|
1
|
Kontoghiorghes GJ. Differences between the European Union and United States of America in Drug Regulatory Affairs Affect Global Patient Safety Standards and Public Health Awareness: The Case of Deferasirox and Other Iron Chelating Drugs. MEDICINES (BASEL, SWITZERLAND) 2021; 8:36. [PMID: 34357152 PMCID: PMC8304852 DOI: 10.3390/medicines8070036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/17/2021] [Accepted: 07/05/2021] [Indexed: 06/13/2023]
Abstract
Regulatory policies on drugs have a major impact on patient safety and survival. Some pharmaceutical companies employ all possible methods to achieve maximum sales in relation to the monopoly of their patented drugs, leading sometimes to irregularities and illegal activities. Misinformation on the orphan drug deferasirox has reached the stage of criminal investigations and fines exceeding USD 100 million. Additional lawsuits of USD 3.5 billion for damages and civil fines were also filed by the FBI of the USA involving deferasirox and mycophenolic acid, which were later settled with an additional fine of USD 390 million. Furthermore, a USD 345 million fine was also settled for bribes and other illegal overseas operations including an EU country. However, no similar fines for illegal practises or regulatory control violations have been issued in the EU. Misconceptions and a lack of clear guidelines for the use of deferasirox in comparison to deferiprone and deferoxamine appear to reduce the effective treatment prospects and to increase the toxicity risks for thalassaemia and other iron loaded patients. Similar issues have been raised for the activities of other pharmaceutical companies promoting the use of new patented versus generic drugs. Treatments for different categories of patients using new patented drugs are mostly market driven with no clear safeguards or guidelines for risk/benefit assessment indications or for individualised effective and safe optimum therapies. There is a need for the establishment of an international organisation, which can monitor and assess the risk/benefit assessment and marketing of drugs in the EU and globally for the benefit of patients. The pivotal role of the regulatory drug authorities and the prescribing physicians for identifying individualised optimum therapies is essential for improving the survival and safety of millions of patients worldwide.
Collapse
Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
| |
Collapse
|
|
2
|
Taher AT, Porter JB, Kattamis A, Viprakasit V, Cappellini MD. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with nontransfusion-dependent thalassemia syndromes. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:4073-4078. [PMID: 28008230 PMCID: PMC5170616 DOI: 10.2147/dddt.s117080] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Ali T Taher
- Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - John B Porter
- Department of Haematology, University College London, London, UK
| | - Antonis Kattamis
- First Department of Pediatrics, University of Athens, Athens, Greece
| | - Vip Viprakasit
- Department of Pediatrics and Thalassemia Center, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - M Domenica Cappellini
- Department of Internal Medicine, Università di Milano, Ca Granda Foundation IRCCS, Milan, Italy
| |
Collapse
|
|
3
|
Kontoghiorghe CN, Kontoghiorghes GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:465-81. [PMID: 26893541 PMCID: PMC4745840 DOI: 10.2147/dddt.s79458] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.
Collapse
Affiliation(s)
| | - George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus
| |
Collapse
|
|
4
|
Kontoghiorghe CN, Andreou N, Constantinou K, Kontoghiorghes GJ. World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients. World J Methodol 2014; 4:163-188. [PMID: 25332915 PMCID: PMC4202455 DOI: 10.5662/wjm.v4.i3.163] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 04/05/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
According to global annual estimates hunger/malnutrition is the major cause of death (36 of 62 million). Cardiovascular diseases and cancer (5.44 of 13.43 million) are the major causes of death in developed countries, while lower respiratory tract infections, human immunodeficiency virus infection/acquired immunodeficiency syndrome, diarrhoeal disease, malaria and tuberculosis (10.88 of 27.12 million) are the major causes of death in developing countries with more than 70% of deaths occurring in children. The majority of approximately 800 million people with other rare diseases, including 100000 children born with thalassaemia annually receive no treatment. There are major ethical dilemmas in dealing with global health issues such as poverty and the treatment of orphan and rare diseases. Of approximately 50000 drugs about 10% are orphan drugs, with annual sales of the latter approaching 100 billion USD. In comparison, the annual revenue in 2009 from the top 12 pharmaceutical companies in Western countries was 445 billion USD and the top drug, atorvastatin, reached 100 billion USD. In the same year, the total government expenditure for health in the developing countries was 410 billion USD with only 6%-7% having been received as aid from developed countries. Drugs cost the National Health Service in the United Kingdom more than 20 billion USD or 10% of the annual health budget. Uncontrollable drug prices and marketing policies affect global health budgets, clinical practice, patient safety and survival. Fines of 5.3 billion USD were imposed on two pharmaceutical companies in the United States, the regulatory authority in France was replaced and clinicians were charged with bribery in order to overcome recent illegal practises affecting patient care. High expenditure for drug development is mainly related to marketing costs. However, only 2 million USD was spent developing the drug deferiprone (L1) for thalassaemia up to the stage of multicentre clinical trials. The criteria for drug development, price levels and use needs to be readdressed to improve drug safety and minimise costs. New global health policies based on cheaper drugs can help the treatment of many categories of orphan and rare diseases and millions of orphan patients in developing and developed countries.
Collapse
|
|
5
|
Kontoghiorghes GJ. A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opin Drug Saf 2013; 12:605-9. [DOI: 10.1517/14740338.2013.799664] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
6
|
Antiproliferative and iron chelating efficiency of the new bis-8-hydroxyquinoline benzylamine chelator S1 in hepatocyte cultures. Chem Biol Interact 2012; 195:165-72. [DOI: 10.1016/j.cbi.2011.12.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 12/05/2011] [Accepted: 12/06/2011] [Indexed: 12/23/2022]
|
|
7
|
Kontoghiorghes GJ. A record of 1320 suspect, deferasirox-related, patient deaths reported in 2009: insufficient toxicity testing, low efficacy and lack of transparency may endanger the lives of iron loaded patients. Hemoglobin 2011; 35:301-11. [PMID: 21599442 DOI: 10.3109/03630269.2011.576906] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
8
|
Kontoghiorghes GJ. The proceedings of the 19Th international conference on chelation held in London, United Kingdom: major changes in iron chelation therapy in the last 25 years using deferiprone (L1) has resulted in the complete treatment of iron overload. Hemoglobin 2011; 35:181-5. [PMID: 21599430 DOI: 10.3109/03630269.2011.575663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Major advances were presented at the 19th International Conference on Chelation (ICOC) in London, UK including changes in iron chelation therapy that led to the complete treatment of transfusional iron overload. The first oral iron chelation results in animals using deferiprone (L1) were published in 1985, and effective iron removal in thalassemia and myelodysplasia patients were reported 2 years later. The results of multicenter clinical trials of L1 were presented at the 1st ICOC in London, UK in 1989. Long-term use of L1 resulted in the reduction of the mortality rate in thalassemia patients due to the effective removal of all excess iron from the heart. In 2008, specific combinations of L1 and deferoxamine (DFO) were reported to cause the complete removal of excess iron load and the achievement of normal range body iron store levels (NRBISL) in thalassemia patients. Patients with NRBISL were identified to require lower doses of L1 for the maintenance of negative iron balance. The introduction of deferasirox (DFRA) may benefit patients not tolerating L1, DFO or their combination. A simple, inexpensive synthesis of L1 has encouraged its manufacture in developing countries for the benefit of patients who could not afford the expensive imported chelating drugs or formulations.
Collapse
Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science Technology, Environment and Medicine, Limassol, Cyprus.
| |
Collapse
|
|
9
|
Abergel RJ, Raymond KN. Multidentate Terephthalamidate and Hydroxypyridonate Ligands: Towards New Orally Active Chelators. Hemoglobin 2011; 35:276-90. [DOI: 10.3109/03630269.2011.560771] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
10
|
Kontoghiorghes GJ, Spyrou A, Kolnagou A. Iron chelation therapy in hereditary hemochromatosis and thalassemia intermedia: regulatory and non regulatory mechanisms of increased iron absorption. Hemoglobin 2011; 34:251-64. [PMID: 20524815 DOI: 10.3109/03630269.2010.486335] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Millions of people are affected by hereditary hemochromatosis (HH) and thalassemia intermedia (TI), the iron overloading disorders caused by chronic increases in iron absorption. Genetic factors, regulatory pathways involving proteins of iron metabolism, non regulatory molecules, dietary constituents and iron binding drugs could affect iron absorption and could lead to iron overload or iron deficiency. Chelators and chelating drugs can affect both iron absorption and excretion. Deferoxamine (DFO), deferiprone (L1) and the DFO/L1 combination therapies have been used effectively for reversing the toxic side effects of iron overload including cardiac and liver damage in TI and HH patients where venesection is contraindicated. Selected protocols using DFO, L1 and their combination could be designed for optimizing chelation therapy in TI and HH. The use of deferasirox (DFRA) in HH and TI could cause an increase in iron and other toxic metal absorption. Future treatments of HH and TI could involve the use of iron chelating and other drugs not only for increasing iron excretion but also for preventing iron absorption.
Collapse
Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus.
| | | | | |
Collapse
|
|
11
|
Vlachaki E, Chatzinikolaou K, Bekiari E, Klonizakis F, Tsapas A. Is deferasirox implicated in multiple organ failure in a patient with homozygous β-thalassemia? Angiology 2011; 62:346-8. [PMID: 21306999 DOI: 10.1177/0003319710394160] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We herein report a case of a thalassemic-patient who was on deferasirox chelation therapy and admitted to the emergency department because of fever, diffuse abdominal pain and altered mental status. Despite the appropriate treatment he died two days later due to cardiac arrest. As we failed to recognize any etiology and the patients' relatives denied a post mortem examination due to religious reasons, we cannot provide any additional data. However, we are wondering whether this incident might be related to deferasirox.
Collapse
Affiliation(s)
- Efthimia Vlachaki
- Second Medical Department, Hippokration University Hospital, Aristotle University Thessaloniki, Greece.
| | | | | | | | | |
Collapse
|
|
12
|
Kontoghiorghes GJ. Introduction of higher doses of deferasirox: better efficacy but not effective iron removal from the heart and increased risks of serious toxicities. Expert Opin Drug Saf 2010; 9:633-41. [PMID: 20553089 DOI: 10.1517/14740338.2010.497138] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
IMPORTANCE OF THE FIELD Thousands of iron loaded patients are using deferasirox, who are not aware of the new, fatal and irreversible serious toxic side effects, the need for prophylaxis and the availability of more effective and less toxic chelation therapies. AREAS COVERED IN THIS REVIEW Updating on efficacy issues in relation to the introduction of higher deferasirox doses and comparison to existing chelation therapies. A new maximum dose of 40 mg/kg/day has been introduced for deferasirox in an attempt to achieve negative iron balance in thalassemia and other transfused iron loaded patients. A marginal increase in cardiac iron removal using doses of 30 - 40 mg/kg/day suggests that the rate of iron removal by deferasirox is insufficient by comparison to the deferiprone/deferoxamine combination, where total and rapid clearance of excess cardiac iron and normalization of the body iron stores could be achieved. WHAT THE READER WILL GAIN Identification of drug interactions and new fatal and permanent toxic side effects of deferasirox and implications on efficacy, toxicity and cost of using higher doses. Deferasirox has been identified to cause fatal gastrointestinal hemorrhages, renal tubulopathy, hepatic and renal failure, alopecia and anaphylactic reactions in addition to previously reported fatal or serious toxic side effects such as agranulocytosis, renal and hepatic toxicity, skin rash and gastric intolerance. Interactions with UDP-glucuronosyl transferase inducers, CYP2C8 and CYP3A4 substrates and drugs affecting enterohepatic recycling are likely to affect deferasirox's efficacy and toxicity. Increased toxicity is expected from the use of higher doses of deferasirox and regular prophylactic monitoring is required to avoid fatal and permanent toxicity incidences. The increased costs from higher doses of deferasirox will mostly affect patients living in the developing countries. TAKE HOME MESSAGE Only few patients may benefit from the introduction of higher doses of deferasirox. There is a need for introducing more effective prophylactic measures. Safer, more effective and less costly chelation treatments are available using deferiprone, deferoxamine and their combination.
Collapse
Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, 3, Ammochostou Street, Limassol 3021, Cyprus.
| |
Collapse
|
|
13
|
Kontoghiorghes GJ, Kolnagou A, Peng CT, Shah SV, Aessopos A. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf 2010; 9:201-6. [PMID: 20059374 DOI: 10.1517/14740330903535845] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
An increased number of thalassaemia patients treated with effective chelation therapy protocols are achieving body iron levels similar to those of normal individuals. Iron chelation therapy has also been recently used in a number of other categories of patients with no excess body iron load such as neurodegenerative, renal and infectious diseases. Chelation therapy in the absence of iron overload in the latter conditions raises many safety issues including chelator overdose toxicity and toxicity related to iron and other essential metal deficiencies. Preliminary preclinical and clinical toxicity evidence suggest that deferoxamine and deferasirox can only be safely used for these non-iron loaded conditions for short-term treatments of a few weeks, whereas deferiprone can be used for longer term treatments of many months. The selection of the chelating drug and appropriate dose protocols for targeting specific organs and conditions is critical for the safety of patients with normal iron stores. Chelation therapy is likely to play a major role as adjuvant, alternative or main therapy in many non-iron loading conditions in the forthcoming years.
Collapse
|
|
14
|
Yeh SP, Yang YS, Yao CY, Peng CT. Iron chelation therapy for patients with myelodysplastic syndrome. Hemoglobin 2010; 33:339-45. [PMID: 19814680 DOI: 10.3109/03630260903212654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Chronic blood transfusions are necessary for patients with hereditary anemia such as thalassemia, and for patients with myelodysplastic syndrome (MDS) who become anemic and transfusion-dependent. A common consequence of chronic transfusion is iron accumulation that can lead to organ damage. While there is general agreement regarding the value of iron chelation therapy to reduce the detrimental effects of iron overload in thalassemia major, the same is not true for MDS. The malignant nature of the disease and the relatively high cost of iron chelation therapy make cost-effectiveness an issue of great concern. Furthermore, the positive assessment of a drug's cost-effectiveness in one country does not necessarily justify its use in another country. More prospective studies are needed to identify the best iron chelator for patients with MDS as well as to identify those patients who will benefit most from iron chelation therapy.
Collapse
Affiliation(s)
- Su-Peng Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
| | | | | | | |
Collapse
|
|
15
|
Kontoghiorghes GJ. A New Era in Iron Chelation Therapy: The Design of Optimal, Individually Adjusted Iron Chelation Therapies for the Complete Removal of Iron Overload in Thalassemia and other Chronically Transfused Patients. Hemoglobin 2009; 33:332-8. [DOI: 10.3109/03630260903217182] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|