HPE HPE 85 – Spring 2017 - Page 62

Practical therapeutics data by focusing on clinical criteria (Table 3). 20 However, the PROPKD score depends on the results of a genetic exam that is not available to the majority of patients, because sequencing of PKD1 and PKD2 is not necessary to make a diagnosis of ADPKD. Nonetheless, the mutation is one of the strongest predictors of the disease course. Obtaining a concise family history may give indications on the underlying mutation but does not provide sufficient information to calculate the PROPKD score. 17 60 Initiation and management of tolvaptan Careful patient selection and counselling before starting therapy is crucial to a successful treatment. 17 Only patients who show signs of rapid progression, therefore expecting to reach end-stage renal disease, should be initiated on tolvaptan. Furthermore, contraindications to this drug need to be excluded – including severe liver disease, hypernatraemia, trouble perceiving or responding to thirst, obstruction of the urinary tract as well as pregnancy and breast-feeding (for details, see Summary of Product Characteristics). Patients need to be advised to drink sufficiently rather before getting thirsty and always carry along a bottle of water. It is crucial that patients on tolvaptan know in which situations they need to stop taking the drug, that is, all events associated with a risk of dehydration such as diarrhoea, lacking access to water, or surgery. The water deficit should preferentially be managed with non- sparkling water. Calorie-rich drinks – which would lead to a tremendous increase in calorie-intake per day – should be avoided. A salt-restricted diet that is not rich in protein may help avoid excessive urine volumes. Patients suffering from accompanying polycystic liver disease have to be informed that tolvaptan does not have any impact on liver cysts. Tolvaptan is then started at a dose of 60mg/day divided into 45mg taken in the morning and 15mg taken eight hours later. According to the strategy employed in the TEMPO 3:4 trial (where more than 50% of patients reached and remained on the maximum dose) up-titration to the target dose of 120mg per day should be attempted in all patients (second dose: 60/30mg, third dose: 90/30mg) while the up-titration period can be extended depending on package size and hospitalpharmacyeurope.com Key points • Autosomal dominant polycystic kidney disease (ADPKD) is the most common polycystic kidney disease and causes end-stage renal disease in up to 10% of dialysis patients. • Tolvaptan is the first targeted therapy available for ADPKD and can slow down loss of renal function, as shown in the TEMPO 3:4 trial. • A good characterisation of ADPKD patients is essential to choose those at risk of rapid progression and who will benefit from tolvaptan. • ADPKD is a systemic disease with numerous extra-renal manifestations that are not addressed by tolvaptan, such as cystic liver disease or intracranial aneurysms. • Supportive measures such as a salt-restricted diet, a sufficient daily fluid intake, refraining from smoking and tight blood pressure control are still important in slowing down disease progression and preventing cardiovascular complications. prescribing frequency (for example, once monthly). If, however, the maximum dose is not tolerable, therapy can be continued returning to a lower dose. Because metabolism of tolvaptan involves CYP3A4, caution is required in patients who take moderate to strong inhibitors of CYP3A4 (for example, clarithromycin, fluconazole, verapamil etc.). In these cases, adaptations of the tolvaptan dose are required. Patients should also be counselled on the avoidance of grapefruit juice, another CYP34A inhibitor. Because the cases of hepatotoxicity described above occurred during the first 18 months of treatment, monthly LFTs are required during this period (extending to three- monthly controls afterwards) and attention needs to be paid to clinical signs of liver injury. 15,16 Despite incidence of polyuria, close to 80% of patients continued taking the drug in TEMPO 3:4, indicating an acceptable adherence to tolvaptan treatment in ADPKD. 17 This was not only the case in this clinical trial but also appears to hold true in the real-life setting (unpublished observation of the authors). References 1 Chebib FT, Torres VE. Autosomal dominant polycystic kidney disease: Core curriculum 2016. Am J Kidney Dis 2016;67:792–810. 2 Hildebrand F et al. Ciliopathies. N Engl J Med 2011;364