Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
Pharmacotherapeutic group: Diuretics, vasopressin antagonists
ATC code: C03XA01
Tolvaptan is a selective vasopressin V2-receptor antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2-receptor of the distal portions of the nephron. Tolvaptan affinity for the human V2-receptor is 1.8 times that of native AVP.
In healthy adult subjects, oral administration of 7.5 to 120 mg doses of tolvaptan produced a increase in urine excretion rate within 2 hours of dosing. Following single oral doses of 7.5 to 60 mg, 24-hour urine volume increased dose dependently with daily volumes ranging from 3 to 9 litres. For all doses, urine excretion rates returned to baseline levels after 24 hours. For single doses 60 mg to 480 mg, a mean of about 7 litres was excreted during 0 to 12 hours, independent of dose. Markedly higher doses of tolvaptan produce more sustained responses without affecting the magnitude of excretion, as active concentrations of tolvaptan are present for longer periods of time.
In 2 pivotal, double-blind, placebo-controlled, clinical trials, a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) due to a variety of underlying causes (heart failure [HF], liver cirrhosis, SIADH and others) were treated for 30 days with tolvaptan (n=216) or placebo (n=208) at an initial dose of 15 mg/day. The dose could be increased to 30 and 60 mg/day depending on response using a 3 day titration scheme. The mean serum sodium concentration at trial entry was 129 mEq/L (range 114-136).
The primary endpoint for these trials was the average daily AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30. Tolvaptan was superior to placebo (p<0.0001) for both periods in both studies. This effect was seen in all patients, the severe (serum sodium: <130 mEq/L) and mild (serum sodium: 130 - <135 mEq/L) subsets and for all disease aetiology subsets (e.g. HF, cirrhosis, SIADH/other). At 7 days after discontinuing treatment, sodium values decreased to levels of placebo treated patients.
Following 3 days of treatment, the pooled analysis of the two trials revealed five-fold more tolvaptan than placebo patients achieved normalisation of serum sodium concentrations (49% vs. 11%). This effect continued as on Day 30, when more tolvaptan than placebo patients still had normal concentrations (60% vs. 27%). These responses were seen in patients independent of the underlying disease. The results of self-assessed health status using the SF-12 Health Survey for the mental scores showed statistically significant and clinically relevant improvements for tolvaptan treatment compared to placebo.
Data on the long-term safety and efficacy of tolvaptan were assessed for up to 106 weeks in a clinical trial in patients (any aetiology) who had previously completed one of the pivotal hyponatremia trials. A total of 111 patients started tolvaptan treatment in an open-label, extension trial, regardless of their previous randomisation. Improvements in serum sodium levels were observed as early as the first day after dosing and continued for on-treatment assessments up to Week 106. When treatment was discontinued, serum sodium concentrations decreased to approximately baseline values, despite the reinstatement of standard care therapy.
In a pilot, randomized (1:1:1), double-blind trial in 30 patients with hyponatremia secondary to SIADH, the pharmacodynamics of tolvaptan following single doses of 3.75, 7.5 and 15 mg were assessed. Results were highly variable with large overlap between dose groups; changes were not significantly correlated with tolvaptan exposure. Mean maximal changes in serum sodium were highest following the 15 mg dose (7.9 mmol/L) but median maximal changes were highest for the 7.5 mg dose (6.0 mmol/L). Individual maximal increases in serum sodium were negatively correlated with fluid balance; mean change in fluid balance showed a dose dependent decrease. Mean change from baseline in cumulative urine volume and urine excretion rates was 2-fold higher for the 15 mg dose compared to the 7.5 and 3.75 mg doses, which showed similar responses.
EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) was a long-term outcome, double-blind, controlled clinical trial in patients hospitalised with worsening HF and signs and symptoms of volume overload. In the long-term outcome trial, a total of 2,072 patients received 30 mg tolvaptan with standard of care (SC) and 2,061 received placebo with SC. The primary objective of the study was to compare the effects of tolvaptan + SC with placebo + SC on the time to all-cause mortality and on the time to first occurrence of cardiovascular (CV) mortality or hospitalisation for HF. Tolvaptan treatment had no statistically significant favourable or unfavourable effects on overall survival or the combined endpoint of CV mortality or HF hospitalisation, and did not provide convincing evidence for clinically relevant benefit.
The European Medicines Agency has deferred the obligation to submit the results of studies with Samsca in one or more subsets of the paediatric population in treatment of dilutional hyponatremia (see section 4.2 for information on paediatric use).
After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurring about 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56%. Co-administration of a 60 mg dose with a high-fat meal increases peak concentrations 1.4 fold with no change in AUC and no change in urine output. Following single oral doses of ≥300 mg, peak plasma concentrations appear to plateau, possibly due to saturation of absorption.
Tolvaptan binds reversibly (98%) to plasma proteins.
Tolvaptan is extensively metabolised by the liver. Less than 1% of intact active substance is excreted unchanged in the urine.
The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose.
Radio labelled tolvaptan experiments showed that 40% of the radioactivity was recovered in the urine and 59% was recovered in the faeces where unchanged tolvaptan accounted for 32% of radioactivity. Tolvaptan is only a minor component in plasma (3%).
Tolvaptan has linear pharmacokinetics for doses of 7.5 to 60 mg.
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 the pharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. No clinically significant changes have been seen in clearance for doses ranging from 5 to 60 mg. Very limited 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 patients were 3.1 and 2.3 times higher than that in healthy subjects.
In an analysis on population pharmacokinetics for patients with heart failure, tolvaptan concentrations of patients with mildly (creatinine clearance [Ccr] 50 to 80 mL/min) or moderately (Ccr 20 to 50 mL/min) impaired renal function were not significantly different to tolvaptan concentrations in patients with normal renal function (Ccr 80 to 150 mL/min). The efficacy and safety of tolvaptan in those with a creatinine clearance <10 mL/min has not been evaluated and is therefore unknown.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.
Teratogenicity was noted in rabbits given 1,000 mg/kg/day (up to 15 times the exposure in humans at the 60 mg dose, based on AUC). No teratogenic effects were seen in rabbits at 300 mg/kg/day (up to 5 times the exposure in humans at the 60 mg dose, based on AUC). In a peri-and post-natal study in rats, delayed ossification and reduced pup bodyweight were seen at the high dose of 1,000 mg/kg/day. Two fertility studies in rats showed effects on the parental generation (decreased food consumption and body weight gain, salivation), but tolvaptan did not affect reproductive performance in males and there were no effects on the foetuses. In females, abnormal oestrus cycles were seen in both studies. The no observed adverse effects level (NOAEL) for effects on reproduction in females (100 mg/kg/day) was about 8-times the total daily dose of 60 mg/day on a mg/m² basis.
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