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Hyponatremia in Heart Failure SIGN UP TO STAY INFORMED

Hyponatremia is prevalent in hospitalized heart failure patients1,2

24%

24% of hospitalized patients with heart failure (n=103) presented with hyponatremia (serum sodium level ≤134 mEq/L) in an analysis of a muticenter, randomized, controlled study of patients (N=433) hospitalized for decompensated heart failure.1,2

Hypervolemic hyponatremia in patients with heart failure is a marker of excess vasopressin secretion3

Patients with heart failure are at risk for hypervolemic hyponatremia as a result of excess sodium and water retention, promoted by increased vasopressin levels and compromised glomerular filtration.3,4

Clinical profile of patients with hyponatremia in heart failure

Hyponatremia and heart failure have several overlapping symptoms.

Hyponatremia and heart failure share several symptoms

Guideline recommendations

ACCF/AHA 2013 Guideline states V2-receptor antagonists may be considered in the short term to improve serum sodium concentration in hospitalized HF patients with persistent severe hypervolemic hyponatremia who are at risk for or are having active cognitive symptoms despite water restriction and guideline-directed medical therapy.12

It has not been established that raising serum sodium with SAMSCA® (tolvaptan) provides a symptomatic benefit to patients.

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
Gheorghiade M, Rossi JS, Cotts W, et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch Intern Med. 2007;167(18):1998-2005.
2
Shah MR, O’Connor CM, Sopko G, et al. Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale. Am Heart J. 2001;141(4):528-535.
3
Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12.
4
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.
5
National Heart, Lung, and Blood Institute. What are the signs and symptoms of heart failure? http://www.nhlbi.nih.gov/health/health-topics/topics/hf/signs.html. Accessed April 28, 2014.
6
Mayo Clinic staff. Heart failure: symptoms. http://www.mayoclinic.com/health/heart failure/DS00061/DSECTION=symptoms. Accessed April 28, 2014.
7
Ghali JK. Mechanisms, risks, and new treatment options for hyponatremia. Cardiology. 2008;111(3):147-157.
8
Ghali JK, Tam SW. The critical link of hypervolemia and hyponatremia in heart failure and the potential role of arginine vasopressin antagonists. J Cardiac Fail. 2010;16(5):419-431.
9
Bagshaw SM, Townsend DR, McDermid RC. Disorders of sodium and water balance in hospitalized patients. Can J Anesth. 2009;56(2):151-167.
10
Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e1-71.e8.
11
Mayo Clinic staff. Hyponatremia: symptoms. http://www.mayoclinic.com/health hyponatremia/DS00974/DSECTION=symptoms. Accessed April 28, 2014.
12
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327.

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May 2021
07US21EBP0001