Conivaptan

Microscopy of kidney tissue showing tubules. The insides of the tubules are dark centers. The cells surrounding the tubules are blue (the nuclei are green). Conivaptan acts on the tubules to increase the excretion of water into the urine. Source: Wikimedia Commons

Conivaptan is a prescription drug used to elevate sodium levels in people with hyponatremia (low levels of sodium in the blood). It blocks the action of arginine vasopressin, a hormone that increases water resorption in the kidneys. Thus, conivaptan increases free water loss through urine without increasing excretion of sodium, resulting in an overall increase in sodium levels.

Other Names

• Vaprisol (US)

Uses

Conivaptan is used to raise low blood sodium levels in hospitalized people with euvolemic hyponatremia. Euvolemic hyponatremia occurs when a person has too little sodium in the bloodstream but a normal amount of fluid in the body. This condition occurs in people with the syndrome of inappropriate antidiuretic hormone release (SIADH) and endocrine (hormone) disorders such as hypothyroidism and adrenal insufficiency as well as in some pulmonary disorders. Conivaptan may also have a role in the treatment of congestive heart failure, although it has not received FDA approval for this indication.

How Conivaptan is Taken

Conivaptan is given intravenously (IV) for up to four days. The initial dose is 20 mg infused over 30 minutes, followed by another 20-mg dose over the next 24 hours. Daily 20-mg doses are given thereafter.

How It Works

Arginine vasopressin, also known as antidiuretic hormone, is released from the pituitary gland when the body is dehydrated. It acts on the tubules of the kidneys to increase resorption of water into the blood, thus concentrating the urine.

Conivaptan is an arginine vasopressin antagonist. It binds to the arginine vasopressin receptor in the tubules of the kidney and prevents arginine vasopressin from acting. The result is an increase in the excretion of water in the urine. Conivaptan has no effect on the secretion or resorption of electrolytes such as sodium, potassium, and chloride. However, conivaptan does restore sodium balance in the blood.

How the Body Affects Conivaptan

Conivaptan reaches peak levels in the blood within approximately 30 minutes of dosing. The concentration of conivaptan in the blood is reduced by half in approximately five hours. Conivaptan is metabolized to a large extent in the liver by the enzyme CYP3A4. The majority of conivaptan is excreted in the feces.

Benefits

Conivaptan has been shown to be effective in the treatment of hypovolemic hyponatremia. ^[1] Benefits include direct targeting of the effects of arginine vasopressin which provides a more predictable correction of the sodium imbalance, and the excretion of free water while electrolytes are retained.

Side Effects

Injection site reactions are the most common side effects of conivaptan. In some cases, the reactions are serious enough to warrant discontinuation of the drug. Some other common side effects that may occur with conivaptan include the following:

• Skin reaction (redness, pain or warmth) at the injection site
• Headache
• Thirst
• Low blood potassium
• Vomiting
• Increased urination
• Diarrhea
• Orthostatic hypotension (a decrease in blood pressure upon standing that may cause lightheadedness)

Risks

Precautions

Because conivaptan increases water excretion, the drug is not used to treat hypovolemic hyponatremia, which is characterized by too little sodium and water in the body.

Some serious side effects that influence brain function can develop if blood sodium rises too quickly during treatment. Sodium levels are frequently monitored during treatment to avoid any risk of these reactions.

Interactions

Conivaptan inhibits the activity of the CYP3A4 enzyme in the liver. Numerous drugs are metabolized by this enzyme. Therefore, conivaptan has the potential to interact with several drugs. Based on an interaction at the CYP3A4 level, conivaptan has been shown to increase blood concentrations of the following drugs:

• Amlodipine (Norvasc)
• Midazolam
• Simvastatin (Zocor, Vytorin)
• Digoxin

Other statins, such as atorvastatin (Lipitor), lovastatin (Mevacor, Altocor, Advicor, Altoprev), and rosuvastatin (Crestor), may also interact with conivaptan.

Drugs that inhibit CYP3A4 could elevate blood concentrations of conivaptan. This has been documented for the antifungal ketoconazole (Nizoral) and could occur with another antifungal itraconazole (Sporanox) or with other strong CYP3A4 inhibitors such as:

• Clarithromycin (Biaxin)
• Ritonavir (Norvir, Kaletra)
• Indinavir(Crixivan)

History

In December 2005, conivaptan became the first vasopressin antagonist approved by the U.S. Food and Drug Administration for the treatment of hyponatremia. Conivaptan is marketed in the United States by Astellas Pharma as Vaprisol.

Research

Recent discoveries

• The effectiveness of IV conivaptan was studied in a trial of 84 hospitalized patients with euvolemic or hypervolemic natremia.^[2] Blood concentrations of sodium had increased significantly over the four-day treatment period and had been significantly greater than that seen in placebo-treated patients. Only 1 patient given 40 mg/day conivaptan had to discontinue treatment because of injection site reactions.
• The efficacy of conivaptan was studied in patients with euvolemic hyponatremia (sodium is normal but total body water is increased) or hypervolemic hyponatremia (sodium is increased, but total body water is increased to a greater extent). ^[3]
• The efficacy of oral conivaptan in these conditions was also evaluated in a multinational study. ^[4]
• There have been a number of studies about the use of conivaptan in congestive heart failure. ^{[5] [6] [7]}

Clinical Trials

A list of current clinical trials is available from ClinicalTrials.gov: conivaptan trials

References

1. ↑ Ghali JK. Mechanisms, Risks, and New Treatment Options for Hyponatremia. Cardiology. 2008 Apr 25;111(3):147-157. (Epub ahead of print). Abstract
2. ↑ Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N; Conivaptan Study Group. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447-57. Abstract
3. ↑ ClinicalTrials.gov. An Open-Label Study of YM087 (Conivaptan) in Patients With Euvolemic or Hypervolemic Hyponatremia
4. ↑ ClinicalTrials.gov. Study of Efficacy & Safety of Oral YM087 in Subjects With Euvolemic or Hypervolemic Hyponatremia
5. ↑ Chen SY, Abrahams Z, Sokos GG. Conivaptan: potential therapeutic implications in heart failure. Recent Patents Cardiovasc Drug Discov. 2008 Jun;3(2):137-40. Abstract
6. ↑ Goldsmith SR. Current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure. Am J Cardiol. 2005 May 2;95(9A):14B-23B. Abstract
7. ↑ ClinicalTrials.gov. Safety and Efficacy Study of YM087 (Conivaptan) in Patients With Acute Decompensated Heart Failure

External Links

U.S. Food and Drug Administration: Conivaptan patient information sheet