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From the National Institutes of HealthNational Institutes of Health

Tolvaptan

pronounced as(tol vap' tan)

Notice:

[POSTED 04/30/2013] ISSUE: FDA has determined that the drug tolvaptan (Samsca) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver transplant or death. FDA has worked with the manufacturer to revise the Samsca drug label to include new limitations.

BACKGROUND: Tolvaptan is a selective vasopression V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH). An increased risk of liver injury was observed in recent large clinical trials evaluating tolvaptan for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD).

RECOMMENDATION: Tolvaptan treatment should be stopped if the patient develops signs of liver disease. Treatment duration should be limited to 30 days or less, and use should be avoided in patients with underlying liver disease, including cirrhosis. Patients should be aware that tolvaptan may cause liver problems, including life-threatening liver failure, and should contact their health care professional to discuss any questions or concerns about Samsca. For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.

[Posted 01/25/2013] ISSUE: Otsuka and FDA notified healthcare professionals of significant liver injury associated with the use of tolvaptan (Samsca). In a double-blind, 3–year, placebo-controlled trial in about 1400 patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and its open-label extension trial, 3 patients treated with the drug developed significant increases in serum alanine aminotransferase (ALT) with concomitant, clinically significant increases in serum total bilirubin. In the trials the maximum daily dose of tolvaptan administered (90 mg in the morning and 30 mg in the afternoon) was higher than the maximum 60 mg daily dose approved for the treatment of hyponatremia.

Most of the liver enzyme abnormalities were observed during the first 18 months of therapy. Following discontinuation of treatment, all 3 patients improved. An external panel of liver experts assessed these 3 cases as being either probably or highly likely to be caused by tolvaptan. These findings indicate that tolvaptan has the potential to cause irreversible and potentially fatal liver injury. These data are not adequate to exclude the possibility that patients receiving tolvaptan for its indicated use of clinically significant hypervolemic and euvolemic hyponatremia are at a potential increased risk for irreversible and potentially fatal liver injury.

BACKGROUND: Tolvaptan is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. Tolvaptan is not approved for the treatment of ADPKD.

RECOMMENDATION: Healthcare providers should perform liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. If hepatic injury is suspected, tolvaptan should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine probable cause. Tolvaptan should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with tolvaptan. For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.

IMPORTANT WARNING:

Tolvaptan may cause the level of sodium in your blood to increase too quickly. This may cause osmotic demyelination syndrome (ODS; serious nerve damage that may be caused by quick increases in sodium levels). Tell your doctor if you drink or have ever drunk large amounts of alcohol, if you have malnutrition (the body lacks the nutrients needed for good health), and if you have or have ever had liver disease or extremely low levels of sodium in your blood.

You and your doctor will take certain precautions to try to prevent ODS. You will begin your treatment with tolvaptan in the hospital so that your doctor can monitor you closely. If your doctor tells you to continue taking tolvaptan after you leave the hospital, you should not stop and re-start treatment on your own. You will need to return to the hospital when you restart the medication.

You will need to drink water whenever you are thirsty to help prevent ODS during your treatment with tolvaptan. Your doctor will not prescribe tolvaptan if you are unable to feel that you are thirsty. You should have drinking water available at all times during your treatment.

If you experience any of the following symptoms of ODS, tell your doctor immediately: difficulty speaking, difficulty swallowing, feeling that food or drinks are getting stuck in your throat, drowsiness, confusion, mood changes, body movements that are difficult to control, weakness of the arms or legs, or seizures.

Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with tolvaptan and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer's website to obtain the Medication Guide.

Talk to your doctor about the risk of taking tolvaptan.

Why is this medication prescribed?

Tolvaptan is used to increase low levels of sodium in the blood in people who have heart or liver disease or certain other conditions. Tolvaptan is in a class of medications called vasopressin V2 receptor antagonists. It works by increasing the amount of water released from the body as urine. Removing fluid from the body helps to increase the level of sodium in the blood.

How should this medicine be used?

Tolvaptan comes as a tablet to take by mouth. It is usually taken once a day with or without food. At the beginning of your treatment, you will be given tolvaptan at a regularly scheduled time in the hospital. If you are told to take tolvaptan at home after you are discharged, you should take it at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tolvaptan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of tolvaptan and gradually increase your dose, not more often than once every 24 hours.

Talk to your doctor about what you should do after you stop taking tolvaptan. You will probably need to limit the amount of fluid you drink, and your doctor will monitor you carefully during this time.

Other uses for this medicine

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This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

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Before taking tolvaptan,

  • tell your doctor and pharmacist if you are allergic to tolvaptan, any other medications, or any of the ingredients in tolvaptan tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor if you are taking certain antifungals such as ketoconazole (Nizoral) or itraconazole (Sporanox); clarithromycin (Biaxin); certain medications for HIV such as indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), or saquinavir (Invirase); nefazodone; or telithromycin (Ketek). Your doctor may tell you not to take tolvaptan if you are taking one or more of these medications.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril, (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik); angiotensin II receptor blockers such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisartan (Micardis), and valsartan (Diovan); aprepitant (Emend); barbiturates such as phenobarbital; carbamazepine (Equetro, Tegretol); cyclosporine (Gengraf, Neoral, Sandimmune); digoxin (Lanoxin); diltiazem (Cardizem, Dilacor, Tiazac); diuretics (water pills); erythromycin (E.E.S., E-Mycin, Erythrocin); fluconazole (Diflucan); phenytoin (Dilantin); potassium supplements; rifabutin (Mycobutin); rifampin (Rimactane, Rifadin); rifapentine (Priftin); and verapamil (Calan, Covera, Isoptin,Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with tolvaptan, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor what herbal products you are taking or plan to take, especially St John's wort.
  • tell your doctor if you have kidney disease and do not produce urine, if you have severe vomiting or diarrhea, or if you have lost a lot of fluid from your body and feel dizzy or faint. Your doctor will probably tell you not to take tolvaptan. Your doctor will also probably not prescribe tolvaptan if your sodium level must be increased very quickly.
  • tell your doctor if you have or have ever had a high level of potassium in your blood.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking tolvaptan, call your doctor.

What special dietary instructions should I follow?

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Do not eat grapefruit or drink grapefruit juice while taking this medication.

What should I do if I forget a dose?

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Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

What side effects can this medication cause?

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Tolvaptan may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • thirst

  • dry mouth

  • frequent, excessive urination

  • nausea

  • constipation

  • loss of appetite

  • fever

  • weakness

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

  • vomiting

  • diarrhea

  • inability to drink normally

  • dizziness

  • faintness

  • vomit that is bloody or looks like coffee grounds

  • bloody or black and tarry stools

Tolvaptan may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online [at http://www.fda.gov/Safety/MedWatch] or by phone [1-800-332-1088].

What should I know about storage and disposal of this medication?

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Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

In case of emergency/overdose

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In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

  • excessive urination

  • excessive thirst

  • dizziness

  • faintness

What other information should I know?

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Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your body's response to tolvaptan.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Brand names

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  • Samsca®

Last Revised - 05/15/2013

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AHFS® Consumer Medication Information. © Copyright, 2013. The American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland. All Rights Reserved. Duplication for commercial use must be authorized by ASHP.