Tolvaptan

Dizziness, asthenia, and/or syncope have been reported when used for ADPKD; advise patients to use caution when performing dangerous tasks (eg, driving, operating machinery).

Tolvaptan may increase the risk of serious hepatotoxicity, including fatal hepatotoxicity. Cases of hepatotoxicity have been reported in patients treated for ADPKD and have usually occurred after 3 months of therapy although some cases occurred prior to 3 months. Therefore, treatment with Samsca should be limited to 30 days. If hepatotoxicity is suspected, discontinue use. Avoid use in patients with liver disease (including cirrhosis) since the ability to recover from further liver injury may be impaired. In the treatment of ADPKD, use of Jinarc [Canadian product] is not limited to 30 days however close monitoring of hepatic function is recommended. Interrupt therapy for signs/symptoms of hepatotoxicity (eg, anorexia, dark urine, jaundice, itching, fatigue, nausea, right upper abdominal pain) and evaluate hepatic function promptly (ie, within 48 to 72 hours) then increase the frequency of hepatic function testing; upon resolution may consider cautious reinitiation of therapy.

Hyperuricemia and gout have been observed; in the treatment of ADPKD, monitoring of serum uric acid is recommended (Jinarc Canadian product monograph, 2015).

Patients should ingest fluids in response to thirst during therapy. Interrupt or discontinue therapy in patients who develop significant signs or symptoms of hypovolemia.

Tolvaptan should be initiated and reinitiated in patients only in a hospital where serum sodium can be closely monitored. Too rapid correction of hyponatremia (ie, >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death. In susceptible patients (including those with severe malnutrition, alcoholism, or advanced liver disease), slower rates of correction may be advisable. Patients with SIADH, very low baseline, or patients who are fluid restricted during the first 24 hours of therapy may be at greater risk of overly-rapid correction. Avoid fluid restriction during the initial 24 hours of therapy. Discontinue or interrupt therapy if sodium correction is too rapid and consider administration of hypotonic fluids. Disease-related concerns:

Avoid use in patients with liver disease, including those with cirrhosis, since the ability to recover from further liver injury may be impaired. In addition, patients with cirrhosis have a higher risk of gastrointestinal bleeding.

Reductions in extracellular fluid volumes may cause hyperkalemia. Patients using concomitant medications that may increase potassium levels or with a pretreatment serum potassium >5 mEq/L should be monitored after initiation of therapy.

Use in patients with creatinine clearance Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Monitor closely for rate of serum sodium increase and neurological status; rapid serum sodium correction (>12 mEq/L/24 hours) can lead to permanent neurological damage. Discontinue use if rate of serum sodium increase is undesirable; fluid restriction during the first 24 hours of sodium correction can increase the risk of overly-rapid correction and should generally be avoided; not intended for urgent correction of serum sodium to prevent or treat serious neurologic symptoms; it has not been demonstrated that raising serum sodium with tolvaptan provides a symptomatic benefit. . In the treatment of ADPKD, patients most likely to benefit from therapy are those with rapidly progressive disease or those who are developing progressive disease but lack extensive renal damage. Factors associated with rapid progression include large total renal cyst mass for a given age (measured by total kidney volume), chronic kidney disease stage 2 to 3, rapid deterioration of renal function, systemic hypertension or albuminuria.

SIADH: Limitations to the use of tolvaptan in SIADH may exist due to concerns about safety, such as overly rapid correction of hyponatremia and potential for hepatotoxicity (Spasovski, 2014). Based on available evidence, European clinical practice guidelines recommend against the use of vasopressin receptor antagonists in the treatment of hyponatremia in patients with SIADH (Spasovski, 2014). Additional data may be necessary to define the appropriate clinical role of tolvaptan in this condition.