TITRATED ORAL TOLVAPTAN TABLET ADMINISTRATION IN PATIENTS W/CHRONIC HYPONATREMIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyponatremia, or low blood sodium, is the most frequently encountered electrolyte abnormality in hospitalized patients, with a reported incidence of approximately 1% (1,2). Most cases of hyponatremia are mild, and generally speaking, asymptomatic. However, as blood sodium falls below a critical level, the possibility of significant neurological problems increase. These neurological problems range from difficulty in concentration, disorientation, confusion, lethargy, and psychosis, to seizures, coma and ultimately respiratory arrest if serum sodium levels fall below 115 - 120 mEq/L (normal sodium is 140 - 145 mEq/L) (3,4) Hyponatremia has many causes including: diuretic (water-pill) induced salt and water loss, congestive heart failure, liver failure, kidney disorders, and a condition called syndrome of inappropriate antidiuretic hormone secretion (SIADH), which may be associated with cancer, lung diseases, pneumonia, brain disorders, and ingestion of certain medications. Interestingly, the common theme underlying all of these causes of hyponatremia is the secretion of a hormone called vasopressin or AVP. Vasopressin causes the kidney to reabsorb water, which leads to fluid retention and dilution of blood sodium. The approach to the treatment of hyponatremia is based on the symptom severity and the underlying cause of the low sodium. In the acute symptomatic hyponatremic patient, presenting with seizures and/or convulsions, rapid correction of the low sodium is indicated. The only effective treatment is hypertonic saline (a concentrated intravenous sodium solution). In the less severely symptomatic patient, for example, patients with decompensated congestive heart failure (CHF), liver failure and SIADH, treatment of hyponatremia can be challenging, since many of the conventional diuretic treatments further potentiate vasopressin release, resulting in aggravation of hyponatremia. Also, in the case of decompensated liver failure and SIADH, conventional diuretic treatments are either minimally effective or completely contraindicated. The treatment for asympomatic hyponatremia is fluid restriction. However, while fluid restriction effectively counteracts the effect of excess vasopressin (AVP) secretion, it does not directly inhibit it's actions. Agents that antagonize AVP could offer a significant treatment option for patients with hyponatremia. Tolvaptan is an oral vasopressin antagonist which has been shown to induce a diuresis with proportionally more free-water then sodium loss. This study is being undertaken to evaluate whether tolvaptan, an oral AVP inhibitor, will be effective in correcting mild to moderate hyponatremia without associated water restricition. Study Objective/Hypothesis: This study will assess the safety of long-term tolvaptan use in patients previously enrolled in shorter-term Phase 3 studies and gather information on the natural history of hyponatremia in the context of tolvaptan therapy and underlying disease states. Study Design: Participation in this study will be up to 26 months or approximately 763 days. Up to 400 adult male and female patients who participated in the Phase 3 studies for hyponatremia (156-02-235 or 156-03-238) may be eligible to participate in this study. Patients must have persistent or recurrent hyponatremia (serum sodium < 135 mEq/L) and in a euvolemic or hypervolemic state at screening. Eligible patients will be consented and screened up to two days prior to potential enrollment. Patients who are enrolled will begin treatment with tolvaptan (15mg tablet once a day). A titration between target doses of 15 mg, 30 mg or 60 mg of study drug will be based on the patient's change in serum sodium concentration and clinical tolerance of the study drug. Patients will remain on tolvaptan for up to 108 weeks. The primary goal of titration will be to effect a slow change in the patient's serum sodium. Such corrections may be made over a few days to a few weeks at the discretion of the investigator. Once the patient's serum sodium is maintained above 135 mEq/L further up-titration will not occur; however down titration may occur if the patient experiences intolerable thirst, polyuria, dehydration or other symptoms attributable to the study drug or if serum sodium increases to a high normal or hypernatremic range. Study visits will fall at the following time points: Days 1, 14, 31, then Weeks 10, 18, 26, 34, 42, 50, 58, 70, 82, 94, 106 and 1 week follow-up visit after the study drug is stopped. This schedule must be adhered to as a minimum; however the investigator may arrange for more frequent laboratory assessments and clinic visits based on the individual patient's clinical situation, particularly during the titration phase. Visits will consist of assessment of adverse event (s) , a physical exam, electrocardiogram (Day 1, Day 14, Week 58,106, 7 day follow-up), questionnaires, review of study drug and concomitant medication(s), and safety laboratory assessment(s).