Tolvaptan 사용의 제한점과 처방

Tolvaptan은 SIADH에서 사용되는 vasopressin receptor antagonists입니다.
비록 tolvaptan이 SIADH 환자에서 효과적으로 혈청 나트륨 농도를 올릴지라도
사용에 몇 가지 제한점이 있습니다.

1. 안정성 
2. 저나트륨혈증의 과도한 빠른 교정이 일으키는 비가역적 신경 손상 
3. 갈증 증가
4. 비용
5. 중증 신경 증상을 치료하기 위해 승인되지 않음

1. Concerns about the safety of tolvaptan were raised by a multicenter trial (TEMPO 3:4) that examined its effect on the progression of kidney disease in polycystic kidney disease. A greater than 2.5-fold increase in liver enzymes was more common among patients who received tolvaptan compared with placebo. Based upon these data, the US FDA issued safety warnings regarding the use of tolvaptan, recommending: that liver function tests be promptly performed among patients who report symptoms that suggest liver injury (eg, fatigue, anorexia, right upper quadrant discomfort, dark urine, jaundice); that tolvaptan should not be used in any patient for longer than 30 days; and that tolvaptan should not be used at all in patients with liver disease (including cirrhosis) because it may potentially lead to liver failure or death.

2. There may be overly rapid correction of the hyponatremia, which can lead to irreversible neurologic injury. In the SALT trials, 1.8 percent of patients exceeded the study goal of limiting daily correction to 12 mEq/L. However, more recent recommendations have suggested a rate of correction of hyponatremia of no more than 8 mEq/L in 24 hours, not ≤12 mEq/L. Thus, it is almost certain that more than 1.8 percent of treated patients exceeded the currently recommended rate of correction. Because of this risk, hospitalization is required for the initiation or re-initiation of therapy.

3. Thirst is increased, which may limit the rise in serum sodium.

4. The cost of tolvaptan may be prohibitive (as high as USD $300 per tablet in some areas).

5. The drug is not approved to treat serious neurologic symptoms. In addition, patients in the Phase III pivotal studies were excluded if their serum sodium was less than 120 mEq/L.

Tolvaptan 사용의 중요한 제한점으로 인하여
이것은 1) 혈청 나트륨 농도가 120 mEq/L 이상으로 유지될 수 없거나 
2) 다른 수단을 이용한 치료에도 불구하고 만성 저나트륨혈증으로 인한 것으로 여겨지는 지속적인 신경학적 증상이 있는 드문 환자에서만 고려되어야 합니다.

이와 같은 경우에 tolvaptan은
hypertonic saline을 이용하여 원내 환자의 혈청 나트륨을 처음에 올린 이후에 
만성적인 외래 환자에서 20 mEq/L 이상으로 혈청 나트륨을 유지하기 위해 처방될 수 있습니다.

REF. UpToDate 2018.11.30