Frederick Alan Rapoport, MD
Hyponatremia occurs frequently in small-cell lung cancer, head and neck cancer, ovarian cancer, some hematologic malignancies, and other cancers, said one of the speakers, Frederick Alan Rapoport, MD, clinical instructor in the Department of Medicine at NYU Langone Medical Center in New York City.
“Certain chemotherapy drugs require hydration. Often, you hydrate patients with hyponatremia and they become more hyponatremic,” Rapoport said. “It’s difficult to give platinum in that setting, so you must correct the hyponatremia before you treat.”
Risk factors for hyponatremia (Box) can initially lead to SIADH, or the syndrome of inappropriate antidiuretic hormone secretion, which in turn results in hyponatremia, explained the second speaker, Jacques Durr, MD, professor of Medicine and director of the Division of Nephrology and Hypertension at the University of South Florida.
In dilutional hyponatremia, in which total body water increases in relation to sodium levels, the hypervolemic type can be caused by heart failure and nephrotic syndrome, and the euvolemic type can be caused by SIADH, hypothyroid disease, and secondary adrenal insufficiency, Durr explained. There is also a depletional, or hypovolemic, form of hyponatremia, caused by diarrhea or vomiting, in which both sodium and water are lost, and for which vaptan therapy is contraindicated.
FDA-approved treatments for hyponatremia include tolvaptan (Samsca), a once-daily oral, selective V2-receptor antagonist for the treatment of hyponatremia, manufactured by the presentation’s sponsor, Otsuka America Pharmaceutical, and the intravenously administered conivaptan (Vaprisol). In addition to routes of administration, the agents differ in that conivaptan is given for a maximum of 4 days and tolvaptan for 30 days.
Hyponatremia is present when serum sodium levels drop below 135 mEq/L, and the condition predicts higher mortality among patients, according to investigators in the SALT-1 and SALT-2 clinical trials that led to tolvaptan’s approval.1 Tolvaptan, which rids the body of excess free water, is indicated for patients with hypervolemic or euvolemic hyponatremia—including those with heart failure or SIADH—who have a sodium level less than 125 mEq/L, or a sodium level of less than 135 mEq/L with symptoms of hyponatremia, Rapoport said. To be eligible for the drug, a patient’s hyponatremia must have resisted correction with fluid restriction, he added.
Tolvaptan must be administered in the hospital, so that response can be monitored every 8 to 12 hours for the first few days, the doctor emphasized. Importantly, he said, healthcare providers must ensure that a patient’s serum sodium level does not increase more than 12 mEq/L per day, as that can cause a swollen brain to shrink too rapidly, resulting in severe neurologic damage. After a patient’s release from the hospital, response to tolvaptan slows, and progress can be checked every couple of days, the doctor added.
Before determining whether to administer tolvaptan, providers face a challenge, the speakers noted: determining whether a patient is hyponatremic in the first place. The condition is not always obvious upon examination of a patient, Durr said, with either no symptoms or signs that can crop up in many illnesses, such as nausea, fatigue, headaches, and an inability to concentrate (often noticed more by family members than by patients themselves).
To confirm hyponatremia, providers can employ a comprehensive metabolic panel including blood sodium, conduct a blood test for osmolality, and/ or check urine for osmolality or sodium levels, according to the National Institutes of Health. In addition, Durr said he has devised an assay for the diagnosis of hyponatremia that is being used in 50 labs.
Tolvaptan is contraindicated in patients who have depletional hyponatremia, since they need their sodium levels raised quickly, Rapoport added. It is also not appropriate for patients who cannot sense or respond to thirst, or for those who cannot urinate, he said. The drug should not be coadministered with hypertonic saline, and should be used only if justified in pregnant or nursing women. Finally, it should be avoided in patients with underlying liver disease, including cirrhosis, he said.
Evidence of tolvaptan’s usefulness in its eligible population came out of the randomized, doubleblind, multicenter SALT-1 and SALT-2 clinical trials, which included 205 and 243 patients, respectively. Serum sodium levels improved more in patients treated with tolvaptan than with placebo in both studies, regardless of whether the patients had mild (130–134 mEq/L) or severe (<130 mEq/L) hyponatremia (P <.0001), and more patients in the tolvaptan group reached normal serum sodium levels (P <.0001), the authors reported.1
Although clinically significant, it was not clear whether response to the drug brought symptomatic relief, Rapoport noted. Adverse events included dry mouth, constipation, thirst, asthenia, pyrexia, hyperglycemia, and some GI bleeding.
In practice, tolvaptan should be given at a starting dose of 15 mg per day and increased to 30 mg after 24 hours if the patient has not responded, with a maximum dose of 60 mg per day, Rapoport said. Each dose increase should occur at 24-hour or greater intervals, and the drug should be given for no longer than 30 days to minimize the risk of liver injury, he said. Fluid restriction should be avoided in the first 24 hours.
1. Schrier R, Gheorghiade M, Verbalis J, et al. Results from the SALT 1 and 2 trials: multicenter, randomized, placebo-controlled trials in patients with euvolemic and hypervolemic hyponatremia. Circulation. 2006;114:II_570.