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Causes of SIADH

Cancer. Tumors are the most common condition associated with SIADH. Lung tumors (small cell type) and head and neck tumors are the two tumor types most frequently associated with this syndrome. It has been noted that the lungs of patients with small cell cancer synthesize and secrete vasopressin.1

Nonmalignant lung disease has also been associated with SIADH. The pathophysiology, decreased oxygen, and increased CO2 that increase plasma vasopressin may decrease systemic resistance. This process impairs water clearance and may lead to dilutional hyponatremia.1

Medication use. Antipsychotic drugs, anticancer agents, antidepressants, anticonvulsants, narcotics, sulfonylureas, and angiotensin-converting enzyme inhibitors are among the various classes of drugs that can cause SIADH by causing inappropriate release of vasopressin.1,2

CNS disorders. The last group of conditions that cause SIADH comprises CNS disorders, such as trauma, infection, and hydrocephalus. These conditions are caused by alteration of the usual signaling pathway from the hypothalamus and brainstem, which regulate pituitary release of vasopressin.1

The role of vasopressin in hyponatremia in SIADH

Changes in sodium in SIADH can be attributed to an increase in vasopressin. The diagnosis of SIADH is made in the context of hyponatremia with plasma hypotonicity; urine osmolality exceeding plasma osmolality; elevated urinary sodium excretion despite normal salt and water intake; absence of edema or volume depletion; and normal renal, adrenal, and thyroid function.1

Several factors explain the changes in sodium excretion seen in SIADH3:

  • Decreased aldosterone secretion secondary to increased extracellular fluid volume
  • Increased filtered sodium as a result of increased glomerular filtration rate (GFR)
  • Suppressed sodium resorption in the proximal tubules

Different patterns of vasopressin release in SIADH


  • Found in approximately 40% of SIADH cases
  • Excessive and erratic vasopressin release unrelated to serum osmolality
  • Ectopic production of vasopressin by tumor tissue may account for this type of SIADH

Type B SIADH (also designated reset osmostat)4

  • Vasopressin response to changes in serum osmolality is preserved
  • Urine-diluting capacity is intact
  • Osmotic threshold for vasopressin release is lowered
In type A SIADH, vasopressin release has no linear relationship to plasma osmolality. In type B SIADH, vasopressin release has a linear relationship to plasma osmolality, but the threshold is lower than normal. Adapted from Raftopoulos, Support Care Cancer, 2007.4

In type A SIADH, vasopressin release has no linear relationship to plasma osmolality. In type B SIADH, vasopressin release has a linear relationship to plasma osmolality, but the threshold is lower than normal. Adapted from Raftopoulos, Support Care Cancer, 2007.4



SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Important Limitations:

  • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA
  • It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients



  • SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
  • Too rapid correction of hyponatremia (e.g., >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


  • Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS.

SAMSCA is contraindicated in the following conditions:

  • — Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA-approved REMS
  • — Urgent need to raise serum sodium acutely
  • — Inability of the patient to sense or appropriately respond to thirst
  • — Hypovolemic hyponatremia
  • — Concomitant use of strong CYP 3A inhibitors
  • — Anuric patients
  • — Hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or its components
  • Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae: During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium.
  • Liver Injury: Tolvaptan can cause serious and potentially fatal liver injury. In clinical trials, cases of serious liver injury have been attributed to chronically administered tolvaptan in patients with ADPKD. Liver failure requiring transplantation has been reported in postmarketing experience with tolvaptan in ADPKD. Limit duration of therapy with SAMSCA to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired.
  • Dehydration and Hypovolemia: In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted
  • Co-administration with Hypertonic Saline: Not recommended
  • Other Drugs Affecting Exposure to SAMSCA:
  • CYP 3A Inhibitors: Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors
  • CYP 3A Inducers: Avoid concomitant use with CYP 3A inducers. If co-administered, the dose of SAMSCA may need to be increased
  • P-gp Inhibitors: The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors
  • Hyperkalemia or Drugs that Increase Serum Potassium: Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels

Adverse Reactions: The most common adverse reactions (SAMSCA incidence  ≥5% more than placebo, respectively): thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%)

Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptan-treated patients vs 2% for placebo

Pregnancy and Nursing Mothers: SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (





Siragy HM. Hyponatremia, fluid-electrolyte disorders, and the syndrome of inappropriate antidiuretic hormone secretion: diagnosis and treatment options. Endocr Pract. 2006;12(4):446-457.
Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist. 2012;17(6):756-765.
Patel GP, Balk RA. Recognition and treatment of hyponatremia in acutely ill hospitalized patients. Clin Ther. 2007;29(2):211-229.
Raftopoulos H. Diagnosis and management of hyponatremia in cancer patients. Support Care Cancer. 2007;15(12):1341-1347.