Conivaptan Hydrochloride

Class: Vasopressin Antagonists
VA Class: HS900
Chemical Name: N - [4 - [(4,5 - Dihydro - 2 - methylimidazo[4,5 - d][1]benzazepin - 6(1H) - yl)carbonyl]phenyl] - [1,1′ - biphenyl] - 2 - carboxamide monohydrochloride
Molecular Formula: C₃₂H₂₆N₄O₂ • HCl
CAS Number: 210101-16-9
Brands: Vaprisol

Introduction

Nonpeptide antagonist of arginine vasopressin (antidiuretic hormone, AVP) V_1A and V₂ receptors; benzazepine derivative.^{1 2 3 4 5 6 7}

Uses for Conivaptan Hydrochloride

Euvolemic or Hypervolemic Hyponatremia

Used to increase serum sodium concentrations in hospitalized patients with euvolemic or hypervolemic hyponatremia.^{1 4 7} Use in patients with hypervolemic hyponatremia associated with heart failure only after consideration of other treatment options; limited data on safety in this patient population.¹ (See CHF under Cautions.)

Not indicated for the treatment of hypovolemic hyponatremia.^{1 4 6}

Use of conivaptan to increase serum sodium concentrations has not been established to provide symptomatic benefit to patients.¹

Not indicated for the treatment of CHF; efficacy not established for this indication.^{1 4 6}

Conivaptan Hydrochloride Dosage and Administration

Administration

Administer by IV infusion; administer to hospitalized patients only.¹ (See Administration Risks under Dosage and Administration.)

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Premixed injection containing 0.2 mg/mL of conivaptan hydrochloride in 5% dextrose injection may be used without further dilution; for administration instructions for premixed injection, consult manufacturer’s labeling.¹

Premixed injection available in single-use flexible containers; discard any unused portions.¹

Do not introduce additives into the premixed injection.¹

Do not use the premixed injection in flexible plastic containers in series connections; such use may result in air embolism.¹

Do not administer simultaneously through the same IV line with other drugs.¹

Rate of Administration

Administer loading dose over 30 minutes.¹

Administer the continuous IV infusion over 24 hours.¹

Administration Risks

Administer only through large veins; change infusion site every 24 hours to decrease risk of venous irritation.¹ (See Infusion Site Reactions under Cautions.)

Dosage

Available as conivaptan hydrochloride; dosage expressed in terms of the salt.¹

Adults

Euvolemic or Hypervolemic Hyponatremia

IV

Initially, 20 mg as a loading dose over 30 minutes, followed by continuous infusion of 20 mg over 24 hours for 2–4 days.¹

If serum sodium is not increasing at the desired rate, may increase dosage to 40 mg daily by continuous infusion.¹

Monitor vital signs, serum sodium, and neurologic and volume status.¹

Discontinue drug if serum sodium concentration increases too rapidly (by >12 mEq/L in 24 hours).¹ Carefully monitor serum sodium and neurologic status.¹ Do not resume conivaptan if serum sodium continues to rise; however, if hyponatremia persists or recurs, and patient has no evidence of neurologic sequelae of rapid serum sodium rise, may resume conivaptan at a reduced dose.¹ (See Overly Rapid Correction of Serum Sodium Concentration under Cautions.)

If hypotension or hypovolemia develops, discontinue conivaptan.¹ Monitor volume status and vital signs frequently; once euvolemic and normotensive, and if hyponatremia persists, may resume conivaptan at a reduced dose.¹

Prescribing Limits

Adults

Euvolemic or Hypervolemic Hyponatremia

IV

Maximum (after loading dose): 40 mg daily.¹ Dosage of 80 mg daily is not substantially more effective than 40 mg daily, but is associated with higher incidence of infusion site reactions and adverse effects requiring drug discontinuance.¹

Maximum duration of therapy: 4 days.¹

Special Populations

Hepatic Impairment

Mild to severe hepatic impairment (Child-Pugh class A, B, or C): 10-mg loading dose, followed by 10 mg daily (by continuous IV infusion over 24 hours) for 2–4 days (maximum: 4 days).¹ If serum sodium is not increasing at desired rate, may titrate dosage to 20 mg daily.¹

Renal Impairment

Cl_cr >60 mL/minute: Dosage adjustment not necessary.¹

Cl_cr 30–60 mL/minute: 10-mg loading dose, followed by 10 mg daily (by continuous IV infusion over 24 hours) for 2–4 days (maximum: 4 days).¹ If serum sodium is not increasing at desired rate, may titrate dosage to 20 mg daily.¹

Cl_cr <30 mL/minute: Use not recommended.¹ (See Contraindications and also see Renal Impairment under Cautions.)

Geriatric Patients

Manufacturer makes no specific recommendations.¹ However, in clinical trials evaluating 20-mg loading dose followed by 20 or 40 mg daily for 2–4 days, 89 or 60% of patients receiving 20 or 40 mg daily, respectively, were ≥65 years of age and 60 or 40% were ≥75 years of age.¹ Adverse effect profile in these patients was similar to that in the overall population.¹

Cautions for Conivaptan Hydrochloride

Contraindications

• 
  

  Hypovolemic hyponatremia.^{1 4 6}

  
  


• 
  

  Concomitant use of potent inhibitors of CYP3A.¹ (See Interactions.)

  
  


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  Anuria.¹ Anuric patients not expected to benefit from therapy.¹

  
  


• 
  

  Manufacturer states that dextrose-containing solutions, including premixed conivaptan hydrochloride injection in 5% dextrose, are contraindicated in patients with known allergy to corn or corn products.¹

  
  

Warnings/Precautions

CHF

Limited data available on safety in patients with hypervolemic hyponatremia associated with heart failure.¹ Adverse cardiac failure events, atrial dysrhythmias, and sepsis reported.¹ Use in patients with hypervolemic hyponatremia associated with heart failure only after consideration of other treatment options.¹

Conivaptan is not indicated for the treatment of CHF; efficacy not established for this indication. ^{1 4 6} (See Euvolemic or Hypervolemic Hyponatremia under Uses.)

Overly Rapid Correction of Serum Sodium Concentration

Increases in serum sodium of >12 mEq/L in 24 hours may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death.^{1 2 4 6} Slower rates of correction recommended in susceptible patients (e.g., those with severe malnutrition, alcoholism, or advanced liver disease).¹

Monitor fluid status, serum sodium concentrations, and neurologic status carefully; if serum sodium concentrations increase too rapidly, discontinue conivaptan and monitor patient carefully.¹ (See Dosage under Dosage and Administration.)

Infusion Site Reactions

Infusion site reactions possible (>60% of individuals receiving 40 mg daily); may be severe and may require discontinuance.¹ May occur even when administered at recommended infusion rates.¹ Administer drug only into a large vein; change infusion site every 24 hours.¹

Hypovolemia and Hypotension

If hypovolemia or hypotension occurs, discontinue conivaptan and monitor fluid status and vital signs frequently.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk in rats; discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 9}

Geriatric Use

Adverse effects similar to those in younger adults.¹

Hepatic Impairment

Potential for increased systemic exposure.¹ (See Special Populations under Pharmacokinetics.)

Dosage adjustment recommended in patients with mild to severe hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Potential for increased systemic exposure.¹ (See Special Populations under Pharmacokinetics.)

Dosage adjustment recommended in patients with moderate renal impairment (Cl_cr 30–60 mL/minute).¹ (See Renal Impairment under Dosage and Administration.)

Use not recommended in severe renal impairment (Cl_cr <30 mL/minute); high incidence of infusion site phlebitis may limit vascular access sites, and clinical benefit is unlikely.¹ Contraindicated in anuric patients.¹

Common Adverse Effects

Infusion site reactions (e.g., erythema, pain, phlebitis),^{1 8} hypokalemia,¹ headache,¹ peripheral edema,¹ vomiting,¹ diarrhea,¹ constipation,¹ hypertension,¹ orthostatic hypotension,^{1 8} hyponatremia,¹ thirst,¹ anemia,¹ hypotension,^{1 8} pyrexia,^{1 8} nausea,¹ confusion.¹

Interactions for Conivaptan Hydrochloride

Metabolized extensively by CYP3A; potent inhibitor of CYP3A.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of conivaptan); concomitant use contraindicated.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A substrates: Potential pharmacokinetic interaction (increased plasma concentrations and AUC of CYP3A substrate); avoid concomitant use with drugs metabolized principally by CYP3A.¹ Allow ≥1 week to elapse following discontinuance of conivaptan and initiation of treatment with a CYP3A substrate.¹

Specific Drugs

Drug	Interaction	Comments
Amlodipine	Increased AUC and half-life of amlodipine1	Avoid concomitant use1
Antifungals, azoles (e.g., ketoconazole, itraconazole)	Increased plasma conivaptan concentrations1	Concomitant use contraindicated1
Captopril	Pharmacokinetic interaction unlikely1
Clarithromycin	Increased plasma conivaptan concentrations1	Concomitant use contraindicated1
Digoxin	Increased AUC and plasma concentrations of digoxin1 Decreased digoxin clearance1	Monitor serum digoxin concentrations1
Furosemide	Pharmacokinetic interaction unlikely1 5
HMG-CoA reductase inhibitors (statins) (e.g., simvastatin)	Simvastatin: Increased AUC1 Possible rhabdomyolysis1	Avoid concomitant use of statins metabolized by CYP3A1
Indinavir	Increased plasma conivaptan concentrations1	Concomitant use contraindicated1
Midazolam	Increased AUC of midazolam1	Avoid concomitant use1
Ritonavir	Increased plasma conivaptan concentrations1	Concomitant use contraindicated 1
Warfarin	Pharmacokinetic interaction unlikely1

Conivaptan Hydrochloride Pharmacokinetics

Distribution

Extent

Crosses the placenta and is found in fetal tissue in rats; not known whether conivaptan crosses the placenta in humans.¹

Not known whether conivaptan is distributed into human milk.¹

Plasma Protein Binding

99%.¹

Elimination

Metabolism

Metabolized, principally in the liver by CYP3A, to active metabolites.^{1 4} Contribution of metabolites to clinical effects of the drug is minimal.¹

Appears to inhibit own metabolism, resulting in nonlinear pharmacokinetics.¹

Elimination Route

Excreted principally in feces (83%) and in urine (12%).¹

Half-life

Terminal half-life averages 5 hours in healthy men.¹

In hyponatremic patients receiving 20-mg loading dose followed by 20 or 40 mg daily for 4 days, median elimination half-life is 5.3 or 8.1 hours, respectively.¹

Special Populations

Effect of hepatic impairment, including ascites, cirrhosis, and portal hypertension, on elimination of IV conivaptan not systematically evaluated.¹ However, exposure to oral conivaptan is increased up to 2.8-fold in patients with stable cirrhosis and moderate hepatic impairment.¹ Consider that exposure to conivaptan in patients without hepatic impairment is greater after IV than oral administration.¹

Effect of renal impairment on elimination of IV conivaptan not established.¹ However, exposure to oral conivaptan is increased 1.7- or 1.9-fold in patients with Cl_cr of 30–60 or 10–29 mL/minute, respectively.¹ Consider that exposure to conivaptan in patients without renal impairment is greater after IV than oral administration.¹

Stability

Storage

Parenteral

Injection

25°C.¹ Protect from excessive heat; brief exposure up to 40°C will not adversely affect stability.¹ Do not freeze; protect from light.¹

For single use only; discard any unused portions.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Commercially available premixed conivaptan hydrochloride solution is compatible with 5% dextrose injection.¹ Also compatible with 0.9% sodium chloride injection for up to 22 hours when administered simultaneously through Y-site connection at flow rates of 4.2 mL/hour for conivaptan hydrochloride injection and 2.1 or 6.3 mL/hour for 0.9% sodium chloride.¹

Do not administer lactated Ringer's injection with conivaptan.¹

ActionsActions

• 
  

  Arginine vasopressin (AVP) V_1A and V₂ antagonist.^{1 2 3 4 5 6 7}

  
  


• 
  

  V₂ antagonism of AVP in renal collecting ducts results in increased free water excretion (i.e., effective water clearance); and, typically, increased net fluid loss, increased urine output, and decreased urine osmolality.^{1 2 3 6}

  
  


• 
  

  Blockade of vascular V_1A receptors may cause splanchnic vasodilation, possibly resulting in hypotension or variceal bleeding in patients with cirrhosis (especially those with portal hypertension).^{3 9}

  
  


• 
  

  Does not appear to have a clinically important effect on cardiac repolarization.¹

  
  

Advice to Patients

• 
  

  Importance of advising patients of common adverse effects, including infusion site reactions (e.g., edema, erythema, pain, phlebitis), orthostatic hypotension (e.g., lightheadedness, syncope), pyrexia, hypokalemia, and headache.¹

  
  


• 
  

  Potential for too rapid an increase in serum sodium concentration, which may result in serious neurologic sequelae.¹ Importance of informing clinician if any signs or symptoms suggestive of osmotic demyelination syndrome (e.g., difficulty speaking or swallowing, drowsiness, confusion, mood changes, weakness or involuntary movements in the extremities, seizures) occur.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.¹

  
  


• 
  

  Importance of alerting clinician if an allergy to corn or corn products exists.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Conivaptan Hydrochloride in Dextrose

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV use only	0.2 mg/mL (20 mg) in 5% Dextrose	Vaprisol (in INTRAVIA flexible containers)	Astellas

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Astellas Pharma US. Vaprisol (conivaptan hydrochloride) injection prescribing information. Deerfield, IL; 2010 May.

2. Ghali JK, Koren MJ, Taylor JR et al. Efficacy and safety of oral conivaptan: a V_1A/V₂ vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006; 91:2145-52. [PubMed 16522696]

3. Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int. 2006; 69:2124-30. [PubMed 16672911]

4. Anon. Conivaptan (Vaprisol) for hyponatremia. Med Lett Drugs Ther. 2006; 48:51-2.

5. Anon. Conivaptan: YM 087. Drugs R&D. 2004; 5:94-7.

6. Munger, MA. New agents for managing hyponatremia in hospitalized patients. Am J Health-Syst Pharm. 2007; 64:253-65.

7. Walter KA. Conivaptan: new treatment for hyponatremia. Am J Health-Syst Pharm. 2007; 64:1385-95. [PubMed 17592003]

8. Zeltser D, Rosansky S, van Rensburg H et al. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007; 27:447-57. [PubMed 17664863]

9. Astellas Pharma US, Deerfield, IL: Personal communication.

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• Conivaptan Hydrochloride Drug Interactions
• Conivaptan Hydrochloride Support Group
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