Health Canada: Status of Rosiglitazone Drugs [Avandia, Avandamet, and Avandaryl] in Canada

July 15, 2010 – In the light of recently published scientific studies and an upcoming U.S. Food and Drug Administration (FDA) Advisory Committee meeting examining the heart-related (cardiovascular) safety of the diabetes drug rosiglitazone, Health Canada is informing health care professionals and Canadians of the current status of this drug in Canada. Rosiglitazone is authorised for use in the treatment of type 2 diabetes. In Canada, three prescription drugs are currently available that contain rosiglitazone: Avandia [contains Rosiglitazone only], Avandamet [contains Rosiglitazone and Metformin], and Avandaryl [contains Rosiglitazone and Glimepiride].

Heart-related events have previously been identified and included in the Canadian Product Monographs for rosiglitazone drugs. In 2007, Health Canada conducted a review of heart-related safety information for rosiglitazone. As a result, the Canadian Product Monographs for Avandia, Avandamet and Avandaryl were updated to include important new restrictions for use. These new restrictions were communicated to the public and to health care professionals in November 2007.

It is important to note that the indications for use for rosiglitazone drugs are more restrictive in Canada than in the United States.

In Canada:

• Rosiglitazone is not approved for use alone (i.e., as a “monotherapy”), unless metformin (another diabetes drug) treatment is inappropriate.

• Rosiglitazone is not recommended for use as part of a “triple therapy” (i.e., in combination with the diabetes drugs metformin and sulfonylurea).

• Rosiglitazone is not to be used (i.e., it is contraindicated) in patients with any stage of heart failure.

Health Canada would like to remind health professionals that, when prescribing rosiglitazone, they should follow the prescribing information in the Canadian Product Monograph. In addition to the restrictions listed above, health professionals are reminded that rosiglitazone is not recommended for use with insulin. Patients with questions or concerns about Avandia, Avandamet, or Avandaryl should talk to their physician or pharmacist.

Health Canada’s review of rosiglitazone safety is ongoing. Rosiglitazone drugs have been the subject of several post-marketing studies that have continued to provide information about the risk of heart-related events. Market Authorization Holders (i.e., companies) are responsible for their marketed therapeutic health products and for continuous assessment of their benefits and risks. As the federal regulator, Health Canada is taking these studies, including their strengths and limitations, into account as we continue to monitor rosiglitazone safety.

No new conclusions or recommendations about the use of rosiglitazone in the treatment of type 2 diabetes have been made at this time. The benefits of rosiglitazone are still considered to outweigh the risks when used as directed in the Canadian Product Monographs and following the advice contained in the public and health care professional communications issued in November 2007.

Health Canada continues to review new scientific evidence as it emerges and will monitor the upcoming U.S. FDA Advisory Committee proceedings on July 13 and 14. Health Canada will take the appropriate regulatory action necessary, including informing health care professionals and Canadians as appropriate.

Product Monographs are available by search of Health Canada’s online Drug Product Database.

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Que She Herbal Supplement Has It All: Undeclared Drug Ingredients Fenfluramine, Propranolol, Sibutramine, Ephedrine

July 11, 2010 – Do the people behind such products at all know what they do?

On July 08, 2010, the FDA has issued the following warning concerning the Que She Herbal Supplement and its Undeclared Drug Ingredients:

AUDIENCE: Consumer, Pharmacy

ISSUE: FDA warned consumers and healthcare professionals that Que She, marketed as an herbal weight loss supplement, contains unlisted and active pharmaceutical ingredients that could harm consumers, especially those with cardiovascular conditions. These active pharmaceutical ingredients also may interact with other medications and result in a serious adverse event.

BACKGROUND: Que She, advertised as “Slimming Factor Capsule” and as “an all-natural blend of Chinese herbs,” has been widely distributed on Internet sites such as the Bouncing Bear Botanicals website, and at retail outlets, including Sacred Journey in Lawrence, Kansas.

FDA analysis of Que She found that it contains:

• Fenfluramine – a stimulant drug withdrawn from the U.S. market in 1997 after studies demonstrated that it caused serious heart valve damage;
• Propranolol – a prescription beta blocker drug that can pose a risk to people with bronchial asthma and certain heart conditions;
• Sibutramine – a controlled substance and prescription weight loss drug, sibutramine was the subject of a recent study whose preliminary findings showed an association between sibutramine use and increased risk of heart attack and stroke in patients who have a history of heart disease;
• Ephedrine – a stimulant drug that is legally marketed over-the-counter for temporary relief of asthma but can pose a risk to people with certain cardiovascular conditions.

RECOMMENDATIONS: People who have purchased Que She should stop taking the product immediately and consult a health care professional.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Online Reporting Program at www.fda.gov/MedWatch/report.htm. Other avenues of reporting also exist.

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When is a drug too risky to stay on the market?

July 04, 2010 – The arthritis pill Rofecoxib [Vioxx] was withdrawn from the market but menopause hormones were not, even though both were tied to heart risks. A multiple sclerosis medicine was pulled and later allowed back on. So, when is a drug too risky to stay on the market?

Drug safety questions arose again this week, as calls mount for the diabetes pill Rosiglitazone [Avandia] to be withdrawn. Surprisingly, the Food and Drug Administration has no firm rules for deciding such cases — just a murky guideline of “when the risks exceed the benefits.”

“Each drug has its own complex story,” so comparisons to previous decisions can’t be made, said Dr. Joshua Sharfstein, the FDA’s principal deputy commissioner. The agency does need better criteria for weighing drug safety, he said. It has asked a group of outside scientists, the Institute of Medicine, to give advice. A report is expected before the July 13-14 hearing on Rosiglitazone [Avandia], a controversial pill whose maker, GlaxoSmithKline PLC, insists is safe.

The actual situation is as follows; The FDA can order a drug off the market, but that can be challenged in court. Usually, a company voluntarily withdraws the medicine at the FDA’s request.

On the FDA side: How the decision is made

Many things influence whether such a request is made, said Dr. Brian Strom, a drug safety expert at the University of Pennsylvania. He is a longtime FDA drug safety adviser who has consulted for Takeda Pharmaceuticals, which makes Pioglitazone [Actos], an Rosiglitazone [Avandia] market rival.

These are some of the factors being considered:

• How serious is the illness being treated? Severe side effects are accepted for cancer drugs, for example, but not for an allergy drug such as Terfenadine [Seldane], which on rare occasions caused sudden death and was withdrawn a decade ago, Strom said.
• How big is the harm? “Causing a little nausea isn’t so bad. Killing people is,” Strom said.
• How frequent are the risks versus the benefits?

A large federal study was stopped in 2002 after researchers saw more breast cancers and heart problems among woman taking estrogen-progestin pills. Yet the absolute risk of suffering one of these problems was relatively small, and hormones remain the most effective treatment for menopause symptoms. The multiple sclerosis drug Natalizumab [Tysabri] was withdrawn because of a rare but serious side effect, then allowed to be sold again under a restricted distribution system. There are few drugs available to help people with that disease.

The central question in all these cases is: Are there safer alternatives?

This may prove to be the strongest argument for those wanting Rosiglitazone [Avandia] withdrawn. A new study this week found Pioglitazone [Actos] — the only other drug that works the way Rosiglitazone [Avandia] does — to be safer.

The trouble with Rofecoxib [Vioxx]

The popular arthritis pill  Rofecoxib [Vioxx] originally won approval because it was a more powerful and safer alternative to painkillers that cause stomach troubles. That advantage disappeared when Rofecoxib [Vioxx]’s heart risks emerged, and a drug without that problem, Pfizer Inc.’s  Celecoxib [Celebrex] was available. Merck & Co. withdrew Rofecoxib [Vioxx] in 2004.

Many see a similar situation with Rosiglitazone [Avandia] and Pioglitazone [Actos]. However, Sharfstein said one of the issues the Institute of Medicine had been asked to advise the FDA on is how to weigh comparison studies, especially if they are not gold-standard trials where similar groups of people are given one or the other pill and followed over time to see how each group fares.

“Rosiglitazone [Avandia] won’t be decided in reference to Rofecoxib [Vioxx],” Sharfstein said. “It will stand on its own.”The internal staff analyses of risks have not been released yet, and will shed more light on the situation, he added.

In Rosiglitazone [Avandia]’s case, some but not all studies have tied it to heart risks and deaths, and the bottom line may be different for various age groups. A new study this week found risks among elderly Medicare patients not seen in younger ones. Also, the drug initially won approval in 1999 because it lowered blood sugar. That’s a less clear benefit than reducing kidney problems or other diabetes complications.

Questionable approval criteria now are coming back to haunt the FDA as harmful effects emerge for drugs already in wide use, said Dr. Alastair Wood. He is a longtime Vanderbilt University professor now at a private equity firm who has led many FDA drug safety panels.

“Ten years since the drug was approved and we still don’t know if it produces the benefits that patients really want. That’s unacceptable,” he lamented. Dr. Robert Califf, a heart research leader at Duke University, agreed. “We’ve got these legacy drugs that are out there without clear evidence one way or another,” because they were approved on “soft” criteria, he said. Given that, it’s hard to see how the FDA can push Glaxo to withdraw Rosiglitazone [Avandia] now, he said. The studies on risk “are all over the place,” said Califf, who has consulted for the company.

The FDA has called the special meeting in July to hear from experts on its endocrinology and drug safety panels, which include physicians from leading hospitals and research universities. Ultimately, though, the decision whether to withdraw the drug rests with federal scientists. In 2007, the agency’s internal panel of drug safety specialists voted 8-7 to keep Rosiglitazone [Avandia] on the market. The agency’s drug safety panel, which consists of high-ranking officials from the FDA and other agencies, was set up in 2005 to resolve safety disputes, after the agency was criticized for its handling of the Rofecoxib [Vioxx] situation. It will likely include FDA drug center leadership who oversaw the initial approval and subsequent labeling of Rosiglitazone [Avandia].

In a recent case, the multiple sclerosis drug Natalizumab [Tysabri] was temporarely withdrawn from the market because of a rare but serious side effect (e.g., progressive multifocal leukoencephalopathy (PML)), then allowed to be sold again under a restricted distribution system mostly because there are few drugs available to help people with that disease, i.e. multiple sclerosis.

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