From July 2006, (when Tysabri marketing resumed) to September 8, 2009, 13 reported cases of Tysabri-related PML were confirmed worldwide in patients being treated for MS with Tysabri monotherapy. There have been no postmarketing reports of PML in patients treated with Tysabri for Crohn’s disease. Less than 2% of Tysabri use in the U.S. has been in patients with Crohn’s disease. Based on available data from the U.S. and outside of the U.S., the current rate of PML in patients who have received at least 24 infusions ranges from 0.4 to 1.3 per 1,000 patients.

The risk appears to increased with the number of infusions administered.

The FDA recommends that healthcare professionals measure serum bicarbonate before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering), and modifying the patient’s antiepileptic treatment as appropriate. If the decision is made to continue patients with metabolic acidosis on zonisamide, then alkali treatment should be considered.

The FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel, or that using certain other drugs with clopidogrel can interfere with how the body metabolizes clopidogrel.

Clopidogrel is an antiplatelet drug that is used to prevent blood clots that could lead to heart attacks or strokes in patients at risk for these problems. The drug clopidogrel is a “pro-drug” which means that it has to be metabolized by the body before it can be biologically active and have the effect of preventing blood clots. Understanding that there are differences in how the body metabolizes clopidogrel and there are effects that other drugs may have on its metabolism is important because decreases in the effectiveness of clopidogrel might be avoided, in part, by using other drugs with clopidogrel that do not interfere with its metabolism.

One class of drugs commonly used with clopidogrel is proton pump inhibitors (PPIs). Some reports suggest that use of certain PPIs may make clopidogrel less effective by inhibiting the enzyme that converts clopidogrel to the active form of the drug. Other reports do not suggest this effect. Proton pump inhibitors decrease stomach acid and are used to treat frequent heartburn and stomach ulcers. Clopidogrel can irritate the stomach so PPIs are commonly used with clopidogrel to help reduce this irritation.

PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. The FDA note that they have no evidence that H2 blockers, such have ranitidine, or antacids have a similar effect, and are currently conducting a review with manufacturers. in the interim they have suggested the following:

• Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.
• Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.
• Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC.

Varenicline and Bubropion: Reports of suicidality associated with use of varenicline (marketed as CHANTIX) and bupropion (marketed as ZYBAN and GENERICS)

Abacavir: Information for healthcare professionals on an abacavir (marketed as ZIAGEN, EPZICOM, and TRIZIVIR) hypersensitivity reaction, HLA-B*5701, and skin patch testing

Atomoxetine: Reports of serious liver injury associated with use of atomoxetine (marketed as STRATTERA)

Post-marketing reports of neuropsychiatric events associated with montelukast, zafirlukast and zileuton have been reported to FDA’s Adverse Event Reporting System (AERS). Most of the reports of neuropsychiatric events are associated with montelukast, currently the most commonly prescribed drug that acts through the leukotriene pathway. The clinical details of some reports involving montelukast are consistent with a drug-induced effect. Because of the paucity of reports involving zafirlukast and zileuton, assessment of a drug–induced effect with these is limited. Accordingly, at this time, patients and prescribers should monitor for the possibility of neuropsychiatric events associated with these agents.

The FDA has completed its review of the final clinical study report of ENHANCE. Following two years of treatment, carotid artery thickness increased by 0.011 mm in the Vytorin group and by 0.006 mm in the simvastatin group. The difference in the changes in carotid artery thickness between the two groups was not statistically significant. However, the levels of LDL cholesterol decreased by 56% in the Vytorin group and decreased by 39% in the simvastatin group. The difference in the reductions in LDL cholesterol between the two groups was statistically significant.

The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about Vytorin, Zetia, or the ENHANCE trial.

Genentech informed healthcare professionals of revisions to prescribing information for Rituxan regarding a case of progressive multifocal leukoencephalopathy (PML) leading to death in a patient with rheumatoid arthritis who received Rituxan in a long-term safety extension clinical study. The patient developed a JC virus infection with resultant PML and death 18 months after taking the last dose of Rituxan. Healthcare professionals treating patients with Rituxan should consider PML in any patient presenting with new onset neurologic manifestations. Additionally, consultation with a neurologist, brain MRI and lumbar puncture should be considered as clinically indicated.

The manufacturer’s letter [PDF] provides further details of the case:

The case of JC virus infection with resultant PML and death was reported in an RA patient treated with Rituxan and was diagnosed approximately 18 months after the last dose of Rituxan. This case was confounded by the patient’s development of oropharyngeal cancer, which was treated with chemotherapy (a platinum containing regimen) and radiation therapy 9 months prior to the development of PML. The patient had longstanding RA treated with immunosuppressants and a complex medical and rheumatologic history including Sjogren’s syndrome and undetectable complement C4 levels. Treatment for RA included methotrexate, steroids, and a TNF antagonist prior to Rituxan therapy; and methotrexate and steroids during and after Rituxan therapy.

The Rituxan package insert WARNING section on PML has previously noted reports of PML in patients with hematologic malignancies and autoimmune diseases for which Rituxan is not approved. It has been updated to reflect the case of PML in an RA patient treated with Rituxan and is enclosed [PDF] for your reference [See WARNINGS and PRECAUTIONS: 5.4 Progressive Multifocal Leukoencephalopathy (PML)].

FDA informed healthcare professionals that the Agency is investigating a report from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of a possible association between the use of Vytorin and a potentially increased incidence of cancer. Vytorin is a combination product of simvastatin and ezetimibe used to decrease the production of cholesterol by the liver and inhibit the absorption of cholesterol in the intestine to reduce LDL-cholesterol levels and reduce the risk of cardiovascular events. Recently, FDA obtained preliminary results from the SEAS trial. The clinical trial tested whether lowering LDL-cholesterol with Vytorin would reduce the risk of cardiovascular events in individuals with aortic stenosis. A lower overall cardiovascular risk was not found with Vytorin. However, there was an additional observation that a larger percentage of subjects treated with Vytorin were diagnosed with and died from all types of cancer combined when compared to placebo during the 5-year study.

FDA anticipates receiving a final SEAS study report in about 3 months and the Agency’s review and evaluation of the clinical trial data and other relevant information should take approximately 6 months. FDA will communicate its conclusions and recommendations at that time. Healthcare professionals and caregivers should continue to monitor patients taking Vytorin and report side effects from the use of this drug to the Agency.

The risk reported in the SEAS trial is noted here:

An adverse event attributable to cancer was noted more frequently in the ezetimibe/simvastatin arm, as compared with placebo (9.9% vs. 7.0%, p = 0.03). Cancer deaths were also more frequent in the ezetimibe/simvastatin arm (4.1% vs. 2.5%, p = 0.05). On further scrutiny, these differences did not seem to be related to any particular type of cancer and did not become significantly larger with more prolonged treatment.

There is already controversy about this news in the media, with the democratic chairman of the U.S. House of Representatives Energy and Commerce Committee getting confused by an apparent discrepancy in cancer figures. This is a red herring related to two snapshots of the trial data release from two differing sources. It should not be taken as evidence of harms being hidden, although it is a shame that calm rational discussion of the possible risk may be derailed by confusion about figures.

As the FDA notes there are two large ongoing trials (IMPROVE-IT and SHARP) being undertaken of the simvastatin/ezetimibe combination, and the full results of the SEAS study are not yet available. Interim data from IMPROVE-IT and SHARP do not show this result. Therefore some caution is required in interpretation of these preliminary results from SEAS.

The FDA are therefore not advising patients to stop or switch treatment, and nor are they suggesting there is a causal relationship between the combination and cancer. They expect to finish their review in 6 months time.

In years gones by regulators may have avoided statements related to associations that where not proven. Improvements in transparency and communications mean that regulators are attempting to be open about their decision making processes. That means sharing information about potential adverse effects – even when proof does not exist. Hopefully, the media and public will accept this for what it is, rather than being alarmed by the information provided.

Genentech, Inc. informed healthcare professionals of reports of several cases of microangiopathic hemolytic anemia (MAHA) in patients with solid tumors receiving Avastin in combination with sunitinib malate. Avastin is not approved for use in combination with sunitinib malate and this combination is not recommended. Twenty-five patients were enrolled in a Phase I dose-escalation study combining Avastin and sunitinib malate. The study consisted of 3 cohorts using a fixed dose of Avastin at 10mg/kg/IV every 2 weeks and escalating doses of sunitinib that included 25, 37.5, and 50 mg orally daily given in a 4 weeks on/ 2 weeks off schedule. Five of 12 patients at the highest sunitinib dose level exhibited laboratory findings consistent with MAHA. Two of these cases were considered severe with evidence of thrombocytopenia, anemia, reticulocytosis, reductions in serum haptoglobin, schistocytes on peripheral smear, modest increases in serum creatinine levels, and severe hypertension, reversible posterior leukoencephalopathy syndrome, and proteinuria. The findings in these two cases were reversible within three weeks upon discontinuation of both drugs without additional interventions. Healthcare professionals should report cases of MAHA or any serious adverse events suspected to be associated with the use of Avastin.

The revisions include a BOXED WARNING about infections, including serious infections leading to hospitalization or death that have been observed in patients treated with Enbrel. Infections have included bacterial sepsis and tuberculosis. The ADVERSE REACTIONS section of the label was updated to include information regarding global clinical studies and the rate of occurrence of tuberculosis in patients treated with Enbrel. Healthcare professionals should screen patients for latent tuberculosis infection before beginning Enbrel. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms of infection during and after treatment with the drug. Patients who develop an infection should be evaluated for appropriate antimicrobial treatment and, in patients who develop a serious infection, Enbrel should be discontinued.