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Pathophysiology SIGN UP TO STAY INFORMED

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

Type A SIADH4

  • 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
Pattern Of Vasopressin Release In SIADH
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

INDICATION and IMPORTANT SAFETY INFORMATION for SAMSCA® (tolvaptan)

INDICATION:

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).

Limitations of Use:

  • 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

IMPORTANT SAFETY INFORMATION:

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM

  • 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

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

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

CONTRAINDICATIONS:

  • Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA-approved REMS
  • Unable to sense or respond to thirst
  • Hypovolemic hyponatremia
  • Taking strong CYP3A inhibitors
  • Anuria
  • Hypersensitivity (e.g., anaphylactic shock, rash generalized) to tolvaptan or any component of the product

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

Drug Interactions – CYP3A Inhibitors: Tolvaptan is a substrate of CYP3A. Moderate to strong CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations. Do not use SAMSCA with strong inhibitors of CYP3A and avoid concomitant use with moderate CYP3A inhibitors. Patients should avoid grapefruit juice beverages while taking SAMSCA

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

Acute Urinary Retention with Outflow Obstruction: Patients with partial obstruction of urinary outflow have an increased risk of developing acute retention. Do not administer tolvaptan in patients with uncorrected urinary outflow obstruction.

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

Other Drug Interactions:

  • Strong CYP3A Inducers: Co-administration of SAMSCA with strong CYP3A inducers reduces exposure to SAMSCA. Avoid concomitant use of SAMSCA with strong CYP3A inducers
  • Angiotensin Receptor Blockers, Angiotensin Converting Enzyme Inhibitors and Potassium Sparing Diuretics: In clinical studies, adverse reactions of hyperkalemia were approximately 1 to 2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.
  • V2-Receptor Agonist: Tolvaptan interferes with the V2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of SAMSCA with a V2-agonist

Pregnancy and Lactation: Based on animal data, SAMSCA may cause fetal harm. Advise women not to breastfeed during treatment with SAMSCA.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch)

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

 

 

References:

1
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.
2
Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist. 2012;17(6):756-765.
3
Patel GP, Balk RA. Recognition and treatment of hyponatremia in acutely ill hospitalized patients. Clin Ther. 2007;29(2):211-229.
4
Raftopoulos H. Diagnosis and management of hyponatremia in cancer patients. Support Care Cancer. 2007;15(12):1341-1347.

© 2021 Otsuka America Pharmaceutical, Inc.

May 2021
07US21EBP0001