FAQs

Many patients appear to be somewhat confused about their options with respect to the use of the oral iron chelating drug deferiprone (L1), marketed by Apotex Inc. and other companies. This confusion is becoming especially apparent to us following the Thalassemia International Foundation 9th International Conference on Thalassemia and Hemoglobinopathies in Palermo, Sicily this October.

Here is the situation with respect to deferiprone therapy in patients in the Toronto program. For further information, please contact Dr. Ian Quirt 416-946-2249 or Dr. Olivieri 416-340-4800 x6507.

We in the Program are frequently asked the following questions:

QUESTION: Is deferiprone approved for use in Canada?
Deferiprone has not been approved in Canada for the treatment and prevention of iron overload, as a first-line or as a second-line therapy. To our knowledge, less than five patients are receiving the drug in Canada.

QUESTION: Is deferiprone approved for use in the USA?
We understand that in the USA, the Food and Drug Administration has not approved deferiprone based on the need for additional studies of the drug in animals.

Most of the patients in the USA receiving the drug (less than five patients to our knowledge) are patients from one center, the Children's Hospital of Philadelphia. Dr. Alan R. Cohen, former director of the thalassemia program in Philadelphia, is an Apotex-supported investigator who may be able to provide any information requested from Canadian patients.

QUESTION: Is deferiprone approved for use in other countries?
In Europe, licensing of deferiprone has been obtained by Apotex for "the treatment of iron overload in patients with thalassemia major for whom deferoxamine therapy is contra-indicated, or who present serious toxicity with deferoxamine therapy."

In Australia, licensing of deferiprone has been obtained by Apotex for "patients who cannot tolerate desferrioxamine."

As well, representatives for Apotex have publicly stated that approval for deferiprone has also been obtained in "twenty [additional] countries". Information about these countries can be obtained from Apotex through Dr. Alan R Cohen at 215-590-1000.

QUESTION: So this means that European authorities believe deferiprone to be safe and effective in the treatment of iron overload in thalassemia?
Not necessarily. In Europe, Apotex obtained licensing of deferiprone under what is called "exceptional circumstances". This means that, to be able to sell deferiprone, Apotex testified that it was "unable to provide comprehensive data on the quality, efficacy and safety [of deferiprone] under normal conditions of use."

QUESTION: But how can a drug even be licensed if evidence of safety or efficacy isn't provided?
There are usually two reasons a company might claim to be unable to provide this information. The first reason is that the indications for the drug are so rare that (quoting from European law) the company "cannot reasonably be expected to provide evidence of safety." That cannot be the case in deferiprone and thalassemia, of course, given that thalassemia is one of the most common monogenic diseases worldwide, and given that thousands of patients have reportedly been treated with deferiprone over the past decade.

QUESTION: What is the other reason?
The second reason a company might testify that it is unable to provide this kind of information is that (again quoting from European law), "in the present state of scientific knowledge, comprehensive information cannot be provided." The lack of available "comprehensive information" is not easy to understand, because, as noted by Apotex Inc., hundreds and thousands of patients are supposed to have taken deferiprone "safely" for over a decade.

QUESTION: What about the Australian authorities?
Australia's approval states: "It will take years before we know if deferiprone safely prevents the complications of iron overload. There are no data on the use of the drug in young children. Until there is a good quality study comparing it with desferrioxamine, deferiprone should only be used in patients who cannot tolerate desferrioxamine."

QUESTION: But I know that I am able to take deferoxamine. I just don't want to. Can I, a patient in the Toronto program, be treated with deferiprone - even if the approvals in Europe and Australia state that I must be unable to tolerate deferoxamine to get deferiprone?
The answer is yes -- any patient in Canada may choose to embark on non-approved therapy. The mechanism by which this is done is called "Emergency Drug Release" or "EDR". A patient wishing to receive a drug under EDR must, under requirements from Health Canada, identify (i) a company willing to provide the drug and (ii) a physician willing to prescribe it and supervise its use. To be clear, a drug does not have to be licensed for you to be treated with this drug.

QUESTION: Is this legal?
EDR is a legal process.

As noted above, many doctors in Italy and England have prescribed deferiprone for hundreds to thousands of patients. These doctors (and the patients themselves, of course) know that the patients truly are able to take deferoxamine - just like you, they simply don't want to take deferoxamine. Just like those patients in Europe did, if you want to take deferiprone, you will need to identify a doctor willing to provide deferiprone to you even though you acknowledge that you can take deferoxamine, have no toxicity associated with deferoxamine, and are not allergic to deferoxamine. We are sure that it should not be difficult to find a physician willing to do this in Canada. Discussion with Dr. Cohen should be helpful here.

QUESTION: Will Apotex, or another company, provide deferiprone for me if I wish?
We believe that the answer to this question is yes. We maintain no contact with representatives of Apotex (outside of continued legal proceedings between Dr. Olivieri and Apotex), but this information can be confirmed from Apotex through Dr. Cohen.

QUESTION: Will I be able to find a doctor to prescribe deferiprone and supervise its use in Canada?
We believe that the answer to this question is yes. There is at least one doctor (possibly more) in Canada supervising the administration of deferiprone to at least one thalassemia patient (possibly more). Again, further information is best obtained from Dr. Cohen.

QUESTION: How many patients are taking deferiprone around the world and where are these patients?
Again, detailed information about this is best obtained from Dr. Cohen. We do know, however, that at least 1000 patients in Europe (and their doctors) claim that they require deferiprone either because "deferoxamine therapy is contra-indicated" or because they have "serious toxicity with deferoxamine therapy" - and that all of these patients are currently receiving deferiprone. Except for Dr. Cohen's patients, the use of deferiprone is uncommon in the USA or, to our knowledge, in most of Australia. In Europe, most deferiprone has been administered by the Apotex-supported investigator Dr. Antonio Piga and others, mainly in Italy and Greece, as well as in parts of London under a doctor called Beatrix Wonke. (The London Program at University College London, under Professor John Porter, does not prescribe deferiprone). We also know that many governments in the Third World, which do not wish to provide deferoxamine to their patients because of expense, are urging patients (for example, in Sri Lanka) to discontinue deferoxamine and begin treatment with (cheaper) deferiprone.

QUESTION: Will the Toronto Program continue to look after me if I decide to begin treatment with deferiprone?
Although direct management of the use of deferiprone (that is, its effects and its toxicity) has not been supervised in our program since 1997, deferiprone treatment is presently supervised in at least one other center in Canada. We are presently uncertain of the nature of the follow-up in this Canadian center or in Philadelphia (for example, we are unsure how often white cell counts, liver biopsies, liver function, heart function, and other endpoints are monitored in deferiprone-treated patients). Information about this and other aspects of management of deferiprone-treated patients can be obtained from Dr. Cohen. The Toronto program will be honored, as it is in all its patients, to continue to supervise every other aspect of your care, should you choose to take deferiprone.

QUESTION: Do you recommend deferiprone as a treatment option in the Toronto program?
No. We therefore will need to ask you to sign an "Against Medical Advice" form, which indicates that you understand that, at this time, we do not recommend the use of deferiprone in the treatment and prevention of iron overload.

QUESTION: What happens if something goes wrong while I am taking deferiprone?
Most medical management of patients in Ontario is presently compensated by OHIP. You will not need to provide your own money for any foreseeable complications that may arise out of deferiprone therapy. The Toronto program will be honored, as it is in all its patients, to participate in all aspects of your care should any complications of any treatment arise. However, we are unsure as to who or what carries liability for serious damages or death, should these occur, during administration of any non-approved drug. If you wish, we would be pleased to arrange discussion with a lawyer or a representative from Health Canada should you choose to embark on a course of deferiprone.

QUESTION: Isn't it true that deferiprone is better for the heart that deferoxamine, as claimed by a Dr. Wonke of the Whittington Hospital in London, England?
Although this document is not intended to provide the scientific background of the many controversies in the treatment of thalassemia, including those surrounding deferiprone, your individual questions can be answered by anyone in the Program at any time. Please don't hesitate to bring any issue forward for discussion, with any of us, at any time.

However, this particular question (and the one immediately below) has been asked so many times we have tried to provide a (short) answer. Keep in mind that our opinion is opposed vehemently by many Apotex-sponsored investigators, who have publicly and repeatedly stated that deferiprone should be first-line therapy for heart disease in thalassemia.

One such investigator, Dr. Beatrix Wonke, has stated publicly among other recommendations, that "We now have evidence, from our own studies, that indicate deferiprone may be more effective than subcutaneous deferoxamine at removing iron from the heart."

A press release from Apotex Inc. following release of a paper authored by a Dr. Piga (the Apotex-supported Italian investigator) and Apotex's own medical director Fernando Tricta, states that "deferiprone has a major advantage in preventing iron-induced heart disease", that "deferiprone can extend survival". and that "Apotex has submitted a patent application for the possible cardioprotective action of deferiprone."

Our answer: We are unable to locate, in the published literature, any data that supports the statement that "deferiprone is more effective than subcutaneous deferoxamine at removing iron from the heart," or that "deferiprone has a major advantage in preventing iron-induced heart disease", or that "deferiprone can extend survival."

However, we are aware of four studies in which cardiac disease has been examined during deferiprone therapy. (There may be other unpublished work, or work published without peer-review; these can be obtained through Dr. Cohen).

- Hoffbrand et al., 1998 reported death from cardiac disease in 4 patients (of 51 treated over 2-4 years).
- Tondury et al., 2001 reported death from cardiac disease in 1 patient (of 11 patients treated over 8 years).
- Ceci et al., 2002 reported death from cardiac disease in 9 patients (of 151 patients treated over 3 years); these patients (quoting from the paper) had no "serious organ dysfunction at start of deferiprone". (One might conclude therefore that these patients' hearts may actually have worsened during deferiprone -- this conclusion has been vigorously denied by some of the authors of this paper).
- Piga et al., 2003 (as announced in the Apotex press releases above). that "deferiprone has greater access to iron within the heart [than subcutaneous deferoxamine]," and "deferiprone has a major advantage in preventing iron-induced heart disease".

Can't I combine deferiprone with deferoxamine and get more iron out?

When deferoxamine and deferiprone are given together, this is called "combination therapy" or "combination treatment". Combination therapy is claimed (by Apotex Inc. and many Apotex-supported investigators) to be more effective than deferoxamine alone. To date, 32 patients have been reported (in peer-reviewed journals) to have received combination therapy. Half (16 of 32) underwent liver biopsy before, and after, combination treatment. After 6-15 months of combination treatment, 13 of the 16 (that is, more than 80%) had liver irons over 15 mg/g (the threshold for premature death). (Liver irons in the other 16 patients were either not done or not reported). We do not believe that this shows that deferiprone adds to the effectiveness of deferoxamine.