FDA Issues a Warning (Cancer Risk) for Regranex—Cream for Leg and Foot Ulcers

Warning for Regranex—Cream for Leg and Foot Ulcers

On June 6, 2008, the Food and Drug Administration (FDA) announced that a boxed warning has been added to the label of Regranex Gel 0.01% (becaplermin). The warning addresses the increased risk of cancer death in patients who use three or more tubes of the product.

Regranex is a topical cream for treating leg and foot ulcers that are not healing in patients with diabetes. A boxed warning on a drug's label calls attention to serious or life-threatening risks.

What is the basis for the revised label?

A study compared cancer incidence and cancer death among 1,622 patients exposed to Regranex to 2,809 otherwise similar patients who were not exposed to the product. Although the study showed no overall increase in cancer incidence among the patients exposed to Regranex, there was a five-fold increased risk of cancer death in the group exposed to three or more tubes of the product.

What is FDA advising in regard to Regranex?

In announcing this label change, FDA cautions health care professionals to carefully weigh the risks and benefits of treating patients with Regranex. The product is not recommended for patients with known malignancies (cancerous tumors).

FDA urges health care professionals to promptly report serious and unexpected adverse reactions associated with Regranex to FDA's MedWatch reporting program. MedWatch reports may be submitted the following ways:

• online at www.fda.gov/medwatch/report.htm
• by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
• by faxing the form to 1-800-FDA-0178
• by phone at 1-800-332-1088

Tags: fda warning, Drug Advisory, Regranex, Leg and Foot Ulcers, Cancer Risk

Varenicline (Champix) and serious psychiatric reactions

Health Canada Advisory.

Varenicline tartrate (Champix) has been marketed in Canada since April 2007 and is indicated for smoking-cessation treatment in adults in conjunction with smoking-cessation counselling. The efficacy of varenicline in smoking cessation is believed to be a result of the drug's partial agonist activity at the a4ß2 nicotinic acetylcholine receptor. By binding to these receptors, varenicline induces 2 results. First, it signals the release of dopamine and creates similar reinforcing effects, but not to the full extent that nicotine does because of its partial binding of the receptor. Second, it acts as a physical antagonist by binding to the nicotine receptor and by blocking the effects of nicotine or a nicotine-replacement agent.

Smoking cessation with or without treatment is associated with various symptoms such as depressed mood, insomnia, irritability, frustration or anger, and anxiety. From Apr. 1 to Nov. 23, 2007, Health Canada received 107 reports of adverse reactions (ARs) suspected of being associated with varenicline. Of these reports, 46 described psychiatric ARs of which 14 reported cases of aggression, depression or suicidal ideation. The remaining cases of psychiatric disorders included ARs such as amnesia, abnormal dreams, anxiety, insomnia, abnormal thinking and somnolence.

The impact of a smoking-cessation product with partial nicotinic-receptor agonist properties in patients with underlying psychiatric illness is unknown, and care should be taken with these patients.¹ Two case reports recently described the exacerbation of schizophrenia in one patient³ and a manic episode in a patient with bipolar disorder taking varenicline.

The Canadian Product Monograph for varenicline was recently revised to indicate that there have been postmarket reports of depressed mood, agitation, changes in behaviour, suicidal ideation and suicide. The product monograph states that not all patients had known pre-existing psychiatric illness and not all had completely discontinued smoking. In November 2007 and February 2008, the US Food and Drug Administration communicated safety notices one and two, concerning psychiatric ARs occurring in patients taking varenicline. Health Canada is continuing to monitor ARs suspected of being associated with varenicline. Any new safety information on results of analysis will be communicated via the MedEffect e-Notice.

Maria Longo, BScPharm; Tanja Kalajdzic, MSc; Marielle McMorran, BSc, BSc(Pharm), Health Canada.

tag: Champix, Drug Advisory, smoking-cessation counselling, varenicline, nicotine-replacement

Epilepsy Drug Carbamazepine May Increase Risk of Serious Skin Reactions In Patients of Asian Ancestry

OTTAWA - Health Canada is advising Canadians about new safety information for carbamazepine, a drug used to treat epilepsy, mania, bipolar disorder and a painful condition of the face called trigeminal neuralgia. In Canada, carbamazepine is sold under the brand name Tegretol, and multiple generic names.

Health Canada has revised the prescribing information for Tegretol, and is currently revising the prescribing information for all generic carbamazepine products to include information about an increased risk of serious skin reactions for patients of Asian ancestry, as compared to patients of non-Asian ancestry. Novartis Pharmaceuticals Canada, the manufacturer of Tegretol in Canada, has issued a letter to health care professionals to inform them of the new safety information.

Serious and sometimes fatal skin reactions known as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been known to occur very rarely with carbamazepine. While all patients treated with carbamazepine are at risk for these serious skin reactions, the risk is approximately 10 times higher in Asian countries than in Western countries. In addition, studies have suggested that patients of Asian ancestry may also be at increased risk if they take carbamazepine.

There is a genetic test that may be useful in identifying a particular genetic marker in patients of Asian ancestry. This marker has been linked to an increased risk of developing serious skin reactions to carbamazepine. Patients of Asian - particularly Han Chinese - ancestry may wish to discuss this test with their doctors as a possible screening tool to determine if they are at increased risk of serious skin reactions.

All patients taking carbamazepine - including those who have had the genetic test done, and regardless of their ethnicity - should immediately consult a physician if they develop any signs of serious skin reactions such as a rash, red skin, blistering of the lips, eyes or mouth, or peeling skin with an accompanying fever.

Patients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine.

Patients who have previously had serious skin reactions during treatment with carbamazepine, regardless of ethnicity, should not take carbamazepine again and should consult their health care professional as soon as possible so that a decision can be made regarding alternative treatments.

Patients taking carbamazepine should not stop treatment before speaking with their doctor.

The prescribing information for all generic carbamazepine-containing products is being revised to include the same new safety information for serious skin reactions that has been added to the Tegretol prescribing information. The following is a list of carbamazepine-containing products being sold in Canada. Each product may have multiple formulations, including tablets, suspension, chewtabs, or controlled release:

• Apo-carbamazepine (Apotex Incorporated)
• Bio-carbamazepine (Biomed 2002 Inc.)
• Carbamazepine (Pro Doc Limitée)
• Dom-carbamazepine (Dominion Pharmacal)
• Gen-carbamazepine (Genpharm ULC)
• Mazepine (Valeant Canada Limitée/Limited )
• Novo-carbamaz (Novopharm Limited)
• Nu-carbamazepine (Nu-Pharm Inc.)
• PHL-carbamazepine (Pharmel Inc.)
• PMS-carbamazepine (Pharmascience Inc.)
• Sandoz-carbamazepine (Sandoz Canada Incorporated)
• Taro-carbamazepine (Taro Pharmaceuticals Inc.)
• Tegretol (Novartis Pharmaceuticals Canada Inc.)

Consumers requiring more information about this advisory can contact Health Canada's public enquiries line at (613) 957-2991, or toll free at 1-866-225-0709.

To report a suspected adverse reaction to these health products, please contact the Canada Vigilance Program of Health Canada by one of the following methods:

Telephone: 1-866-234-2345
Facsimile: 1-866-678-6789

Canada Vigilance Program
Marketed Health Products Directorate
Ottawa, Ontario, AL 0701C
K1A 0K9

E-mail: CanadaVigilance@hc-sc.gc.ca

The Canada Vigilance adverse reaction reporting form, including a version that can be completed and submitted online, is located in the MedEffect area of the Health Canada Web site.

tag: Health Canada, Drug Advisory, carbamazepine, epilepsy, mania, bipolar disorder, trigeminal neuralgia, Tegretol, Novartis Pharmaceuticals Canada, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis

Drug Safety Information: Spiriva HandiHaler (Tiotropium)

[03/18/2008] Boehringer Ingelheim and FDA notified healthcare professionals that ongoing safety monitoring has identified a possible increased risk of stroke in patients who take Spiriva. This product contains tiotropium bromide and is used to treat bronchospasm associated with chronic obstructive pulmonary disease. Boehringer Ingelheim reported to the FDA that it has conducted an analysis of the safety data from 29 placebo controlled clinical studies (“pooled analysis”). Based on data from these studies, the preliminary estimate Drug Advisory, s of the risk of stroke are 8 patients per 1000 patients treated for one year with Spiriva, and 6 patients per 1000 patients treated for one year with placebo. This means that the estimated excess risk of any type of stroke due to Spiriva is 2 patients for each 1000 patients using Spiriva over a one year period.

It is important to interpret these preliminary results with caution. FDA is working with Boehringer Ingelheim to further evaluate the potential association between Spiriva and stroke. FDA has not confirmed these analyses and while pooled analyses can provide early information about potential safety issues, these analyses have inherent limitations and uncertainty that require further investigation using other data sources. Patients should not stop taking Spiriva HandiHaler before talking to their doctor, if they have questions about this new information. This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs.

[March 18, 2008 - Early Communication about an Ongoing Safety Review - FDA]
tag: FDA, Drug Advisory, Boehringer Ingelheim, Spiriva, tiotropium bromide, bronchospasm, chronic obstructive pulmonary disease,

Amylin Pharmaceuticals, Inc. Adds acute pancreatitis to the Byetta's PRECAUTIONS section of the product label.

Byetta (exenatide)

Audience: Endocrinologists, other healthcare professionals, consumers
[UPDATED 02/27/2008] Dear Healthcare Professional letter posted.

[Posted 10/16/2007] FDA has reviewed 30 postmarketing reports of acute pancreatitis in patients taking Byetta (exenatide), a drug used to treat adults with type 2 diabetes. An association between Byetta and acute pancreatitis is suspected in some of these cases. Amylin Pharmaceuticals, Inc. has agreed to include information about acute pancreatitis in the PRECAUTIONS section of the product label.

Healthcare professionals should be alert to the signs and symptoms of acute pancreatitis and instruct patients taking Byetta to seek prompt medical care if they experience unexplained, persistent, severe abdominal pain which may or may not be accompanied by vomiting. If pancreatitis is suspected, Byetta should be discontinued. If pancreatitis is confirmed, Byetta should not be restarted unless an alternative etiology is identified.

[October 16, 2007 - Information for Healthcare Professionals - FDA]
[October, 2007 - Letter - Amylin Pharmaceuticals, Inc. and Eli Lilly and Company]

tag: FDA Advisory, Drug Advisory, Byetta, acute pancreatitis, type 2 diabetes, type 2 diabetes drug Byetta,

Reports of Clinically Significant Liver Injury With Tysabri (natalizumab)

Tysabri (natalizumab)
Audience: Neurologists, other healthcare professionals, patients
[Posted 02/27/2008] Biogen Idec, Elan and FDA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of Tysabri. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Tysabri should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians should inform patients that Tysabri may cause liver injury.

February, 2008 - Letter - Biogen Idec, Elan]
[January, 2008 - Prescribing Information - Biogen Idec, Elan]

tag: FDA Alert, Drug Advisory, Tysabri, natalizumab, Biogen Idec, Elan, liver injury, serum hepatic enzymes, bilirubin,