Clinical Experience of the Efficacy and Safety of Low-dose Tolvaptan Therapy in a UK Tertiary Oncology Setting

Abstract

Background In patients with cancer, hyponatraemia is associated with increased morbidity and mortality and can delay systemic therapy. Methods The safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatraemia due to Syndrome of Inappropriate Antidiuresis (SIAD), and co-existing malignancy were retrospectively evaluated in a tertiary cancer centre. Results Fifty-five patients with mean baseline serum sodium (sNa) 117.9±4.6 mmol/L were included. 90.9% had severe hyponatraemia (sNa<125 mmol/L). Mean age was 65.1±9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9(1-19) mmol/L. Within one week, 39 patients (70.9%) reached sNa≥130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and seventeen (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24hrs, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median[quantiles]: 14[9-16] versus 8[5-11] mmol/L, p=0.036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24hrs) demeclocycline was appropriately discontinued only in 60% compared to 91.7% of the remaining participants (P=0.047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (p=0.01). Conclusion In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatraemia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.

Tolvaptan for the treatment of the syndrome of inappropriate antidiuresis (SIAD)

“…The largest study to date of low-dose tolvaptan reported the outcomes of using a starting 7.5 mg tolvaptan dose in 55 patients with malignant SIAD and a mean baseline serum sodium of 117.9 mmol/litre. 36 After the initiation of tolvaptan, the median serum sodium increase was 9 and 10 mmol/litre at 24 and 72 h, respectively, with the vast majority of patients (87.3%) achieving a serum sodium rise of at least 5 mmol/litre over 48 h. However, the high efficacy of low-dose tolvaptan was accompanied by a high rate (30.9%) of overly rapid hyponatraemia correction. 36 Post-marketing assessments of tolvaptan use in Europe have reported that a significant proportion of physicians use a low 7.5 mg tolvaptan starting dose on a patient-by-patient case basis, with the hope of lowering the risk of overly rapid sodium correction.…”

“…36 After the initiation of tolvaptan, the median serum sodium increase was 9 and 10 mmol/litre at 24 and 72 h, respectively, with the vast majority of patients (87.3%) achieving a serum sodium rise of at least 5 mmol/litre over 48 h. However, the high efficacy of low-dose tolvaptan was accompanied by a high rate (30.9%) of overly rapid hyponatraemia correction. 36 Post-marketing assessments of tolvaptan use in Europe have reported that a significant proportion of physicians use a low 7.5 mg tolvaptan starting dose on a patient-by-patient case basis, with the hope of lowering the risk of overly rapid sodium correction. 37,38 All real-world studies suggest that a starting 7.5 mg dose, half the approved initiation dose of tolvaptan, is effective in treating hyponatraemia.…”

“…• Confirm the diagnosis of SIAD and exclude hypovolaemic hyponatraemia. We follow a stringent protocol 18,36,69 for the first 24 h of tolvaptan use: decision to offer stat doses on a day-to-day basis, if and when required, since two to four doses in total are adequate treatment for most inpatients with SIAD of short duration. 47 Tolvaptan dose titration usually takes place during hospitalisation according to the serum sodium concentration.…”

The management of acute and chronic hyponatraemia

“…However, subsequent real world studies have reported much higher rates of overcorrection, 12.1–31%. 17 , 69 , 70 Overcorrection is a possibility with all effective therapies for hyponatraemia, and the key issues are awareness of the possibility, frequent monitoring of plasma sodium concentration in the 24 hours after initiation of therapy, and willingness to correct early with dextrose or dDAVP. Concurrent use of other hyponatraemia treatments should be avoided.…”

“… 69 , 71 A case series of 61 hospital inpatients by Tzoulis et al reported a significant negative correlation between baseline plasma sodium concentration and 24 hour sodium rise; 29% of patients with starting pNa <125 mmol/L exceeded the safe rate for pNa correction at any timepoint compared with none of those with pNa ⩾125 mmol/L. 69 , 71 Lower doses of tolvaptan (7.5 mg or less) are efficacious, 70 , 72 , 73 and may be safer, though it is important to stress that plasma sodium responses to lower doses of tolvaptan have not been subjected to rigorous prospective study.…”