Label Change for Asthma/Hives Drug; Risk of Cardiovascular and Brain Events

An FDA review of safety studies of the asthma drug Omalizumab (marketed as Xolair) suggests an increased risk of problems involving the heart and blood vessels supplying the brain among patients being treated with the Xolair than in those who were not treated with Xolair. As a result, the FDA added information about these potential risks to the drug label. Patients taking Xolair should continue to take the medication as prescribed and discuss any questions or concerns with their health care professionals.


The FDA approved Xolair in 2003 to treat patients 12 years and older with moderate to severe persistent asthma who have a positive skin or blood test to year-round allergens in the air and whose symptoms are not well-controlled by asthma medicines called inhaled corticosteroids. Xolair is administered by a health care professional by subcutaneous injection under the skin every two to four weeks. Xolair is only used in asthma patients who have elevated levels of a substance called IgE in their blood. A blood test must be performed prior to starting Xolair to determine the appropriate dose and dosing frequency. Xolair has been shown to decrease the number of asthma attacks in these patients. Asthma is a chronic disease that affects the airways in the lungs and can cause serious trouble breathing, so it is important to take all asthma medicines exactly as they are prescribed. Xolair is also approved for patients 12 years and older with chronic hives without a known cause?a condition called chronic idiopathic urticaria or CIU?who continue to have hives that are not controlled by H1 antihistamine treatment. Xolair is not used to treat other allergic conditions, other forms of urticaria, acute bronchospasm, or status asthmaticus.


The review of a five-year safety study found a slightly higher rate of heart and brain blood vessel problems occurred in patients being treated with Xolair compared to those patients not treated with Xolair. The heart and brain blood vessel problems included mini-strokes known as transient ischemic attacks or TIAs; heart attacks; sudden, unexpected chest pain; high blood pressure in the arteries of the lungs called pulmonary hypertension; and blood clots in the lungs and veins. Although the data are suggestive of a serious safety signal, due to weaknesses in how the safety study was designed and carried out, the FDA is unable to definitively confirm or determine the exact increased level of these risks with Xolair.


More specifically, the manufacturer of Xolair, Genentech, initiated the post-marketing commitment study titled “An Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma” (EXCELS) in June 2004 to assess the long-term safety of Xolair. EXCELS was a five-year observational cohort study conducted in patients 12 years of age and older with moderate to severe persistent asthma and a positive skin test reaction to a perennial aeroallergen. A total of 5,007 Xolair-treated and 2,829 non-Xolair-treated patients were enrolled. Similar percentages of patients in both cohorts were current (5 percent) or former smokers (29 percent). Patients had a mean age of 45 years and were followed for a mean of 3.7 years. More Xolair-treated patients were diagnosed with severe asthma (50 percent) compared to the non-Xolair-treated patients (23 percent). Additionally, 88 percent of patients in the Xolair-treated cohort had been previously exposed to Xolair for a mean of 8 months (prevalent users). Forty-six percent and 40 percent of patients in the Xolair-treated and non-Xolair-treated cohorts, respectively, prematurely discontinued the study.


To further evaluate the heart and brain risks noted in the five-year safety study, the FDA reviewed a combined analysis of 25 randomized double-blind clinical trials comparing Xolair to a placebo, a treatment that does not contain any medicine. The clinical trials lasted between 8 and 52 weeks and were completed by December 31, 2010. A total of 3,342 Xolair-treated patients and 2,895 placebo-treated patients were included in this pooled analysis. The primary outcomes of interest included cardiovascular death, myocardial infarction, arrhythmias, heart failure, stroke, transient ischemic attack, pulmonary hypertension, pulmonary embolism, and unstable angina. An increased risk of heart- and brain-related problems in patients treated with Xolair was not noted in this combined analysis, but the low number of these events, the young patient population, and the short duration of follow-up prevent the researchers from making any definite conclusions about the absence of a risk.


Across all the studies evaluated in the combined analysis, a total of eight events occurred in the Xolair-treated patients compared with 15 in the placebo patients, and no notable differences were observed in the rates of specific cardiovascular events. Although no association was found in this pooled analysis, the results were based on a low number of events, relatively young patients (i.e., mean age 38 years and only 5.5 percent elderly), shorter duration of follow-up (mean 6.8 months) than the EXCELS study, and low incidence of baseline cardiovascular disease. Therefore, the results of the pooled analysis are insufficient to confirm or reject the findings noted in the EXCELS study.


As a result of the review of the safety study and the combined clinical trials, information about the potential risks of heart- and brain-related problems has been added to the Adverse Reactions section of the drug label.


Some previous clinical trials have shown slightly higher rates of various cancers in patients treated with Xolair compared with non-Xolair-treated patients. The review of the five-year safety study found no difference in the rates of cancer between those patients being treated with Xolair and those who were not being treated with Xolair. However, due to limitations in the five-year study, the FDA cannot rule out a potential risk of cancer with Xolair, so this information has been added to the Warnings and Precautions section of the drug label. These limitations include the potential for unmeasured/uncontrolled confounding, the bias introduced by allowing enrollment of patients previously exposed to Xolair (prevalent users), an initial enrollment criterion that excluded patients with a history of cancer or a premalignant condition (56 percent), and a high study discontinuation rate.


The risk of malignancy was the original intent of the EXCELS study. In the clinical trials that supported approval of Xolair, higher numbers of various malignant neoplasms were observed in Xolair-treated patients compared with control patients. The majority of the patients in these clinical trials were observed for less than one year. In the EXCELS study, the incidence rates of primary malignancies per 1,000 patient years were similar among Xolair-treated (12.3) and non-Xolair-treated patients (13.0).


See the FDA Safety Announcement


See also Medical Law Perspectives, May 2013 Report: Drugs, Dosage, and Damage: Physician Liability for Prescribing or Administering Medication


See also Medical Law Perspectives, December 2013 Report: Thicker Than Water: Liability When Blood Clots Cause Injury or Death


See also Medical Law Perspectives, November 2013 Report: Diagnosis and Treatment of Heart Attacks: Liability Issues


See also Medical Law Perspectives, October 2013 Report: Brain Aneurysm and Subarachnoid Hemorrhage: Failure to Diagnose, Delayed Diagnosis, Misdiagnosis