FDA modifies boxed warning for pulmonary arterial hypertension drug Letairis

The U.S. Food and Drug Administration today (March 4) announced that monthly liver enzyme tests are no longer required for those taking Letairis tablets (ambrisentan), used to treat high blood pressure in the vessels that carry blood to the lungs (pulmonary arterial hypertension, or PAH).

Citing data from clinical trials and postmarket reports, the FDA said that the drug poses only a low risk of liver injury. Information related to potential serious liver injury and the need to monitor for such serious injury is being removed from the drug’s boxed warning.

In patients with PAH, Letairis slows the worsening of symptoms and improves the ability to exercise. Approved in 2007, Letairis is in a class of medications called endothelin receptor antagonists, which stop the action of endothelin, a substance that narrows blood vessels and prevents normal blood flow in those with PAH.

“We have concluded that monthly liver enzyme testing for patients taking Letairis, as previously noted in the boxed warning, is not necessary,” said Mary Ross Southworth, Pharm.D., deputy director for safety in the Division of Cardiovascular and Renal Products at the FDA’s Center for Drug Evaluation and Research. “Health care professionals should still continue to order liver enzyme tests when they consider it clinically indicated.”

Letairis was approved with a Risk Minimization Action Plan (RiskMAP) to manage liver damage and fetal malformation. The RiskMAP called for liver enzyme testing prior to treatment and monthly during treatment for all patients. It also required monthly pregnancy testing for women of childbearing potential because Letairis causes birth defects in animals, like other drugs in this class. The Letairis RiskMAP was converted to a Risk Evaluation and Mitigation Strategy in 2009.

The boxed warning on the risk of serious birth defects and the contraindication for use during pregnancy will remain in the labeling. Letairis will continue to be available only through a restricted distribution program called the Letairis Education and Access Program (LEAP). For women who can become pregnant, monthly pregnancy tests will still be required before Letairis is shipped.

The liver warnings were based on experience with other drugs in Letairis’ drug class, as well as a few observed instances of increased liver enzymes in people treated with Letairis. The FDA’s further evaluation has shown that rates of liver problems in Letairis-treated patients are consistent with rates within the general PAH population. In the controlled clinical trials, the rates of liver problems in Letairis-treated patients are similar to the rates in people receiving an inactive pill (placebo).

For a discussion of the FDA’s rationale and regulatory decisions regarding Letairis, refer to the Drug Safety Communication issued today.

People who take Letairis should not stop taking it without talking to their health care professional. Health care professionals should order and review tests for liver function as necessary based on the patient’s condition and history. Adverse events involving Letairis should be reported to the FDA MedWatch program1.

Letairis is made by Gilead Sciences Inc., Foster City, Calif.

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FDA Limits Acetaminophen in Prescription Combination Products; Requires Liver Toxicity Warnings

/PRNewswire/ -- The U.S. Food and Drug Administration is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule.

The FDA also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.

Acetaminophen, also called APAP, is a drug that relieves pain and fever. It is combined in many prescription products with other ingredients, usually opioids such as codeine (Tylenol with Codeine), oxycodone (Percocet), and hydrocodone (Vicodin).

"FDA is taking this action to make prescription combination pain medications containing acetaminophen safer for patients to use," said Sandra Kweder, M.D., deputy director of the Office of New Drugs in FDA's Center for Drug Evaluation and Research (CDER). "Overdose from prescription combination products containing acetaminophen account for nearly half of all cases of acetaminophen-related liver failure in the United States; many of which result in liver transplant or death."

The elimination of higher-dose prescription combination acetaminophen products will be phased in over three years and should not create a shortage of pain medication. Patients and health care professionals are being notified of the new limitation on acetaminophen content, and of the labeling change, in a drug safety communication issued by CDER. The FDA believes that prescription combination products containing no more than 325 mg of acetaminophen per tablet are effective for treating pain.

"There is no immediate danger to patients who take these combination pain medications and they should continue to take them as directed by their health care provider," said Kweder. "The risk of liver injury primarily occurs when patients take multiple products containing acetaminophen at one time and exceed the current maximum dose of 4,000 milligrams within a 24-hour period."

Acetaminophen also is widely used as an over-the-counter pain and fever medication, and is combined with other OTC ingredients, such as cough and cold ingredients. The actions FDA is taking for prescription acetaminophen products do not affect OTC acetaminophen products.

Because of continued reports of liver injury, FDA proposes that boxed warnings, the agency's strongest warning for prescription drugs, be added to all acetaminophen prescription products. Most of the cases of severe liver injury occurred in patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period, took more than one acetaminophen-containing product at the same time, or drank alcohol while taking acetaminophen products.

An FDA advisory committee discussed the issue at a meeting in June, 2009, and recommended strengthening the warning about severe liver injury on the drug labels of prescription products containing acetaminophen.

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FDA: Rare Cases of Liver Injury Reported with Use of Xenical, Alli

The U.S. Food and Drug Administration today advised consumers and health care professionals about potential rare occurrences of severe liver injury in patients taking the weight-loss medication orlistat, marketed as Xenical and Alli.

The FDA has approved a revised label for the prescription drug Xenical. The agency is working with the manufacturer of Alli on label revisions to reflect this rare occurrence.

Both Xenical and Alli are medications contain the same active ingredient, orlistat. Xenical, available only by prescription, contains 120 milligrams of orlistat. Alli, sold over-the-counter without a prescription, contains 60 mg of orlistat. An estimated 40 million people worldwide have taken either Xenical or Alli.

The FDA’s safety information and labeling changes are based on a review of cases of severe liver injury reported in individuals taking orlistat. The agency has identified 13 cases of severe liver injury, 12 of which were reports from outside of the United States. The only U.S. report of severe liver injury involved Alli. At this time, a cause-and-effect relationship of severe liver injury with orlistat use has not been established.

People who take Xenical or Alli should be aware that liver injury with orlistat – while rare – has been reported. Those taking the drug also should be aware of the signs and symptoms of liver injury, which include itching, yellow eyes or skin, dark urine, loss of appetite, or light-colored stools.

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FDA Approves New Use of Xifaxan for Patients with Liver Disease

The U.S. Food and Drug Administration today approved the use of Xifaxan for reduction in the risk of the recurrence of overt hepatic encephalopathy (HE) in patients with advanced liver disease. This is a new use for Xifaxan (rifaximin), a drug that has been approved for the treatment of traveler’s diarrhea.

Hepatic encephalopathy is a worsening of brain function that can occur in patients whose liver can no longer remove toxins from the blood. Increased levels of ammonia in the blood are thought to play a role in the development of HE, and Xifaxan works by reducing these levels.

“The approval of Xifaxan for this new indication provides an additional treatment option for patients with liver disease,” said Joyce Korvick, M.D., deputy director for safety of FDA’s Division of Gastroenterology Products. “Hepatic encephalopathy occurs commonly in patients with liver disease, and there are few effective treatments for this serious condition.”

The efficacy of Xifaxan was established in a randomized placebo-controlled clinical trial of adult patients from the United States, Canada, and Russia. Patients with liver disease who entered the trial had no or mild symptoms of HE. Patients treated with Xifaxan were less likely to develop HE during the trial, compared to placebo-treated patients.

Xifaxan was not studied in patients with the most severe forms of liver disease. Since most patients were also taking lactulose (a synthetic sugar which helps prevent absorption of ammonia from the intestine) during the trial, the efficacy of Xifaxan as a stand-alone treatment for HE could not be assessed.

The most common adverse reactions reported with the use of Xifaxan in patients with liver disease include swelling of the arms and legs (peripheral edema), nausea, gas, and headache.

Xifaxan received a priority review under FDA’s new drug application process and was granted orphan designation status. Xifaxan is manufactured by Salix Pharmaceuticals Inc. of Morrisville, N.C.

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FDA Announces Safety Risk Associated with HIV Drug

The U.S. Food and Drug Administration announced on January 29 that non-cirrhotic portal hypertension, a rare, but serious, liver disorder, has been reported in some HIV patients taking Videx/Videx EC (didanosine).

Videx is an antiretroviral medicine first approved by the FDA in 1991. Videx EC is a delayed-release version of Videx approved in 2000. Videx/Videx EC is used in combination with other antiretroviral medicines to treat HIV infection in children and adults.

During an 18-year period, 42 cases of non-cirrhotic portal hypertension were reported to the FDA’s Adverse Event Reporting System for patients taking Videx/Videx EC. Four patients died from bleeding or liver failure after developing the condition.

Non-cirrhotic portal hypertension occurs when blood flow in the portal vein – a major vein in the liver – slows down and leads to severely enlarged veins in the esophagus. These enlarged veins, called esophageal varices, are thin and can break open, resulting in serious, and potentially fatal, bleeding.

The Videx and Videx EC product labels have been revised to help ensure that health care professionals and patients are aware of the risk and the signs and symptoms of non-cirrhotic portal hypertension.

The FDA evaluation concluded that the clinical benefits of Videx/Videx EC in certain patients with HIV continue to outweigh potential safety risks. Videx/Videx EC does not cure HIV infection, may not prevent development of HIV-related illnesses, and may not prevent the spread of HIV to other people.

Videx/Videx EC is marketed by Princeton, N.J.-based Bristol-Myers Squibb.

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Researchers Find High-Dose Therapy for Liver Disease Not Effective

/PRNewswire/ -- A national team of researchers led by scientists at Mayo Clinic has found that a common treatment for primary sclerosing cholangitis, a chronic liver disease, is not helpful for patients, according to a study published this month in the journal Hepatology.

Primary sclerosing cholangitis (PSC) is a disease of the bile ducts. In this case, the term "cholangitis" refers to inflammation of the bile ducts, while "sclerosing" describes the hardening and scarring of the bile ducts that result from chronic inflammation.

"Primary sclerosing cholangitis is a serious liver disease lacking an effective medical therapy," says Keith Lindor, M.D., Mayo Clinic gastroenterologist and the study's lead researcher. "Some studies have shown that the use of ursodeoxycholic acid, a naturally occurring bile acid, may be a potential solution for patients. Our research, however, showed long-term use of this treatment in high dosages is not suitable for patients."

In this six-year, multicenter trial, 150 patients were enrolled in the study to determine the effectiveness of ursodeoxycholic acid (UDCA) in treatment of PSC. Seventy-six patients were treated with higher doses (28 to 30 mg/kg/day) of UDCA and 74 patients were given a placebo. Serious adverse events were more common in the UDCA group than the placebo group, which prompted researchers to halt the study. UDCA has been thought to be a possible treatment solution for PSC patients, but this trial indicates that the drug, used at this higher dose, is not helpful.

"All of us were surprised that the higher doses of UDCA did not help; in fact, the risk of developing even more liver problems increased with the higher dosages," says Dr. Lindor. "While this was thought to be the best potential treatment for PSC, our study found that not to be the case."

Dr. Lindor says that patients who are currently on higher doses of UDCA should consult with their doctors. He also points out that these study findings highlight the need for more research to look into better treatment options for PSC.

PSC is a progressive disease that leads to liver damage and, eventually, liver failure. Liver transplant is the only known cure for PSC, but transplant is typically reserved for people with severe liver damage.

PSC most often affects people in their 30s to 50s. The average age at diagnosis is 40. However, the condition can arise in childhood. About 60 to 75 percent of people diagnosed with the disease are men. Approximately 70 percent of people with PSC have an associated disease such as inflammatory bowel disease, osteoporosis, gallbladder disease and bile duct cancer or cholangiocarcinoma. However, only 1 to 5 percent of people with inflammatory bowel disease have PSC.

Mayo Clinic's Division of Gastroenterology and Hepatology has been ranked #1 in the U.S. News & World Report Honor Roll of Top Hospitals since the rankings began 20 years ago.

Other members of the Mayo Clinic research team include M. Edwyn Harrison, M.D.,Denise Harnois, D.O., Roberta Jorgensen, Jan Petz, Jill Keach, Julie Braaten, M.D., Ellen Miceli, Jeff Schmoll, Tanya Hoskin, Prabin Thapa and Felicity Enders, Ph.D. Other researchers include Kris Kowdley, M.D., and Jody Mooney, M.D., Virginia Mason Medical Center; Velimir Luketic, M.D., and Carol Sargeant, M.D., Virginia Commonwealth University School of Medicine; Timothy McCashland, M.D., and Tamara Bernard, M.D., University of Nebraska; and Alex Befeler, M.D., and Debra King, M.D., Saint Louis University.

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