Deferiprone

Last updated

Deferiprone
Deferiprone.svg
Clinical data
Trade names Ferriprox
AHFS/Drugs.com Monograph
MedlinePlus a612016
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Glucuronidation
Elimination half-life 2 to 3 hours
Excretion Kidney (75 to 90% in 24 hours)
Identifiers
  • 3-hydroxy-1,2-dimethylpyridin-4(1H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.157.470 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H9NO2
Molar mass 139.154 g·mol−1
3D model (JSmol)
  • O=C\1C(\O)=C(/N(/C=C/1)C)C
  • InChI=1S/C7H9NO2/c1-5-7(10)6(9)3-4-8(5)2/h3-4,10H,1-2H3 Yes check.svgY
  • Key:TZXKOCQBRNJULO-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. [5] It was first approved and indicated for use in treating thalassaemia major in 1994 [6] and had been licensed for use in the European Union for many years while awaiting approval in Canada and in the United States. [5] On 14 October 2011, it was approved for use in the US under the FDA's accelerated approval program. [7] [8]

Contents

The most common side effects include red-brown urine (showing that iron is being removed through the urine), nausea (feeling sick), abdominal pain (stomach ache) and vomiting. [9] [7] Less common but more serious side effects are agranulocytosis (very low levels of granulocytes, a type of white blood cell) and neutropenia (low levels of neutrophils, a type of white blood cell that fights infections). [9] [7]

Medical uses

Deferiprone monotherapy is indicated in the European Union for the treatment of iron overload in those with thalassaemia major when current chelation therapy is contraindicated or inadequate. [9]

Deferiprone in combination with another chelator is indicated in the European Union in those with thalassaemia major when monotherapy with any iron chelator is ineffective, or when prevention or treatment of life-threatening consequences of iron overload (mainly cardiac overload) justifies rapid or intensive correction. [9]

The researchers found that the oral drug, deferiprone, reactivates the “altruistic suicide response” of an HIV-infected cell, killing the HIV RNA it carries. Effective suppression of HIV-1 generation and induction of apoptosis both require deferiprone at a concentration around 150 μM in infected T-cell lines. Since a 0.5 log10 decrement in HIV-1 RNA corresponds to an additional 2 years of AIDS-free survival and a 0.3 log10 decrement reduces the annual risk of progression to AIDS-related death by 25%, the measurements suggested biological significance. [10]

Controversy

Deferiprone was at the center of a protracted struggle between Nancy Olivieri, a Canadian haematologist and researcher, and the Hospital for Sick Children and the pharmaceutical company Apotex, that started in 1996, and delayed approval of the drug in North America. [11] Olivieri's data suggested that deferiprone can lead to progressive liver failure. [12] [13] [14]

History

Deferiprone was approved for medical use in the European Union in August 1999. [9]

It was approved for medical use in the United States in October 2011. [7] [8] Generic versions were approved in August 2019. [15]

The safety and effectiveness of deferiprone is based on an analysis of data from twelve clinical studies in 236 participants. [7] Participants in the study did not respond to prior iron chelation therapy. [7] Deferiprone was considered a successful treatment for participants who experienced at least a 20 percent decrease in serum ferritin, a protein that stores iron in the body for later use. [7] Half of the participants in the study experienced at least a 20 percent decrease in ferritin levels. [7]

Related Research Articles

Chelation is a type of bonding of ions and the molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate ligand and a single central metal atom. These ligands are called chelants, chelators, chelating agents, or sequestering agents. They are usually organic compounds, but this is not a necessity.

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A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Thalassemia is also known as Cooley's anemia or Mediterranean anemia.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary but may also be secondary to repeated blood transfusions. Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.

Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an underlying genetic condition, and aluminium toxicity in people on dialysis. It is used by injection into a muscle, vein, or under the skin.

<span class="mw-page-title-main">Deferasirox</span> Oral iron chelator

Deferasirox, sold under the brand name Exjade among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the United States for this purpose.

<span class="mw-page-title-main">Beta thalassemia</span> Blood disorder

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

Nancy Fern Olivieri is a prominent Toronto haematologist and researcher with an interest in the treatment of haemoglobinopathies. She is best known for a protracted struggle with the Hospital for Sick Children and the pharmaceutical company Apotex about the drug deferiprone.

Transfusional hemosiderosis is the accumulation of iron in the body due to frequent blood transfusions. Iron accumulates in the liver and heart, but also endocrine organs. Frequent blood transfusions may be given to many patients, such as those with thalassemia, sickle cell disease, leukemia, aplastic anemia, or myelodysplastic syndrome, among others. It is diagnosed with a blood transferrin test and a liver biopsy. It is treated with venipuncture, erythrocytapheresis, and iron chelation therapy.

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<span class="mw-page-title-main">Hemosiderosis</span> Iron metabolism disease

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

<span class="mw-page-title-main">Congenital dyserythropoietic anemia</span> Red blood cell disorder

Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood. CDA may be transmitted by both parents autosomal recessively or dominantly.

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Treatment of the inherited blood disorder thalassemia depends upon the level of severity. For mild forms of the condition, advice and counseling are often all that are necessary. For more severe forms, treatment may consist in blood transfusion; chelation therapy to reverse iron overload, using drugs such as deferoxamine, deferiprone, or deferasirox; medication with the antioxidant indicaxanthin to prevent the breakdown of hemoglobin; or a bone marrow transplant using material from a compatible donor, or from the patient's mother. Removal of the spleen (splenectomy) could theoretically help to reduce the need for blood transfusions in people with thalassaemia major or intermedia but there is currently no reliable evidence from clinical trials about its effects. Population screening has had some success as a preventive measure.

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<span class="mw-page-title-main">Ferric maltol</span> Chemical compound

Ferric maltol, sold under the brand names Accrufer (US) and Feraccru (EU), is an iron containing medication for the treatment of adults with low iron stores. It is taken by mouth.

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<span class="mw-page-title-main">Transfusion-dependent anemia</span>

Transfusion-dependent anemia is a form of anemia characterized by the need for continuous blood transfusion. It is a condition that results from various diseases, and is associated with decreased survival rates. Regular transfusion is required to reduce the symptoms of anemia by increasing functional red blood cells and hemoglobin count. Symptoms may vary based on the severity of the condition and the most common symptom is fatigue. Various diseases can lead to transfusion-dependent anemia, most notably myelodysplastic syndromes (MDS) and thalassemia. Due to the number of diseases that can cause transfusion-dependent anemia, diagnosing it is more complicated. Transfusion dependence occurs when an average of more than 2 units of blood transfused every 28 days is required over a period of at least 3 months. Myelodysplastic syndromes is often only diagnosed when patients become anemic, and transfusion-dependent thalassemia is diagnosed based on gene mutations. Screening for heterozygosity in the thalassemia gene is an option for early detection.

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References

  1. ↑ "Deferiprone (Ferriprox) Use During Pregnancy". Drugs.com. 30 March 2020. Retrieved 20 May 2020.
  2. ↑ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada . 4 May 2016. Retrieved 7 April 2024.
  3. ↑ "Ferriprox 100 mg/ml oral solution - Summary of Product Characteristics (SmPC)". (emc). 26 November 2019. Retrieved 20 May 2020.
  4. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  5. 1 2 Savulescu J (February 2004). "Thalassaemia major: the murky story of deferiprone". BMJ. 328 (7436): 358–9. doi:10.1136/bmj.328.7436.358. PMC   341373 . PMID   14962851.
  6. ↑ Staff. "Cipla's History". Cipla. Archived from the original on 27 October 2015.
  7. 1 2 3 4 5 6 7 8 "FDA Approves Ferripox (deferiprone) to Treat Patients with Excess Iron in the Body". U.S. Food and Drug Administration (FDA) (Press release). 14 October 2011. Archived from the original on 10 October 2016.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. 1 2 "Drug Approval Package: Ferriprox (deferiprone) Tablet NDA #021825". U.S. Food and Drug Administration (FDA). 30 November 2011. Retrieved 20 May 2020.
  9. 1 2 3 4 5 "Ferriprox EPAR". European Medicines Agency (EMA). Retrieved 20 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. ↑ Deepti Saxena, Michael Spino, Fernando Tricta, John Connelly, Bernadette M. Cracchiolo, Axel-Rainer Hanauske, Darlene D’Alliessi Gandolfi, Michael B. Mathews,Jonathan Karn,Bart Holland, Myung Hee Park, Tsafi Pe’ery, Paul E. Palumbo, Hartmut M. Hanauske-Abel (18 May 2016). Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial.
  11. ↑ Viens AM, Savulescu J (February 2004). "Introduction to The Olivieri symposium". Journal of Medical Ethics. 30 (1): 1–7. doi:10.1136/jme.2003.006577. PMC   1757126 . PMID   14872065.
  12. ↑ Brittenham GM, Nathan DG, Olivieri NF, Porter JB, Pippard M, Vichinsky EP, Weatherall DJ (June 2003). "Deferiprone and hepatic fibrosis". Blood. 101 (12): 5089–90, author reply 5090–1. doi: 10.1182/blood-2002-10-3173 . PMID   12788794.
  13. ↑ Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, et al. (September 2002). "Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia". Blood. 100 (5): 1566–9. doi: 10.1182/blood-2002-01-0306 . PMID   12176871.
  14. ↑ Cribb R (27 February 2019). "UHN patients given unlicensed drug that led to diabetes, liver dysfunction and one death, study finds". The Star. Toronto. Retrieved 27 February 2019.
  15. ↑ "Deferiprone: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 20 May 2020.
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