Healthcare Professional Common Questions

Does Ferriprox® confer any cardioprotective benefits?
Results from clinical studies that assessed myocardial iron content and cardiac function in patients treated with Ferriprox or DFO (deferoxamine) show that Ferriprox was more effective in removing excess cardiac iron and improving cardiac function, and that its use is associated with a lower incidence of iron-induced cardiac disease.(Piga A, et al, 2003) (Anderson, 2001 & 2002)(Pennell,2006); (Peng 2003)(Borgna-Pignatti, 2006)

The greater efficacy of deferiprone versus deferoxamine in removing excess cardiac iron is most likely related to the compound’s molecular size, lack of charge, and partition characteristics, which favour penetration of cellular and subcellular membranes. (Kontoghiorghes, 1988)

The most relevant studies on the morbidity and survival of patients with thalassemia major have been published by a group of investigators from seven of the major thalassemia treatment centres in Italy by conducting natural history studies on the survival of thalassemia patients over the past 25 years. They have documented the marked decrease in mortality and morbidity in patients with thalassemia major since the early 1980s following the introduction of chelation therapy with deferoxamine in the 1970s. They have also documented that cardiac disease continued to occur and remained the most common cause of death in these patients.

In their latest study (Borgna-Pignatti, 2006), they compared the occurrence of cardiac disease and of survival of thalassemia patients treated with either deferiprone or deferoxamine. Similar to their previous studies, the authors evaluated all patients followed at their centres who had been diagnosed with transfusion-dependent thalassemia before the age of 3 years. For this particular study, they included only those patients born after 1970, to ensure they evaluated only those patients who had had an opportunity to receive what was considered appropriate therapy with deferoxamine. They evaluated the occurrence of cardiac disease and deaths after January 31, 1995, which is when deferiprone became available to a significant number of thalassemia patients in Italy. To avoid potential bias, they excluded from the analysis all patients who had had a cardiac event prior to that date. During the nine-year period of this study, 52 subject developed cardiac disease. All of them were receiving treatment with deferoxamine. No patient treated with deferiprone developed cardiac disease. In order to estimate the significance of the difference in the occurrence in cardiac disease between the two therapies, the authors artificially created one cardiac event in a deferiprone patient. With the addition of this artificial case, the hazard ratio for deferiprone compared with deferoxamine was 0.09 (CI 0.012, 0.66; p = 0.017).

Can Ferriprox® cause Yersinia enterocolitica infection?
Unlike deferoxamine, which is a microbial siderophore that can be used by Yersinia enterocolitica for the acquisition of iron, deferiprone is a synthetic iron chelator with a structure markedly different from that of microbial siderophores. It has been demonstrated that deferiprone is unable to promote growth of Yersinia enterocolitica in vitro, even after prolonged contact (48 h), or when concentrations of the drug as high as 150 µM are used (Lesic, 2002). Furthermore, in contrast to deferoxamine, deferiprone does not have the potential to promote Yersinia enterocolitica septicemia, as shown in the mouse experimental model of infection (Lesic, 2002). Consistent with the in vitro and animal studies, rare reports of Yersinia infections have been identified in patients undergoing chelation therapy with Ferriprox®.

Does Ferriprox® exacerbate hepatic fibrosis?
In 1998, an article by Olivieri et al. was published implying that deferiprone exacerbated liver fibrosis in thalassaemia patients. An independent and objective review on the same randomized and blinded histology slides did not find an exacerbation of liver fibrosis by deferiprone (Callea, 1998).

Studies by Piga et al., Hoffbrand et al., Tondury et al., Berdoukas et al, Peng et al, and Maggio et al. which studied sequential liver biopsies in patients with thalassaemia major who have been regularly transfused with deferiprone or deferoxamine, indicated that therapy with deferiprone does not exacerbate liver fibrosis in thalassaemia patients. The increase in fibrosis score observed in some patients in either treatment group was most likely related to hepatitis C infection (which can, itself, cause fibrosis) and/or high concentrations of hepatic iron over a long period of time.

A carefully controlled blinded study evaluated liver biopsy samples of 56 patients treated with Ferriprox® for a mean of 3.1 years (Wanless, 2002). This was the largest study to evaluate liver biopsy samples over time (in Ferriprox® treated patients) and revealed no progression of fibrosis attributed to Ferriprox® use, in agreement with the other studies listed above.

What is the dose of Ferriprox®?
Ferriprox is approved over the dose range of 75-100 mg/kg/day. The most frequently used dose of Ferriprox® dose is 25 mg/kg three times daily, for a total daily dose of 75 mg/kg. For Ferriprox tablets, the dosage should be calculated to the nearest half tablet. For Ferriprox oral solution, the dose should be calculated to the nearest 2.5 mL increment. This dose stabilizes iron balance in the majority of transfusion-dependent patients (keeping in mind that iron excretion is dependent on both the dose of Ferriprox® and the initial iron load in the body). Increasing the dose up to 100 mg/kg/day provides greater excretion. Doses above 100 mg/kg/day are not currently recommended due to the potential for increased adverse reactions.

How is the effectiveness of Ferriprox® monitored?
The efficacy of Ferriprox® can be monitored in several ways:

• Cardiac MRI T2*, which is an assessment of the heart iron load.
• Serum ferritin concentrations (which is the most common way to evaluate body iron load) must be monitored periodically to assess the long-term effectiveness of the chelation regimen at controlling the body iron load
• Assessment of the hepatic iron concentrations by biopsy, SQUID or MRI are used to assess liver iron loading, the liver being the largest store of excess iron in the body
• Urinary iron excretion is highly variable from day to day but can provide additional information. Each method provides a different insight into iron overload and if all are used, a more complete picture is provided.

What is the recommended management of Ferriprox® side effects?

Neutropenia/ Agranulocytosis

• The neutrophil count should be monitored every week during Ferriprox therapy.
• Therapy should be interrupted if the neutrophil count drops to less than 1.5 x 10⁹/L.
• Patients should be advised to immediately report to their physicians if they experience symptoms of infection such as fever/sore throat or flu-like symptoms.
• In clinical trials, the neutrophil counts returned to normal upon withdrawal of the drug.
• If a patient develops infection, Ferriprox® therapy should be interrupted immediately and the neutrophil count monitored more frequently
• Granulocyte-stimulating growth factors (GCSF) should be used in cases of agranulocytosis.

Increased liver enzymes

• An increase in serum liver enzymes levels has been observed in some patients treated with Ferriprox®. This increase is more frequently observed during the first 3 months of therapy, is generally asymptomatic, and, in the majority of patients, returns to baseline levels without discontinuation of therapy. The clinical significance of this increase has not been identified, and is not understood. Liver enzyme levels should be monitored periodically and if a continuous increase in those values is observed, interruption of therapy should be considered.

Gastrointestinal

• Nausea, vomiting or gastrointestinal distress is more frequent during the first 2 weeks of therapy and with most patients resolves within a few weeks without a reduction of dosage or discontinuation of therapy. Taking Ferriprox® with meals may reduce these symptoms.
• In some patients with severe effects, it may be beneficial to reduce the dose of Ferriprox® and then scale it back up to 75 or 100 mg/kg/day.
• Anti-nausea drugs may also be used.

Arthropathies

• Most patients who experience joint pains recover in 2-4 weeks, without discontinuing Ferriprox®. If pain persists, follow-up investigations are warranted and interruption of therapy should be considered.

Zinc deficiency

• Increased zinc excretion is observed in some patients, but zinc deficiency is rare. If oral zinc supplements are used, they should not be given together with Ferriprox, but precede it by a few hours.

What is the safety of Ferriprox® in pregnancy/lactation?
The safety of Ferriprox® in women or nursing mothers has not been formally established. Reproductive studies in non-iron loaded rats and rabbits have indicated that deferiprone is teratogenic and embryotoxic at doses as low as 10 mg/kg body weight (deferiprone can penetrate the placenta and remove iron from the fetus). Therefore, based on animal studies, Ferriprox® is contraindicated in pregnant or lactating women. Women of childbearing potential should take contraceptive measures and should be advised to immediately stop taking Ferriprox® should they become pregnant or plan to become pregnant.

Can Ferriprox® be crushed or chewed?
Ferriprox® tablets have a film coating. Crushing the tablet should pose no problem as long as the product is administered immediately after doing so. However there are no data to support this and there is no guarantee of the stability of the product if it is left in a crushed form for periods of time. In addition, because of the film coating present, the tablet may not crush elegantly to a fine powder.

There are no data or studies on file regarding Ferriprox® tablet stability in different food or liquid media. From a compatibility perspective there should be no potential problems in administering the crushed tablet with liquid foods (i.e. apple sauce or pudding), to facilitate swallowing, as long as the dose is given immediately following mixture. However, because no formal studies have been conducted with those foods and this can be considered only as a suggestion. It should not be administered with aluminium containing antacids. As an alternative to tablets, Ferriprox® oral solution can also be considered.

Is Ferriprox® oral solution bioequivalent to Ferriprox Tablets?
Yes, Ferriprox® oral solution and tablets are bioequivalent.

How does a patient take Ferriprox® oral solution?
Each mL of oral solution contains 100 mg of Ferriprox®. Using the dosing table, calculate the number of mL of oral solution your patient must take 3 times per day based upon body weight. Then instruct your patient to measure out the correct amount of liquid using the plastic cup included with the bottle of Ferriprox® oral solution.

If my patient is taking Ferriprox® tablets, can h/she begin using the oral solution immediately?
Yes.

What is the shelf life of Ferriprox® oral solution?
2 years unopened, or 35 days from date of opening.

Does Ferriprox® oral solution need to be refrigerated?
No. Also, do not store above 30 degrees Celsius.

Is Ferriprox® oral solution safe for patients with diabetes?
Ferriprox® oral solution uses sucralose as a sweetener, so it may be used by patients with diabetes.

Where can I get more information about Ferriprox® oral solution?
For full prescribing information, please see the Summary of Product Characteristics.

Patient Common Questions

Should Ferriprox® be taken with food?
Ferriprox® can be taken with or without food. For individuals who experience gastrointestinal problems, it is recommended that they try taking Ferriprox® with food.

How many times a day is Ferriprox® taken?
Ferriprox® should be taken exactly as your physician has prescribed. It is usually taken three times a day, in the morning, afternoon and at night. Check the instruction provided with the prescription for Ferriprox® and be sure to follow them carefully.

What do Ferriprox® look like?
Ferriprox® tablets are white to off-white, capsule-shaped, and film coated. They are imprinted with ”APO” bisect ”500” on one side and plain on the other. Because the tablets are scored they can be broken in half to provide a 250 milligram dose.

How many tablets are in a bottle?
There are 100 tablets in each bottle of Ferriprox.

Does Ferriprox® interact with other prescription medicines?
Interactions between deferiprone and other medicinal products have not been reported. However, since deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and trivalent cation-dependent medicinal products such as aluminium based antacids. Therefore, it is not recommended to ingest aluminium based antacids and deferiprone at the same time.
The safety of concurrent use of Ferriprox® and vitamin C has not been formally studied. Based on the reported adverse interaction that can occur between deferoxamine (another chelator) and vitamin C, caution should be used when administering Ferriprox® and vitamin C concurrently.
Due to the unknown mechanism of deferiprone induced neutropenia (an abnormally low level of neutrophils in the blood), patients must not take medicinal products known to be associated with neutropenia or those that can cause agranulocytosis (A serious condition in which white blood cells decrease even further in number or disappear altogether)

Does Ferriprox® cause drowsiness?
There is no clinical evidence of Ferriprox® causing drowsiness. For a complete list of side effects associated with the use of Ferriprox® consult the product information leaflet.

How long will Ferriprox® keep?
You should use Ferriprox® as soon as it is prescribed. Ferriprox® tablets have a shelf-life of 3 years from the date it was manufactured. Check the expiry date stated on the container to find out exactly how much time is left before the tablets expire.

What are the side effects of Ferriprox?
Agranulocytosis (a major decrease in the number of white blood cells in the blood) is the most serious potential side effect and studies have found that about 1 patient in 100 who have taken Ferriprox® in clinical trials have experienced this condition. For a complete list of side effects consult the patient information leaflet.

Why do I have to have my blood monitored weekly?
Your blood has to be monitored because it is important to know whether you might be one of the patients who is at risk of experiencing a significant lowering of white blood cells. This condition, known as severe neutropenia or agranulocytosis, has occurred in about 1 out of 100 people who have taken Ferriprox® in clinical studies. A low white blood cell count can lead to a serious and life-threatening infection. Report immediately to your doctor any symptoms of infection such as: fever, sore throat or flu-like symptoms.

How long is Ferriprox® taken for?
Ferriprox® should be taken until iron levels in the body are reduced to normal levels. For some patients with severe iron loading this may take years or for as long as you have blood transfusions.

Where should Ferriprox® be stored?
Store Ferriprox® where it is out of reach and sight of children. Do not store the product above 30 degrees Celsius. Do not use Ferriprox® after the expiry date printed on the container.

What should I do if I miss a dose of Ferriprox?
If you miss one dose take it as soon as you remember and take your next dose at its regularly scheduled time. If you miss more than one dose do not take the missed tablets, just continue with your normal schedule. Do not change your daily dose without first talking to your doctor.

Can I use Ferriprox® if I am pregnant or breastfeeding?
Do not take this medication if you are breast-feeding, if you are pregnant, or if you are trying to become pregnant. This medication might seriously harm your baby. Effective contraception must be used while you are taking Ferriprox. Ask your doctor which method is best for you. If you become pregnant while taking Ferriprox, stop taking the medication immediately and tell your doctor.

What is the shelf life of Ferriprox® oral solution?
2 years unopened, or 35 days from date of opening.

Does Ferriprox® oral solution need to be refrigerated? No. Also, do not store above 30 degrees Celsius.

Is Ferriprox® oral solution safe for patients with diabetes? Ferriprox® oral solution uses sucralose as a sweetener, so it may be used by patients with diabetes.