Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
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, the period of onset of hepatocellular injury (by ALT elevations >3 × ULN) was within 3 to 14 months after initiating treatment and these increases were reversible, with ALT returning to <3 × 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 (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 transaminases and 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 (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 below), the use of tolvaptan is contraindicated (see section 4.3). 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, 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, 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 hours to 72 hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point Jinarc may be re-initiated.
Current clinical practice suggests that 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:
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 during continued therapy in some patients.
Tolvaptan may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, and pollakiuria (see section 4.8). Therefore, patients must have access to water (or other aqueous fluids) and be able to drink sufficient amounts of these fluids (see section 4.2). 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 to 2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia.
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. Accurate monitoring of body weight is recommended. A progressive reduction in body weight could be an early sign of progressive dehydration. 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 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 status must be monitored in all patients. Administration of tolvaptan induces copious aquaresis and may cause dehydration and increases in serum sodium (see section 4.8) and is contraindicated in hypernatraemic patients (see section 4.3). 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.
Pre-treatment sodium abnormalities (hyponatraemia or hypernatraemia) must be corrected prior to initiation with tolvaptan therapy.
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 section 4.3).
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 section 4.3) treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.
Diabetic patients with an elevated glucose concentration (e.g. in excess of 300 mg/dL) may present with pseudo-hyponatraemia. This condition must be excluded prior and during treatment with tolvaptan.
Tolvaptan may cause hyperglycaemia (see section 4.8). Therefore, diabetic patients treated with tolvaptan must be managed cautiously. In particular this applies to patients with inadequately controlled type II diabetes.
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 Jinarc therapy, and as indicated during treatment based on symptoms.
A reversible reduction in GFR has been observed in ADPKD trials at the initiation of tolvaptan treatment.
The safety and efficacy of Jinarc in CKD late stage 4 (eGFR <25 mL/min/1.73 m²) and stage 5 have not been explored. Tolvaptan treatment should 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 prodcut.
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) for tolvaptan.
Co-administration of tolvaptan and fluconazole, a moderate CYP3A inhibitor, produced a 200% and 80% increase in tolvaptan AUC and Cmax, respectively. Co-administration of tolvaptan with grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak tolvaptan concentrations (Cmax).
Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3A inhibitors (see section 4.2). Patients taking moderate or strong CYP3A inhibitors must be managed cautiously, 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 decrease tolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces Cmax and AUC for tolvaptan by about 85%. Therefore, concomitant administration of tolvaptan with potent CYP3A inducers (e.g. rifampicin, rifabutin, rifapentin, phenytoin, carbamazepine, and St. John’s Wort) is to be avoided.
There is no experience from controlled clinical trials with concomitant use of tolvaptan and hypertonic sodium chloride solution, oral sodium formulations, and medicinal products that increase serum sodium concentration. Medicinal products with high sodium content such as effervescent analgesic preparations and certain sodium containing treatments for dyspepsia may also increase serum sodium concentration. Concomitant use of tolvaptan with medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia (see section 4.4) and is therefore not recommended.
Tolvaptan has not been extensively studied in ADPKD in combination with diuretics. While there does not appear to be a synergistic or additive effect of concomitant use of tolvaptan with loop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration or renal dysfunction becomes evident, appropriate action must be taken which may include the need to interrupt or reduce doses of tolvaptan and/or diuretics and increased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated and addressed.
In healthy subjects, tolvaptan, a CYP3A substrate, had no effect on the plasma concentrations of some other CYP3A substrates (e.g. warfarin or amiodarone). Tolvaptan increased plasma levels of lovastatin by 1.3-to 1.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan can potentially increase exposure to CYP3A4 substrates.
In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitor of P-glycoprotein (P-gp). In vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OATP1B3, OAT3, BCRP and OCT1 transporters. Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [Cmax] and 1.2-fold in area under the plasma concentration-time curve over the dosing interval [AUCτ]) when co-administered with multiple once daily 60 mg doses of tolvaptan. Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g. dabigatran) must therefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan. Statins commonly used in the tolvaptan phase 3 pivotal trial (e.g. rosuvastatin and pitavastatin) are OATP1B1 or OATP1B3 substrates, however no difference in adverse events profile was observed during the phase 3 pivotal trial for tolvaptan in ADPKD. If OATP1B1 and OATP1B3 substrates (e.g. statins such as rosuvastatin and pitavastatin), OAT3 substrates (e.g. methotrexate, ciprofloxacin), BCRP substrates (e.g. sulfasalazine) or OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.
Standing blood pressure was not routinely measured in ADPKD trials. Therefore, a risk of orthostatic/postural hypotension due to a pharmacodynamic interaction with tolvaptan cannot be excluded.
In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V2 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 such analogues to prevent or control bleeding when co-administered with tolvaptan. It is not recommended to administer Jinarc with vasopressin analogues.
Data related to smoking or alcohol history in ADPKD trials are too limited to determine possible interactions 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 animals have shown reproductive toxicity (see section 5.3). Jinarc is not recommended in women of childbearing 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 excretion of tolvaptan in milk. A risk for the newborns/infants cannot be excluded. Jinarc is contraindicated during breast-feeding (see section 4.3).
Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans is unknown.
Jinarc has minor influence on the ability to drive or use machines. When driving vehicles or using machines 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 alanine aminotransferase (ALT; 4.4%) and aspartate aminotransferases (AST; 3,1%) with infrequent cases of concomitant elevations in bilirubin-total (BT; 0,2%).
The incidences of the adverse drug reactions (ADRs) associated with tolvaptan therapy are tabulated below. 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as “not known”.
Not known: Anaphylactic shock, Generalised rash
Very common: Polydipsia
Common: Dehydration, Hypernatraemia, Decreased appetite, Hyperuricaemia, Hyperglycaemia, Gout
Common: Insomnia
Very common: Headache, Dizziness
Common: Palpitations
Common: Dyspnoea
Very common: Diarrhoea, Dry mouth
Common: Abdominal pain, Abdominal distension, Constipation, Dyspepsia, Gastroesophageal reflux disease
Common: Abnormal hepatic function
Not known: Acute hepatic failure1
Common: Rash, Pruritus
Common: Muscle spasms
Very common: Nocturia, Pollakiuria, Polyuria
Very common: Fatigue, Thirst
Common: Asthenia
Common: Alanine aminotransferase increased, Aspartate aminotransferase increased, Weight decreased
Uncommon: Bilirubin increased
1 observed in post-marketing with tolvaptan in ADPKD. Liver transplantation was necessary.
Elevation (>3 × 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 × ULN) of AST was observed in 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. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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