Boxed Warning Updated: TNF Blockers and Cancer Risks in Children

November 3, 2009 – As we learn from it’s todays announcement, FDA is requiring stronger warnings about an increased risk of lymphoma and other cancers in children and adolescents who are treated with drugs that block tumor necrosis factor. TNF blockers include Infliximab [Remicade], Etanercept [Enbrel], Adalizumab [Humira], Certolizumab [Cimzia], and Golimumab [Simponi]. These drugs are used to treat juvenile rheumatoid arthritis, Crohn’s disease, and other inflammatory diseases.

The warnings, which include an updated boxed warning, are based on an FDA analysis of reports of cancer that occurred in children and adolescents treated with TNF-blockers. The cancers, some of which were fatal, occurred after an average of 30 months of treatment. About half of the cancers were lymphomas. The labeling will also include updated information on cases of leukemia and new onset psoriasis associated with TNF-blockers.

Healthcare professionals should monitor patients for development of malignancies during and after treatment with TNF blockers. They should also talk to patients and their families about this risk and tell them to report signs and symptoms of cancer such as unexplained weight loss or fatigue, easy bruising or bleeding, or swollen lymph nodes in the neck, underarms or groin.

Patients should also be monitored for signs or symptoms of new onset psoriasis or worsening psoriasis. The patient Medication Guide will be updated with this new information.

Additional Information: FDA MedWatch Safety Alert. Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). August 4, 2009.

Considerable stroke risk linked to anemia drug; Darbepoetin-α [Aranesp] nearly doubled risk in people with diabetes

November 1, 2009 – A new study raises fresh safety concerns about widely used anemia medicines, finding that the drug Darbepoetin-α [Aranesp] nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis. The study is the largest ever of these blood-boosting drugs and the only one that compared them to a dummy treatment. The medicines have become blockbuster sellers because they lessen the need for transfusions, but their ability to prevent heart attacks, kidney failure or other problems have not been proven.

Over the last two years, the federal Food and Drug Administration has repeatedly strengthened warning labels not only on Darbepoetin-α [Aranesp] , but on the similar drug products Epoetin-α [Epogen] and Epoetin-α [Procrit] as concerns rose that they may worsen survival in certain cancer patients, especially at higher doses.

The new study tested Darbepoetin-α [Aranesp] in a different group of patients: 4,038 people with Type 2 diabetes, kidney problems and moderate anemia  problems that often go hand in hand. The goal was to see if the drug could prevent heart attacks, heart failure, strokes or the need for dialysis. The leader of the study, Dr. M. Pfeffer, noted that the study did not only fail to do that, but a susbstantial  hightened risk for stroke was uncovered.  Strokes occurred in 101 patients given Aranesp and 53 patients given dummy shots. Looked at another way, the risk of suffering a stroke was about 1 percent per year in the placebo group and about 2 percent in those given Aranesp. Results were published online Friday by the New England Journal of Medicine (NEJM). For many patients, this risk will outweigh its potential benefits, the study’s authors concluded.

On a positive note, in the present study, Darbepoetin-α [Aranesp] did reduce the need for transfusions;  297 people on the drug needed them versus 496 of those getting dummy shots. However, there was only a modest improvement in how fatigued people said they felt in the Aranesp group.

For your convenience, you find the abstract of the study be Pfeffer M.A., et al., published at www.nejm.org October 30, 2009 (10.1056/NEJMoa0907845). Please read the full study result at the link provided.

ABSTRACT
Background Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.

Methods In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.

Results Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.

Conclusions The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015 [ClinicalTrials.gov] .)

Schizophrenia drugs in kids cause weight gain

October 30, 2009 – Schizophrenia drugs, increasingly prescribed to children with bipolar disorder and other conditions, can cause youngsters to experience rapid weight gain, according to a new study. Thus, children and adolescents who take the drugs, known as atypical antipsychotics, gain an average of 10 to 19 pounds in the first few months, depending on which drug they are prescribed. The findings were published this week in the Journal of the American Medical Association (JAMA).

Use of atypical antipsychotics in children has increased fivefold since the early 1990s. Prescriptions for one of these drugs, Risperidone [Risperdal], were up 10 percent in 2007. That year, 389,000 children and teens nationwide were prescribed the drug, and 240,000 of those were 12 or younger, according to information presented to a U.S. Food and Drug Administration (FDA) panel in 2008.

At the same time, more children are being diagnosed with bipolar disorder than in the past. Although experts agree that the medications can help some young patients (for example, bipolar children who have severe manic episodes or autistic kids who endanger themselves and others with violent behavior), many question their widespread use for other conditions, such as attention deficit hyperactivity disorder (ADHD).

The new findings suggest that these medications could have lasting consequences for young patients, in the form of weight problems (including obesity), heart disease, and diabetes. Families already under the stress of coping with a young one’s mental illness may have a particularly hard time helping their child maintain a healthy weight.

Experts have long known that atypical antipsychotics can cause patients to gain weight. But the current study is the first, and one of the largest, to investigate how these drugs affect children who haven’t used the medications previously. Researchers looked at 205 children and teens with mood disorders, schizophrenic illness, or disruptive or aggressive behavior disorders. Fifteen children who refused medication or stopped taking it acted as a control group. The children ranged in age from 4 to 19, with an average age of about 14 years. Children who took Olanzapine [Zyprexa] gained the most weight in the first 11 weeks, an average of 18.7 pounds, and also had higher total cholesterol and triglyceride levels. Those taking Quetiapine [Seroquel] gained 13.4 pounds and also had a rise in total cholesterol and triglycerides. Risperidone [Risperdal] didn’t seem to affect cholesterol levels but was associated with higher triglyceride levels, and patients gained an average of 11.7 pounds. At 9.7 pounds, weight gain was lowest with Aripiprazole [Abilify]. Overall, half of the children gained more than 7 percent of their original body weight. Children in the control group gained less than half a pound.

At present, the FDA has approved only two drugs, Risperidone [Risperdal] and Aripiprazole [Abilify], for use in children; both are approved to treat schizophrenia and bipolar disorder, and Risperidone [Risperdal] is also approved for “irritability associated with autistic disorder.”

One should point out here that most of the clinical research performed to back up the use of atypical antipsychotics in children has actually been done in adults, and the makers of the drugs have funded much of it. The present study wasn’t funded by the pharmaceutical industry, but its authors report consulting for many drug companies, including the makers of the drugs they looked at in the current study, namely AstraZeneca for Quetiapine [Seroquel], Bristol-Myers Squibb for Aripiprazole [Abilify], Eli Lilly for Olanzapine [Zyprexa], and Ortho-McNeil-Janssen for Risperdone [Risperdal]. In recent years, there has  been a broadening of the use of atypical antipsychotics in children. For example, they are sometimes added on to other medications, or used to treat children with impulse control problems or oppositional behavior who could probably benefit from therapy or behavior management strategies.

Doctors should carefully decide to prescribe these medications, and must absolutely be convinced their patients need them, especially since patients may be on the medication for months or even years, resulting in major weight gain that could quickly lead to obesity and the health problems that accompany it. Atypical antipsychotics are sometimes the only thing that can help autistic children with severe aggression, and that the medications are also very helpful for bipolar children with severe mania who aren’t helped by mood-stabilizing drugs like lithium.

Although their use remains controversial, especially for treating autistic children’s aggressive behavior and outbursts, based on the idea that therapy and other approaches should be tried first, it seems that therapy sometimes isn’t possible for these children until they are medicated. What the findings make clear, however, is that families need to be informed of the risk of weight gain, and that children should be prescribed the lowest-risk atypical antipsychotics first. These medications are definitively not created equal when it comes to side effects, particularly for inducing weight gains. Accordingly, doctors should monitor patients closely for weight gain, and work with their families to help them “really focus on a healthy lifestyle” before the child has gained weight.

Sperm donor passed on sudden death heart defect

October 24, 2009 – Sperm donation is an increasingly common practice for achieving pregnancy in the absence of a male partner or when fertility is problematic. The unintended consequence in which genetic diseases are unwittingly transmitted to offspring is an underrecognized public health issue not previously prioritized by US Food and Drug Administration guidelines.

An asymptomatic 23-years old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases, repeatedly donated sperm over a 2-year period (1990-1991). The donor was later shown to be affected (in 2005) by a novel β-myosin heavy-chain mutation that caused hypertrophic cardiomyopathy (HCM), after an offspring was clinically diagnosed with this disease.

Of the 24 children known to be offsprings of the donor, including 22 children who were products of fertilization via sperm donation and 2 children conceived by the donor’s wife, a total of 9 genetically affected children, age 2 to 16 years (6 of them being male), have been identified with HCM.  Three of the 9 gene-positive children have currently expressed phenotypic manifestions of HCM, including one child who died at the age of 2 years due to progressive and unrelenting heart failure with marked hypertrophy, and also 2 survivors with extreme left ventricular hypertrophy at the age of 15 years. The latter two children and the donor are judged likely to be at increased risk for sudden death.

This case series underscore the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases (e.g., HCM) such as consideration for 12-lead electrocardiograms.

Hypertrophic cardiomyopathy (HCM) thickens the heart and makes it harder to pump blood. It affects about one in 500 people; many more likely have the genetic defect without symptoms, Symptoms can include an irregular heartbeat and shortness of breath but many cases go undetected until sudden death. The condition is often the culprit when young athletes collapse and die suddenly. Treatment includes medication and an implanted defibrillator to prevent sudden death.

Neither the sperm bank nor the donor were identified. The donor, now 42, had no symptoms of genetic heart disease and no obvious family history when he donated sperm in the early 1990s. His own condition wasn’t diagnosed until after a child born through sperm donation was diagnosed. Maron declined to provide more details on the donor’s health, citing privacy concerns.

Access the full study report at JAMA, the Journal of the American Medical Association.

Rituximab [Rituxan] – Progressive Multifocal Leukoencephalopathy [PML]

October 23, 2009 – Today, Genentech and FDA notified healthcare professionals about a third case of progressive multifocal leukoencephalopathy [PML], the first case of PML in a patient with rheumatoid arthritis [RA] treated with Rituximab [Rituxan] who has not previously received treatment with a TNF antagonist. Information to date suggests that patients with RA who receive Rituximab [Rituxan] have an increased risk of PML.

Physicians should consider PML in any patient being treated with Rituximab [Rituxan] who presents with new onset neurologic manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated.

Please read the full text of the- Dear Healthcare Professional Letter sent out by Genentech. Please read also carefully the drug labeling document of Rituximab [Rituxan].

Bristol-Myers gets approval for its diabetes drug Saxagliptin [Onglyza] in the European Union (EU)

October 14, 2009 – On October 5, 2009, drug maker Bristol-Myers Squibb Co. announced that its new diabetes drug, Saxagliptin [Onglyza], has been approved for sale in the European Union’s (EU) 27 countries.

Saxagliptin [Onglyza] is the first diabetes drug to be launched in Europe by a partnership of New York-based Bristol-Myers and British drugmaker AstraZeneca PLC to develop drugs for type 2 diabetes. It was approved for use with three other standard diabetes drugs, based on six late-stage studies including more than 4,100 patients. Saxagliptin [Onglyza] and Merck & Co.’s Sitagliptin [Januvia] both are in a newer class of diabetes medicines called DPP-4 inhibitors. They work by increasing insulin production and lowering the production of glucose

Saxagliptin [Onglyza] will compete with Merck & Co.’s blockbuster diabetes drug Sitagliptin [Januvia] both in the EU and in the United States, where the Bristol Myers drug was approved on July 31, 2009. Whitehouse Station, N.J.-based Merck’s Sitagliptin [Januvia] and a related drug called Janumet, which includes metformin, constitute Merck’s fastest-growing product line, third in overall sales with a total of $1.75 billion in revenue last year. Saxagliptin [Onglyza] is to be launched in the European Union by year’s end; it’s already on sale in the U.S. Analysts have forecast that Saxagliptin [Onglyza] sales could hit as high as $1 billion a year, given the alarming increase in the number of people in developed countries with diabetes. The U.S. market for diabetes medicines alone already exceeds $5 billion annually.

Meanwhile, Bristol and AstraZeneca are in late-stage testing of another potential diabetes drug, dapagliflozin, that works by helping the kidneys eliminate excess glucose. Saxagliptin [Onglyza] was approved to be used with metformin or another drug from one of two different classes that are often prescribed, along with diet and exercise, when patients are first diagnosed with type 2 diabetes. People with the disorder, most often caused by obesity and inadequate exercise, do not use the insulin made by their body efficiently and may eventually need injected insulin as well as pills to control the disease.

Also Monday, Bristol and AstraZeneca released results of a new study showing that Saxagliptin [Onglyza] with metformin works roughly the same as Sitagliptin [Januvia] with metformin, reducing a key measure of long-term blood sugar level by 0.52 percent, compared with a 0.62 percent reduction for the patients in the Januvia group.

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FDA: Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2009

October 9, 2009 -  The American Food and Drug Administration (FDA) has just published the list below with the names of drug products and potential signals of serious risks/new safety information that were identified for these products during the period January – March 2009 in the AERS database. The appearance of a drug on this list does not mean that FDA has concluded that the drug has the listed risk. It means that FDA has identified a potential safety issue, but does not mean that FDA has identified a causal relationship between the drug and the listed risk. If after further evaluation the FDA determines that the drug is associated with the risk, it may take a variety of actions including requiring changes to the labeling of the drug, requiring development of a Risk Evaluation and Mitigation Strategy (REMS), or gathering additional data to better characterize the risk.

FDA wants to emphasize that the listing of a drug and a potential safety issue on this Web site does not mean that FDA is suggesting prescribers should not prescribe the drug or that patients taking the drug should stop taking the medication. Patients who have questions about their use of the identified drug should contact their health care provider. FDA will complete its evaluation of each potential signal/new safety information and issue additional public communications as appropriate.

Please find here the list of drugs, i.e. Active Ingredient [Brand Name] with potential signals of serious risks/new safety information Identified from the Adverse Event Reporting System (AERS) between January – March 2009, along with some additional comments for each drug listed.

Ceftriaxone [Rocephin] – Hemolytic Anemia
Hemolytic anemia was added to the Warnings section of labeling in June 2009.

Diclofenac Epolamine Patch [Flector] – Hypersensitivity Reactions
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Didanosine [Videx] – Portal Hypertension
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Entacapone [Comtan] – Colitis
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Gadolinium-based Contrast Agents – Anaphylaxis
FDA is evaluating this issue to determine if labeling for the various gadolinium-based contrast agents, which include descriptions of hypersensitivity reactions, are adequate.

Alpha-Interferon Products – Pulmonary Hypertension
Pulmonary hypertension was added to the Warnings section of labeling for all alpha interferon products.  See September 2009 FDA announcement: New Class Safety Labeling Updates for Alpha-Interferon Products.

Mecasermin [Increlex, Iplex] – Hypersensitivity Reactions
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Methylnaltrexone [Relistor] – Gastrointestinal Perforation
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Minocycline [Solodyn] – Autoimmune Disorders in Pediatric Patients
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Promethazine Injection – Severe Tissue Injury including Gangrene
In September 2009 FDA informed manufacturers of promethazine injection to include a Boxed Warning in the labeling to highlight the risk of serious tissue injury when this drug is administered incorrectly. FDA Requires Boxed Warning for Promethazine Hydrochloride Injection.

Sunitinib [Sutent] – Liver Failure
FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Tenofovir [Viread] -  Safety during Pregnancy
FDA decided that no action is necessary at this time based on available information. FDA is continuing to monitor the issue.

Zoledronic Acid [Reclast] – Renal Impairment
Renal impairment was added to the Warnings and Precautions section of labeling in March 20o9.

EPA reviews the health impact of the weed killer atrazine

October 9, 2009  -  The American Environmental Protection Agency (EPA)  announced on Wednesday that it is reviewing the health impacts of  the herbicide atrazine, a widely used weed killer that recent studies have tied to birth defects, low birth weight and premature babies.

The EPA said it is reviewing the risks of the herbicide and whether new restrictions are necessary to better protect public health. As part of the study, the EPA said it will use data produced since 2003 and the agency will seek input from an independent panel.

“Our examination of atrazine will be based on transparency and sound science, including independent scientific peer review, and will help determine whether a change in EPA’s regulatory position on this pesticide is appropriate,” said Steve Owens, assistant administrator for EPA’s Office of Prevention, Pesticides and Toxic Substances.

Atrazine is used to control broadleaf and grassy weeds and is primarily used on corn, sorghum, and sugarcane. It is used mostly in the Midwest. The concern is that the chemical can contaminate the water supply and can cause health problems even at low levels.

Syngenta AG of Switzerland, a manufacturer of atrazine, has long defended its safety. The firm has said it is one of the best studied herbicides available and pointed to prior safety reviews from the EPA and World Health Organization, among others.

Natalizumab [Tysabri]: The Progressive Multifocal Leukoencephalopathy (PML) Saga Continues

September 22, 2009 – From a MedWatch Alert, we learn that the American Food and Drug Administration (FDA) continues to receive reports of progressive multifocal leukoencephalopathy (PML) in patients receiving Natalizumab [Tysabri].  Natalizumab [Tysabri] was approved by the FDA for the treatment of relapsing forms of multiple sclerosis (MS) in November 2004 and for moderately to severely active Crohn’s disease in January 2008.  From July 2006, (when Natalizumab [Tysabri] marketing resumed) to September 8, 2009, 13 reported cases of Natalizumab [Tysabri]-related PML were confirmed worldwide in patients being treated for MS with Natalizumab [Tysabri] monotherapy. There have been no postmarketing reports of PML in patients treated with Natalizumab [Tysabri] for Crohn’s disease. Less than 2% of Natalizumab [Tysabri] use in the United Staates 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 for developing PML appears to increase with the number of Natalizumab [Tysabri] infusions received. At this time, the FDA is not requiring changes regarding PML to the Natalizumab [Tysabri] prescribing information or to the Natalizumab [Tysabri] management plan, called the TOUCH Prescribing Program.

Healthcare Professionals can find more information here.

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FDA Clears a Test for Ovarian Cancer: Test can help identify potential malignancies, guide surgical decisions

September 11, 2009 – Please find here the text (in italics) of a press release by the FDA on the newly approved OVA1 diagnostic test. This test may well add to the options physicians have today in treating patients based on the  individual status of their diseases (i.e., within the framework of personalized medicine).

The U.S. Food and Drug Administration today cleared a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test, called OVA1, helps patients and health care professionals decide what type of surgery should be done and by whom.

OVA1 identifies some women who will benefit from referral to a gynecological oncologist for their surgery, despite negative results from other clinical and radiographic tests for ovarian cancer. If other test results suggest cancer, referral to an oncologist is appropriate even with a negative OVA1 result.

OVA1 should be used by primary care physicians or gynecologists as an adjunctive test to complement, not replace, other diagnostic and clinical procedures.

OVA1 uses a blood sample to test for levels of five proteins that change due to ovarian cancer. The test combines the five separate results into a single numerical score between 0 and 10 to indicate the likelihood that the pelvic mass is benign or malignant.

OVA1 is intended only for women, 18 years and older, who are already selected for surgery because of their pelvic mass. It is not intended for ovarian cancer screening or for a definitive diagnosis of ovarian cancer. Interpreting the test result requires knowledge of whether the woman is pre- or post-menopausal.

The American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncologists published recommendations in 2002 for the role of generalist obstetrician-gynecologists in the early detection of ovarian cancer, which included a recommendation of patient referral to a gynecological oncologist when specific indicators of malignancy are present.

These recommendations and later reports indicate that patients with ovarian cancer have improved survival when the surgery is performed by gynecologic oncologists as opposed to general gynecologists or surgeons.

“Tests such as OVA1 personalize and improve public health by providing patients and health care providers with more information to support medical decisions that impact survival rates and reduce surgical complications,” said Jeffrey Shuren, M.D., J.D., acting director of the FDA’s Center for Devices and Radiological Health.

The FDA reviewed a study of 516 patients, including 269 evaluated by non-gynecological oncologists, which compared OVA1 results with biopsy results. When combined with pre-surgical information, such as radiography and other laboratory tests, results from the OVA1 tests identified additional patients who might benefit from oncology referral who were not identified using pre-surgical information alone.

OVA1 is developed by Vermillion Inc., headquartered in Fremont, Calif., in conjunction with researchers at The Johns Hopkins University in Baltimore.