Risk of serious fungal infections with Golimumab [Simponi]

May 31, 2009 – In a safety information to rheumatological healthcare professionals, posted May 27, 2009, FDA and Centocor Ortho Biotech remind healthcare professionals of the risk of srious fungal infections associated with Tumor Necrosis Factor – alpha (TNF-α) inhibitors, including Golimumab [Simponi].

In earlier communications, FDA has reported that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking other TNF-α inhbitors such as Certolizumab [Cimzia], Etanercept [Enbrel], Adalimumab [Humira], and Infliximab [Remicade]. This has resulted in delays in the approriate antifungal treatment of affected patients, sometimes even resulting in death. It is important that all adverse events potentially associated with Golimumab [Simponi] be reported by patients and healthcare professionals alike so that the adverse event profile reported in the prescribing information can be updated appropriately as post-approval experience is gathered.

Read the May 2009 Dear Healthcare Professional Letter sent out by Centocor here. The Prescribing Information and Medication Guide for Golimumab [Simponi] is available here. Please report any adverse event with Golimumab [Simponi] to the FDA MedWatch Program.

It should be noted here that all TNF-α inhibiting drugs mentioned herein, inclusive Golimumab [Simponi] carry in their prescribing information “Boxed Warnings” which alert to the serious riks for infections and sometimes other serious conditions (follow the links above for further details).

Gene Responsible For Acetaminophen-induced Liver Injury Identified

May 14, 2009 – Drugs containing the pharmacologically active ingredient acetaminophen are among the most commonly used over-the-counter (OTC) drugs in the United States (US).

Acetaminophen is considered safe over long-term use, but recent studies have indicated that even over a relatively short period, the maximum allowable dose can induce elevated levels of the liver enzyme ALT in blood serum in approximately one third of healthy individuals, suggesting possible liver injury. It is possible that if given high doses, many of these individuals would be susceptible to acute liver failure. There is likely to be a genetic predisposition, but finding the responsible variant genes by scanning human subjects alone may be very difficult, requiring large studies with many participants.

A team of researchers at the North Carolina State University used the help of mouse genetics in the search for candidate genes linked to acetaminophen-induced liver injury in humans.  The group used a genetically diverse population of mice to model human genetic variation, taking advantage of the known genetic differences in these strains to find genes linked to variable responses to acetaminophen treatment. Once the researchers narrowed their search to a few candidate genes in mouse, they sequenced the genetic code of the counterparts of the same genes in human patients exhibiting elevated levels of serum ALT in response to acetaminophen. They found that a single letter change (i.e. a so called single nucleotide polymorphism (SNP) to the DNA sequence in one of these candidate genes, called CD44, is significantly associated with elevated serum ALT in these patients. While the role of this gene in liver toxicity is not yet known, CD44 could serve as a potentially useful marker to identify people at risk for acetaminophen-induced liver damage.

There is still some research  to be done in order to determine the allele frequency of the CD44 T-Allele in the general population versus its abundance in patients with acetaminophen-induced liver damage (measured by elevated serum ALT-levels) as well as both the positive and the negative predictive values for the association of the CD44 T-Allele with acetaminophen-induced liver damage.

This article is adapted from materials at Cold Spring Harbor Laboratory. “Gene Responsible For Acetaminophen-induced Liver Injury Identified.” ScienceDaily 11 May 2009. 15 May 2009 <http://www.scienceddaily.com= /releases/2009/05/090504171943.htm>. See also the full journal article  reference: Harrill, A.H., Watkins, P.B., Su, S., Ross, P.K., Harbourt, D.E., Stylianou, I.M., Boorman, G.A., Russo, M.W., Sackler, R.S., Harris, S.C., Contractor, T., Wiltshire, T., Rusyn, I., and Threadgill, D.W. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res, DOI: 10.1101/gr.090241.108

See also the drug labels for  FDA-approved  drugs  and generics containing  the pharmacologically active ingredient acetaminophen at Drugs@FDA or at DailyMed.

The HLA-B*5801 Allele as a Genetic Marker in Han Chinese for Severe Cutaneous Adverse Reactions (SCAR) Caused by Allopurinol

May 12, 2009 – Drugs that contain the pharmacologically active ingredient allopurinol are commonly prescribed for the treatment of gout, hyperuricemia, and Lesch Nyhan Syndrome. They are frequently the cause of severe cutaneous adverse reactions (SCAR), which include drug hypersensitivity syndromes such as Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). So far, these adverse events are unpredictable and they carry significant morbidity and mortality.

In recent years, pharmacogenetic case-control association studies have been carried out in order to identify genetic markers for allopurinol-induced SCAR. For example, in one large study in Han Chinese which enrolled 51 patients with allopuriol-induces SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), genotyping for 823 single nucleotide polymorphisms (SNPs) in genes related to drug metabolism and immune response was performed. The HLA-B*5801 allele was present in all (100%) of the 51 patients with allopurinol-induced SCAR, but only in 20 (15%) of the 135 allopurinol-tolerant individuals, giving rise to an odds ratio of 580 at the 95% confidence interval level (CI (95%), 34 to 978), and in 19 (20%) of the 93 healthy individuals, giving rise to an odds ratio of 494 (at 95% CI, 23 to 665).

These results indicate that the HLA-B*5801 allele is an important genetic risk factor for allopurinol-induced SCAR, at least in an extended ethnic group such as the Han Chinese. In this study, the HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed and extended risk haplotype in combination with the HLA-B*5801 allele.

A strong association of the HLA-B*1502 allele with Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrosis (TEN), induced by drugs that contain the pharmacologically active ingredient carbamazepine, or by drugs that contain the pharmacologically active ingredients phenytoin or fosphenytoin, has previously been recognized. Moreover, cutaneous hypersensitivity reactions to HIV-combating drugs that contain the active ingredient abacavir, are strongly associated with the HLA-B*5701 allele. Taken together, these data suggest that HLA-B alleles and/or other genetic polymorphisms in the MHC region might play a major role in the pathogenesis of immune-mediated drug-induced SCAR. A specific HLA-B molecule may function as antigenic presentation of certain drugs or their metabolites for HLA-restricted T cell activation.

It is interesting to note that the HLA-B*1502 allele and the HLA-B*5701 allele occur at high frequency in populations of Asian ancestry as does the HLA-B*5801 allele in Han Chinese. This puts patients belonging to these ethnic groups at high risk for the development of SJS and/or TEN when exposed to drugs containing the pharmacologically active ingredients allopurinol, carbamazepine, phenytoin, fosphenytoin, and abacavir. In fact, the American Food and Drug Administration (FDA) recommends that patients be genotyped for the HLA-B*1502 and the HLA-B*5701 allele, respectively, before therapies with carbamazepine and abacavir are initiated, and that carriers of these alleles should not be started on these drug unless the expected benefit clearly outweighs the risks.

A similar recommendation by the FDA for testing for the HLA-B*5801 allele before initiation of therapies with allopurinol-containing drugs has not yet been added to the labels of the according drugs. Nevertheless, it might be wise to discuss with your treating physician the testing for the HLA-B*5801 allele before starting a therapy on allopurinol if you are a patient of Han Chinese ancestry .

In the US, allopurinol-containg drugs are on the market as Allopurinol, Aloprim, Lopurin, and Zyloprim. Please find the newest drug labels for drugs containing allopurinol, carbamazepine, phenytoin, fosphenytoin, or abacavir at Drugs@FDA. Also, read more on the HLA-B*5801 allele.

Erlotinib [Tarceva] Updated Warnings and Precautions

May 08, 2009 – Erlotinib [Tarceva] monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. In combination with Gemcitabine [Gemzar], Tarceva is also indicated for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.

OSI, Genentech and FDA today notified healthcare professionals of new safety information added to the “Warnings” and “Precautions”  sections of the prescribing information for Tarceva. Gastrointestinal perforation (including fatalities), bullous, blistering and exfoliative skin conditions including cases suggestive of Stevens-Johnson Syndrome (SJS) and/or Toxic Epidermal Necrolysis (TEN), in some cases fatal, and ocular disorders, including corneal perforation or ulceration have been reported during use of Tarceva. The new safety information comes from routine pharmacovigilance activities of clinical study and postmarketing reports.

Please read the Dear Health Care Professional Letter and the announcement by FDA. Read also the current drug label information on Erlotinib [Tarceva] and Gemcitabine [Gemzar].

Antiepileptic Drugs: FDA updated labeling to warn about increased risk of suicidal thoughts and behaviors

May 06, 2009 – From its newest safety alert dated May 05, 2009, we learn that the Food and Drug Administration (FDA) has now approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes) and notified healthcare professionals accordingly.

FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.

From the earlier safety alert posted January 01, 2008, we understand that in FDA’s analysis of reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies, patients receiving these drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

The drugs (some of which are available in generic form also) included in  the present analysis were the following: Carbamazepine [Carbatrol, Equetro, Tegretol, Tegretol XR], Felbamate [Felbatol], Gabapentin [Neurontin], Lamotrigine [Lamictal], Levetiracetam [Keppra], Oxcarbazepine [Trileptal], Pregabalin [Lyrica], Tiagabine [Gabitril], Topiramate [Topamax], Valproate [Depakote, Depakote ER, Depakene, Depacon], and Zonisamide [Zonegran].

FDA expects that the increased risk of suicidality is shared, besides by the eleven drugs listed above, by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

Read the original safety alert here. More information can be found at the FDA Drug Information Page and the Healthcare Professional Information Sheet.

FDA, FTC Warn Public of Fraudulent 2009 H1N1 Influenza Products

May 03, 2009 – The two antiviral drugs approved by the FDA for treatment and prophylaxis of the 2009 H1N1 influenza virus are Oseltamivir [Tamiflu] and Zanamivir [Relenza].  Tamiflu and Relenza, in addition to their approved labeling, have Emergency Use Authorizations that describe specific authorized uses during this public health emergency.

However, the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC) are urgently alerting the public to be wary of Internet sites and other promotions for products that claim to diagnose, prevent, mitigate, treat or cure the 2009 H1N1 influenza virus.  The agencies are also advising operators of offending web sites that they must take prompt action to correct and/or remove promotions of these fraudulent products or face enforcement action.

“Consumers who purchase products to treat the novel 2009 H1N1 virus that are not approved, cleared or authorized by the FDA for the treatment or prevention of influenza risk their health and the health of their families,” said Michael Chappell, acting FDA Associate Commissioner for Regulatory Affairs. “In conjunction with the Federal Trade Commission, the FDA has developed an aggressive strategy to identify, investigate, and take regulatory or criminal action against individuals or businesses that wrongfully promote purported 2009 H1N1 influenza products in an attempt to take advantage of the current flu public health emergency.”

Products that are offered for sale to the public with claims to diagnose, prevent, mitigate, treat, or cure infections caused by the H1N1 influenza virus that have not  been proven to be safe and effective for these uses must be carefully evaluated. Many of these deceptive products are being sold over the Internet via illegitimate web sites. The operators of these web sites take advantage of the public’s concerns about H1N1 influenza and their desire to protect themselves and their families.  These fraudulent products come in all varieties and could include dietary supplements or other food products, or products purporting to be drugs, devices or vaccines.  Such fraudulent products will not prevent the transmission of the virus or offer effective treatments against infections caused by the H1N1 influenza virus.

More information about FDA-approved antiviral drugs for influenza is available here. More information on CDC recommendations regarding use of antiviral drugs against the current novel 2009 H1N1 influenza is available here. Consumers should also visit FDA’s web site for tips about how to protect themselves when buying medicines online.

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Tardive Dyskinesia: FDA requires Boxed Warning for Metoclopramide-Containing Drugs

May 02, 2009 – FDA is requiring that manufacturers of metoclopramide add a boxed warning to the label about the risk of tardive dyskinesia if the drug is used for long periods of time or at high doses. Metoclopramide stimulates motility in the upper GI tract and its uses include diabetic gastroparesis and gastroesophageal reflux disease.

Metoclopramide is marketed as a generic and under several trade names, including Reglan (see graphic to the left, generated from within ThassoBase).

Tardive dyskinesia is characterized by involuntary, repetitive movements of the extremities, as well as grimacing, rapid blinking and impaired movement of the fingers. The risk of tardive dyskinesia associated with metoclopramide is increased among long-term users of the drug, and also among elderly patients, especially women. There is no known treatment, and the symptoms, which are rarely reversible, may persist even after the metoclopramide is discontinued. However, in some patients, the symptoms may lessen or resolve when the drug is stopped.

FDA’s advice to practitioners is to avoid the chronic use of metoclopramide except in rare cases where they believe the benefit outweighs the risk. FDA is requiring manufacturers of the drug to develop a medication guide explaining the risks, which will be provided to patients with each prescription.

Please read the current announcement by the FDA here. Additional information  in an earlier announcement may be found here. A status overview  on metoclopramide-containing drug products can be found at Drugs@FDA and latest drug label information is accesible at DailyMed. Overview information on Tardive Dyskinesia is available here.

FDA urges consumers to stop using Hydroxycut products because of the danger of serious liver injuries

May 01, 2009 – FDA warned consumers to immediately stop using Hydroxycut products by Iovate Health Sciences, Inc. Hydroxycut products are associated with a number of serious liver injuries. Hydroxycut products are dietary supplements that are marketed for weight-loss, as fat burners, as energy-enhancers, as low carb diet aids, and for water loss under the Iovate and MuscleTech brand names.

FDA has received 23 reports of serious health problems ranging from jaundice and elevated liver enzymes, an indicator of potential liver injury, to liver damage requiring liver transplant. One death due to liver failure has been reported to FDA. Other health problems reported include seizures; cardiovascular disorders; and rhabdomyolysis, a type of muscle damage that can lead to other serious health problems such as kidney failure. The agency has not yet determined which ingredients, dosages, or other health-related factors may be associated with risks related to these Hydroxycut products. The FDA continues to investigate the potential relationship between Hydroxycut dietary supplements and liver injury or other potentially serious side effects.

Read the complete MedWatch Safety summary including links to the FDA news release, Q&A’s and a listing of all products included in this alert here.

FDA Requires Boxed Warning for All Botulinum Toxin Products

April 30, 2009 – Prompted by reports of serious adverse events, the U.S. Food and Drug Administration today announced that safety label changes, including a boxed warning, and a Risk Evaluation and Mitigation Strategy (REMS), are necessary for all botulinum toxin products.

The agency said it took the action because of reports that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism, including unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids. These symptoms have mostly been reported in children with cerebral palsy being treated with the products for muscle spasticity, an unapproved use of the drugs. Symptoms have also been reported in adults treated both for approved and unapproved uses.

The agency also took the action because of the potential for serious risks associated with the lack of interchangeability among the three licensed botulinum toxin products.

“Updated labels for this class of products will help health care professionals and patients better understand the risks and benefits,” said Russell Katz, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Botulinum toxin products have benefits but can cause serious health problems and it is important that anyone who administers or uses these products understands these

The products required to add the new label and a REMS include Botox and Botox Cosmetic (botulinum toxin type A), marketed by Allergan; Myobloc (botulinum toxin type B), marketed by Solstice Neurosciences; and a new FDA-approved product, Dysport (abobotulinum toxin A), marketed by Ipsen Biopharm Ltd.

Botox, Myobloc, and Dysport are approved by the FDA for the treatment of a condition marked by repetitive contraction of the neck muscles (cervical dystonia). Botox Cosmetic and Dysport are approved by the FDA for dermatologic use in the temporary improvement in the appearance of frown lines between the eyebrows called glabellar lines. In addition, Botox is approved for the treatment of severe underarm sweating (primary axillary hyperhidrosis), crossed eyes (strabismus), and abnormal tics and twitches of the eyelids (blepharospasm).

Read the full announcement here.