Access to water: Tolvaptan may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, and pollakiuria (see Adverse Reactions). Therefore, patients must have access to water (or other aqueous fluids) and be able to drink sufficient amounts of these fluids (see Dosage &Administration). Patients have to be instructed to drink water or other aqueous fluids at the first sign of thirst in order to avoid excessive thirst or dehydration.
Additionally, patients have to drink 1-2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia.
Dehydration: Volume status must be monitored in patients taking tolvaptan because treatment with tolvaptan may result in severe 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 must 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 diarrhoea.
Urinary outflow obstruction: Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention.
Fluid and electrolyte balance: Fluid and electrolyte status must be monitored in all patients. Administration of tolvaptan induces copious aquaresis and may cause dehydration and increases in serum sodium (see Adverse Reactions) and is contraindicated in hypernatraemic patients (see Contraindications). Therefore, serum creatinine, electrolytes and symptoms of electrolyte imbalances (e.g. dizziness, fainting, palpitations, confusion, weakness, gait instability, hyper-reflexia, seizures, coma) have to be assessed prior to and after starting tolvaptan to monitor 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 to initiation with tolvaptan therapy.
Anaphylaxis: In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalised) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the first administration of tolvaptan. Patients have to be carefully monitored during treatment. 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 (see Contraindications).
If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan must be discontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication (see Contraindications) treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.
Lactose: Tolvaptan (JINARC^®) contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Diabetes mellitus: Diabetic patients with an elevated glucose concentration (e.g. in excess of 300 mg/dl) may present with pseudohyponatraemia. This condition must be excluded prior and during treatment with tolvaptan. Tolvaptan may cause hyperglycaemia (see Adverse Reactions). Therefore, diabetic patients treated with tolvaptan must be managed cautiously. In particular this applies to patients with inadequately controlled type 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 (greater than 10 mg/dL) was reported at a higher rate in tolvaptan-patients (6.2%) compared to placebo-treated patients (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 of allopurinol 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 hemodynamic changes 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 discontinuation of therapy in the double-blind, placebo-controlled trial. Uric acid concentrations are to be evaluated prior to initiation of Tolvaptan (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 tolvaptan treatment.
Effects on ability to drive and use machines: Tolvaptan (JINARC^®) has minor influence on the ability to drive or use machines. However, when driving vehicles or using machines it has to be taken into account that occasionally dizziness, asthenia or fatigue may occur.