Please orient your device into the portrait position to return to the site.
Role of Vasopressin in Hyponatremia SIGN UP TO STAY INFORMED

Vasopressin is synthesized in the hypothalamus and secreted from the pituitary gland

Vasopressin Synthesis - Hypothalamus and Vasopressin Secretion - Posterior Pituitary

Vasopressin, also known as antidiuretic hormone, is a 9-amino-acid peptide that is synthesized in the nerve bodies in the supraoptic and paraventricular nuclei of the hypothalamus and is secreted from the posterior pituitary gland.1

Vasopressin is released in response to decreased plasma volume and increased serum osmolality2

Vasopressin Secretion - Pituitary Gland

Secretion of vasopressin is normally stimulated by increased plasma osmolality via activation of osmoreceptors in the anterior hypothalamus and by decreased blood volume or pressure via activation of baroreceptors in the carotid sinus, aortic arch, cardiac atria, and pulmonary venous system.1,3

The primary role of vasopressin is to control water balance, electrolyte balance, and blood pressure

Effects Of Vasopressin On The Kidneys

Vasopressin controls the body’s water and electrolyte balance, and blood pressure through its antidiuretic effects on the kidney, resulting in decreased plasma osmolality, and/or increased arterial circulating volume.3,4

The antidiuretic effects of vasopressin occur when it binds to the V2-receptors

Vasopressin -Antidiuretic Effects

Vasopressin contributes to water homeostasis by promoting the reabsorption of fluid through the V2-receptors by binding to these receptors, causing the translocation of aquaporin-2 water channels to the apical membrane in the collecting duct of the kidney.3,4

The diagram below illustrates the mechanism of antidiuresis by vasopressin.

Vasopressin V2 Receptor Activation

Adapted from Finley, Circulation, 2008.

Vasopressin V2-receptor activation: The binding of vasopressin to the V2-receptor stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A. This pathway increases the exocytosis of aquaporin water channel–containing vesicles and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin-2 channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct.5

Relationship of vasopressin to hyponatremia

Inappropriately elevated plasma levels of vasopressin in conditions such as SIADH and heart failure increase water reabsorption and retention, which will disproportionately expand the plasma volume, thus resulting in dilutional hyponatremia. In patients with syndrome of inappropriate antidiuretic hormone (SIADH), vasopressin release is not fully suppressed, despite hypo-osmolality, owing to other causes, including ectopic production of vasopressin by some tumors. The persistence of vasopressin release due to nonosmotic hemodynamic stimuli is also predominantly responsible for water retention and hyponatremia with hypervolemia and edema-forming disorders, such as heart failure.3

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
Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.
2
Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12.
3
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 suppl 1):S1-S4.
4
Knoers NVAM. Hyperactive vasopressin receptors and disturbed water homeostasis. N Engl J Med. 2005;352(18):1847-1850.
5
Finley JJ, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation. 2008;118(4):410-421.

© 2021 Otsuka America Pharmaceutical, Inc.

May 2021
07US21EBP0001