Drug Saf DOI 10.1007/s40264-017-0606-2
ORIGINAL RESEARCH ARTICLE
Utilisation and Safety of Deferasirox: Results from an Observational Cohort Study in England Vicki Osborne1,3
•
Miranda Davies1,2 • Deborah Layton1,2 • Saad A. W. Shakir1,2
Springer International Publishing AG 2017
Abstract Introduction Deferasirox (EXJADE, Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. Objective The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. Method A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers C 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. Results The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2–17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior
measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. Conclusion These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.
Key Points Deferasirox is mostly being prescribed according to the licensed indications and at licensed doses within the UK. Events reported after treatment initiation, including raised serum creatinine, are consistent with the known safety profile.
1 Introduction Electronic supplementary material The online version of this article (doi:10.1007/s40264-017-0606-2) contains supplementary material, which is available to authorized users. & Saad A. W. Shakir [email protected] 1
Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton SO31 1AA, UK
2
School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
3
Department of Epidemiology, University of Florida, Gainesville, FL, USA
Iron overload is a condition that occurs when iron is deposited in multiple organs and serum ferritin value is greater than 1000 lg/L [1]. It can be caused by both regular blood transfusions and genetic conditions such hereditary haemochromatosis [1, 2]. Many rare anaemias such as sickle cell anaemia or beta thalassaemia are treated with regular red blood cell (RBC) transfusions, since there can be a decrease in RBC production or increase in cell destruction with these disorders [3]. Such chronic blood transfusions will usually lead to chronic iron overload and so patients with these rare anaemias often require iron
V. Osborne et al.
chelation therapy [3]. The aim of this therapy is to maintain safe iron levels for the patient [4]. Three iron-chelating medications are currently available for the treatment of iron overload: deferoxamine, deferasirox and deferiprone [4]. Deferasirox (EXJADE, Novartis, UK) is an oral medication indicated for the treatment of chronic iron overload due to frequent blood transfusions (C 7 mL/kg/month of packed RBCs) in patients with beta thalassaemia major aged 6 years and older [5]. It is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy (another iron-chelating agent) is contraindicated or inadequate in the following patient groups: •
•
•
aged 2–5 years with beta thalassaemia major and overload due to frequent blood transfusions (C 7 kg/month of packed RBCs); aged C 2 years with beta thalassaemia major and overload due to infrequent blood transfusions (\ 7 kg/month of packed RBCs); aged C 2 years with other anaemias [5].
iron mL/ iron mL/
Deferasirox is also indicated for the treatment of chronic iron overload requiring chelating therapy in situations whereby deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older [5]. Deferasirox is to be taken at an initial dose of 20 mg/kg body weight, with a maximum dose of 40 mg/kg [5]. It provides 24-h chelation for both intra- and extracellular excess iron in the body including in the heart, liver, reticuloendothelial system and the circulation [6]. Randomised controlled trials in the pre-marketing phase included 1005 patients with transfusional iron overload in various diseases (beta thalassemia, rare anaemias, sickle cell disease) of whom 652 received deferasirox and 353 deferoxamine [6]. The safety issues that were identified with deferasirox during these studies included increases in serum creatinine of [ 30 to [ 90% that occurred mainly during the first month of treatment, hepatobiliary disorders and increases in liver transaminases that occurred within a few months of starting deferasirox, skin rash (though these resolved spontaneously for most cases) and, as with other iron-chelating agents such as deferoxamine, high-frequency hearing loss and lenticular opacities (early cataracts) [6]. In order to study the safety and utilisation of deferasirox in the post-marketing phase, an observational single exposure cohort study was conducted using PrescriptionEvent Monitoring (PEM). PEM studies provide active surveillance of targeted medicines on a national scale in England [7]. These studies can provide information on the safety and utilisation of medicines in the real-world setting to contribute to the post-marketing information of a
product [7]. The overall aim of this study was to examine the utilisation and safety of deferasirox used in general medical practice in England.
2 Methods 2.1 Study Design An observational post-marketing cohort study (PEM) was conducted to monitor the safety and utilisation of deferasirox as used in general practice in England. A detailed description of PEM is published elsewhere [7]. Briefly, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for deferasirox, supplied to the Drug Safety Research Unit (DSRU) in confidence by the National Health Service Business Services Authority (NHSBSA). All patients who were dispensed a script, written by a GP for deferasirox in England during the study period, would have been identified using data from the NHSBSA. The GPs were sent a short postal questionnaire (see Electronic Supplementary Material 1) at least 6 months following the date of the first prescription for deferasirox for each individual patient between September 2006 and September 2014, requesting information including reason for prescribing, initial dose, maintenance dose, start and stop dates of treatment (if stopped), age, gender, reasons for stopping deferasirox and details of events1 experienced by patients after starting therapy. GPs were also asked whether serum creatinine was measured prior to commencing treatment and, if so, the measurement and date obtained. Questionnaires were sent in monthly batches and processed as soon as they were returned to the DSRU. In order to maximise the GP response rate, a second questionnaire was posted to GPs relating to specific patient(s) for whom they had not responded, within 2 months of the date the initial questionnaire was sent. A flow diagram of the study methodology is provided in Fig. 1. Reason for prescribing deferasirox was captured through tick boxes since the indications were highly specific to the product; however, a free-text option remained. The information provided for these patients was coded onto a database; events and free-text reasons for prescribing were extracted according to MedDRA (v17). Analyses were performed using STATA v12 (StataCorp, TX, USA).
1
An ‘event’ in PEM is defined as ‘‘any new diagnosis, any reason for referral to a consultant or admission to hospital, any unexpected deterioration (or improvement) in a concurrent illness, any alteration of clinical importance in laboratory values, or any other complaint that was considered of sufficient importance to enter in the patient’s notes.’’
Utilisation and Safety of Deferasirox Fig. 1 Flow diagram of study methodology. DRSU Drug Safety Research Unit, GP General Practitioner, NHSBSA National Health Service Business Services Authority, PEM Prescription-Event Monitoring
2.2 Inclusion and Exclusion Criteria For this study, eligible subjects were those patients who received a prescription from a GP for deferasirox in the primary care setting and for whom deferasirox was subsequently dispensed at an NHS contracted pharmacy in England. Thus, patients were identified from prescription data for deferasirox. Patients were admitted to the study regardless of the strength or frequency of administration of deferasirox and irrespective of whether any medicines were concurrently administered. Those patients for whom any of the following applied were excluded from the final evaluable cohort: questionnaire was returned with no information (blank), the GP reported that the patient did not take, and had never been prescribed, deferasirox, the GP reported that the patient was no longer registered with the practice and no information was provided (where information was available up to a specific date it was included). 2.3 Analysis Summary descriptive statistics were calculated. All percentages were calculated using a denominator of the total cohort size for each stratum. Missing data were defined as non-response to a specific question or where the GP specified that the answer was not known. These numbers are provided in the tables, where applicable. 2.4 Quality Assurance in Prescription-Event Monitoring (PEM) Good data management is a high priority in all PEM studies, including for deferasirox. A number of strategies were used to minimise biased results. Data quality was assured through a number of methods such as operator training, on-screen validation during data entry, adoption of and adherence to study-specific data coding conventions,
coding and convention meetings, double entry (10%) with error reporting, data cleaning using logical checks and analysis of outliers.
3 Results The final evaluable study cohort consisted of 122 patients (Fig. 2). 3.1 Age and Gender The median age of the whole cohort was 23 years (interquartile range [IQR] 11–61 years). The median age for male patients was 21 years (IQR 9–64); and for female patients the median age was 26 years (IQR 13–58). Seventy-one patients (58.2% of cohort) were male. In total, 12 patients (9.8% of cohort) were aged 2–5 years, 17 patients (13.9% of cohort) were aged 6–9 years and 22 patients (18.0% of cohort) were aged 10–17 years. No patients were younger than 2 years of age. Summary characteristics for the cohort are provided in Table 1. 3.2 Reasons for Prescribing Deferasirox GPs were asked to report the reasons for prescribing deferasirox, which may have been reported as the clinical condition leading to the need for blood transfusions, but could also have been reported as laboratory findings (e.g. iron overload, increased serum ferritin). More than one reason for prescribing could have been reported and these were coded as primary, secondary and tertiary reasons for prescribing. A primary reason for prescribing deferasirox was reported for 103 patients (84.4% of total cohort). The most frequently reported primary reasons for prescribing were sickle cell anaemia (n = 27, 22.1%) and beta thalassaemia (n = 26, 21.3%), respectively. Of the patients with beta thalassaemia, 14 patients had frequent blood
V. Osborne et al. Fig. 2 Cohort flow diagram
transfusions (as indicated by C 7 mL/kg/month of packed RBCs); three patients had reported infrequent blood transfusions (packed RBC \ 7 mL/kg/month). For nine patients with beta thalassaemia, it was unknown if they had frequent or infrequent blood transfusions. 3.3 Initiation of Treatment For 103 (84.4%) of the 122 patients in the cohort, it was specified whether a ‘specialist’ or a GP initiated the patient’s treatment. Treatment was initiated by a specialist for 100 patients (82.0%) and by their GP for only three patients (2.5%). 3.4 Initial Dose and Maintenance Dose of Deferasirox The initial dose at start of treatment with deferasirox was reported for 51 (41.8%) of the 122 patients in the cohort. For 23 patients the initial dose was 10 mg/kg/day (18.9%). There were a further 20 patients prescribed deferasirox at a starting dose of 20 mg/kg/day (16.4%). For 40 patients in the cohort, the maintenance dose was specified. Twenty-eight of the 40 patients for whom maintenance dose was specified also had a reported initial dose. Of the 28 patients for whom this information was available, the majority of patients increased their daily dose from start of treatment to maintenance dose (n = 17, 60.7% where initial dose and
maintenance dose were specified). Eight patients remained on the same dose for maintenance as the initial dose at start of treatment (28.6% where initial dose and maintenance dose were specified) and three patients had a lower maintenance dose than their initial starting dose (10.7% where initial dose and maintenance dose were specified). 3.5 Serum Creatinine Levels Prior to Starting Treatment Prescribing guidelines for deferasirox recommend that serum creatinine should be measured in duplicate prior to initiating therapy, due to observed increases in serum creatinine levels during clinical trials [5]. A tick box question was included on the questionnaire to ask whether serum creatinine was measured and if so, the date of measurement and the value. Of the 18 patients for whom prior serum creatinine levels were provided, the median value was 69 lmol/L (IQR 51–95; reference range 60–110 lmol/L [male], 45–90 lmol/L [female]) [8]. Four values were above the upper limit of normal; 95–139 lmol/L in two male and two female patients, respectively; however, the initial starting dose was not provided for any of these patients. Events reported in these four patients included raised ferritin, renal function decline, ear wax and cellulitis of the leg; one patient was also noted to have been started on warfarin for atrial fibrillation.
Utilisation and Safety of Deferasirox Table 1 Cohort characteristics
Characteristicsa
Total cohort N = 122
Aged 2–5 years N = 12
Aged 6–9 years N = 17
Aged 10–17 years N = 22
Age at start of treatment (years), n (%) 2–5
12 (9.8)
6–9
17 (13.9)
10–17
22 (18.0)
18–64
44 (36.1)
C 65
27 (22.1)
Median age (IQR)
23 (11, 61)
Not known
0
Sex, n (%) Males
71 (58.2)
8 (66.7)
11 (64.7)
12 (54.5)
Females Not known
51 (41.8) 0 (0.0)
4 (33.3) 0 (0.0)
6 (35.3) 0 (0.0)
10 (45.5) 0 (0.0)
Reasons for prescribing, n (%) Beta thalassaemia
26 (21.3)
5 (41.7)
2 (11.8)
6 (27.3)
Sickle cell anaemia
27 (22.1)
5 (41.7)
10 (58.8)
6 (27.3)
Myelodysplastic syndrome
13 (10.7)
0 (0.0)
0 (0.0)
0 (0.0)
Congenital aplastic anaemia
8 (6.6)
1 (8.3)
2 (11.8)
2 (9.1)
Other
29 (23.8)
1 (8.3)
1 (5.9)
4 (18.2)
Not known
19 (15.6)
0 (0.0)
2 (11.8)
4 (18.2)
100 (82.0)
11 (91.7)
15 (88.2)
15 (68.2)
3 (2.5)
0 (0.0)
0 (0.0)
2 (9.1)
19 (15.6)
1 (8.3)
2 (11.8)
5 (22.7)
10 mg/kg/day
23 (18.9)
2 (16.7)
1 (5.9)
3 (13.6)
20 mg/kg/day
20 (16.4)
4 (33.3)
2 (11.8)
2 (9.1)
30 mg/kg/day Other
3 (2.5) 5 (4.1)
1 (8.3) 0 (0.0)
1 (5.9) 1 (5.9)
0 (0.0) 3 (13.6)
71 (58.2)
5 (41.7)
12 (70.6)
14 (63.6)
10 mg/kg/day
4 (3.3)
0 (0.0)
0 (0.0)
0 (0.0)
20 mg/kg/day
10 (8.2)
2 (16.7)
1 (5.9)
2 (9.1)
30 mg/kg/day
9 (7.4)
0 (0.0)
2 (11.8)
2 (9.1)
Other
17 (13.9)
3 (25.0)
2 (11.8)
5 (22.7)
Not known
82 (67.2)
7 (58.3)
12 (70.6)
13 (59.1)
Initial prescriber, n (%) Specialist GP Not known Initial dose, n (%)
Not known Maintenance dose, n (%)
a
All percentages are % of total
3.6 Serum Creatinine Levels After Starting Treatment Of the 11 patients for whom serum creatinine values were provided following the start of treatment, seven patients (two male, five female) had values which exceeded the upper limit of normal. The two male patients were aged 24 and 40 years; creatinine values provided were 122 and 137 lmol/L. The only events reported for these two patients were low back pain, prostatism and investigations into loss of weight. The five female patients (aged 38–75 years) had creatinine
values of 96–267 lmol/L, respectively; the value of 267 lmol/L was obtained approximately 18 months following the start of treatment and this patient was reported to have pre-existing renal disease and was on renal dialysis during treatment with deferasirox. Clinical events reported in the other patients included indigestion and heartburn. 3.7 Events Events were collected as free-text responses on the questionnaire and 91 incident (first report) events were reported
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in the cohort. All events where the number reported was two or more are shown in Table 2. There were two reports of increased serum creatinine (MedDRA preferred term: blood creatinine increased) in the cohort, one of which occurred 4 months after starting treatment and the other occurred 6 months after starting treatment. Both events occurred during treatment with deferasirox. Of the 91 events reported in the cohort, 20 of these occurred in patients aged 2–17 years (children and adolescents). One event was reported in a patient aged 2–5 years (refusal of treatment by relative), nine events were reported in patients aged 6–9 years and ten events were reported in patients aged 10–17 years (Table 3). One of the two reported cases of increased serum creatinine in the cohort occurred in a child aged 6–9 years.
patients in total, with 51 patients aged 2–17 years (children and adolescents). Of these 51 patients, 12 were aged 2–5 years, 17 patients were aged 6–9 years and 22 patients were aged 10–17 years. In this study, treatment was initiated by a specialist for 100 patients (82.0%) and by their GP for three patients (2.5%); this information was not specified for the remaining 19 patients. Since it is recommended that treatment with deferasirox is ‘‘initiated and maintained by physicians experienced in the treatment of chronic iron overload due to blood transfusions’’ [5], it is not unexpected that for many of the patients identified in this study their treatment was initiated by hospital specialists. Of the 51 patients (41.8% of cohort) for whom the initial dose at start of treatment with deferasirox was reported in this cohort, the majority of patients (84.3% where specified) were prescribed 10 or 20 mg/kg/day. The recommended initial daily dose of deferasirox is 20 mg/kg body weight or 10 mg/kg/day (in certain circumstances, for example if ‘‘the patient does not require reduction of body iron levels and is receiving \ 7 mL/kg/month of packed red blood cells’’ [5]). As such, this finding is in concordance with the prescribing recommendations for deferasirox. However, due to the large number of patients for whom dose was not reported (n = 71, 58.2% of cohort), any final conclusions on adherence to dosage guidelines cannot be drawn based on these results alone. It is recommended that serum creatinine be assessed in duplicate before initiating therapy, due to the identified risk of raised serum creatinine levels after initiating deferasirox therapy [5]. Only 18 patients were reported to have had a creatinine value measured prior to starting treatment. As such, it appeared that very few patients had their creatinine levels assessed prior to initiating therapy. However, it is possible that creatinine levels were initially assessed under care of a specialist and these results were not available to the GP at the time of completing the questionnaire.
3.8 Reasons for Stopping Deferasirox Treatment with deferasirox had not been stopped for 67 of 102 (65.7%) patients for which definite information was obtained during the observation period. For 20 patients (16.4% of cohort) it was not known if treatment was discontinued. GPs recorded 17 reasons for stopping deferasirox in 14 patients (11.5% of cohort, 40.0% of patients who stopped treatment) (Table 4). Eleven reasons were reported within the first 6 months. Three patients had more than one reason reported for discontinuing deferasirox. Increased serum creatinine was the reason for stopping treatment in two patients.
4 Discussion In this study, we aimed to examine the utilisation and safety of deferasirox used in general medical practice in England. The final evaluable cohort consisted of 122
Table 2 Events reported in total cohort where number of events C 2 (including events reported in both adults and children) MedDRA preferred term
Number reported in month 1
Number reported in months 2–6
Number reported in months 7?
Total number of events reported
Rash
3
1
1
5
Therapy regimen changed Serum ferritin increased
1 2
1 0
2 1
4 3
Pre-existing condition improved
1
1
1
3
Abdominal pain
1
0
1
2
Death
1
1
0
2
Lower respiratory tract infection
1
1
0
2
Arthralgia
0
1
1
2
Blood creatinine increaseda
0
2
0
2
This is the MedDRA preferred term which refers to increased serum creatinine
a
Utilisation and Safety of Deferasirox Table 3 Events reported in children and adolescents (aged 2–17 years)
MedDRA preferred term
Aged 2–5 years Na
Aged 6–9 years N
Abdominal pain
0
0
Abnormal behaviour
Aged 10–17 years N 2
0
1
Blood creatinine increasedb
0
1
0
Endoscopy upper gastrointestinal tract
0
0
1
Gastritis
0
0
1
Gastrointestinal haemorrhage
0
0
1
Lower respiratory tract infection
0
1
0
Pharyngitis
0
1
0
Proteinuria
0
1
0
Rash
0
0
2
Refusal of treatment by relative Renal function test normal
1 0
0 1
0 0
Snoring
0
1
0
Staphylococcal skin infection
0
0
1
Therapy regimen changed
0
0
1
Ultrasound Doppler
0
1
0
Unevaluable eventc
0
2
0
Total
1
9
10
a
Number of events This is the MedDRA preferred term which refers to increased serum creatinine
b c
Reported event terms: drug restarted (n = 1), left practice (n = 1)
Table 4 Reasons for stopping deferasirox Reasons for stopping (MedDRA preferred term)
Total cohort N = 122
Aged 2–5 years N = 12
Aged 6–9 years N = 17
Aged 10–17 years N = 22
Pre-existing condition improved
3
0
0
0
Blood creatinine increaseda
2
0
1
0
Unevaluable eventb
2
0
0
0
Pharyngitis
1
0
1
0
Visual acuity reduced
1
0
0
0
Gastritis
1
0
0
1
Abdominal pain
1
0
0
1
Arthralgia
1
0
0
0
Muscle spasms
1
0
0
0
Death
1
0
0
0
Drug ineffective
1
0
0
0
Refusal of treatment by patient
1
0
0
0
Refusal of treatment by relative
1
1
0
0
17
1
2
2
Total
Multiple reasons for stopping may have been reported per patient This is the MedDRA preferred term which refers to increased serum creatinine
a
b
Reported event terms: ‘‘hospital stopped it’’ (n = 1) and ‘‘only 1 prescription’’ (n = 1)
Increased serum creatinine was an event of interest in the study as the EU Summary of Product Characteristics (SmPC) states that during clinical trials increases in serum creatinine of [ 33% on two or more occasions was
observed in about 36% of patients. Increased blood creatinine is listed as very common in the EU SmPC, though it occurred at a lower frequency in this study (n = 2, 1.6% of cohort) [5]. No events reported in this study were found to
V. Osborne et al.
have occurred at greater frequency than that reported in the EU SmPC [5]. The results of this study are in concordance with a recent systematic review evaluating the safety of oral iron-chelating agents in young patients \ 25 years of age. The review concluded that such therapy is generally safe and other studies have shown that adverse events do not occur at greater frequency than that reported in the EU SmPC [4]. 4.1 Strengths and Limitations of the Study Design In PEM, exposure is based on dispensed prescription data which are more accurate than exposure data based solely on written prescriptions. However, as with many observational studies, the degree of patient compliance in taking the prescribed medication cannot be ascertained. PEM is reliant on the GP confirming the prescription was issued from the patient’s medical records—human error can occur in this process. Data errors are also possible in dispensed prescription data. We excluded questionnaires where the GP could not confirm the prescription was issued. In addition, the amount of information available to the GP to complete the questionnaire is dependent on the amount of information provided to the GP by the specialist, especially in relation to lab test values and previous medications prescribed in secondary care. Since 97% of patients were initiated on treatment by a specialist, it is possible that the study may be limited by the amount of information available in GP notes. The proportion of total scripts issued by general practitioners in England cannot be determined as we do not have data available on prescriptions issued by specialists. However, GP notes should contain all information on events that were reported to the GP. Where events occurred in secondary care, the GP will likely have been made aware of these through communication with secondary care. We acknowledge that non-response bias may have been a potential bias in this study. It is unknown whether the characteristics of patients for whom the GP returned a valid questionnaire may differ to those of patients for whom no response was received from the GP, as such this represents a potential source of selection bias and may impact on the representativeness of patients included in this cohort. However, the response rate in this study (61.3%) is comparable to response rates reported elsewhere for GP postal surveys [9] and higher than the reporting rates of suspected adverse drug reactions (ADRs) in the Yellow Card scheme [10, 11]. Under-reporting may have occurred in this study if events that occurred under the care of the specialist were not communicated to the GP. As such, under-reporting of events including serious or fatal events is possible. Missing data was observed in this study and so the ‘true’ proportions
for some variables may differ from those observed in this study. 4.2 Generalisability This study was based in the primary care setting in England, although deferasirox is usually prescribed by specialists in secondary care. As such, this study would not have identified patients that were started on and stopped treatment in the secondary care setting only. Patients must have been continued on treatment in the primary care setting to be identified in this study. The results of this study in terms of utilisation should be generalisable to patients prescribed deferasirox under shared care arrangements (between specialists and GPs) in England. No conclusions can be drawn on generalisability to other populations.
5 Conclusion The final results of this PEM study show that deferasirox is largely being prescribed for its licensed indications in general practice in England. The results of this study contribute to the post-marketing information on this product. No previously unrecognised ADRs were identified. However, considering the small cohort size and that treatment is more likely to be initiated in secondary care, any conclusions on utilisation or safety of the product from this study should be put into context with results from other post-authorisation studies. Acknowledgements We would like to record our keen appreciation of the co-operation of the general practitioners and numerous other colleagues who have helped in this investigation. We also wish to thank Mr Shayne Freemantle and Mrs Rachel Green for their assistance in the preparation of this paper. Compliance with Ethical Standards Funding The Drug Safety Research Unit (DSRU) has received an unconditional grant from Novartis, the manufacturer of EXJADE (deferasirox) to conduct this study. Conflict of interest The Drug Safety Research Unit (DSRU) is an independent charity (No. 327206), and is an Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth. It receives unconditional grants from pharmaceutical companies; however, the DSRU retains operational, scientific and communications controls. Vicki Osborne, Miranda Davies, Deborah Layton and Saad Shakir have no other conflicts of interest to declare. Ethics This study was conducted in accordance with national and international guidelines [12–14]. In addition, under Section 251 of the NHS Act 2006, the DSRU have received support from the Ethics and Confidentiality Committee of the National Information Governance Board to gain access to and process patient identifiable information without consent for the purposes of medical research (October 2009).
Utilisation and Safety of Deferasirox
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ORIGINAL RESEARCH ARTICLE
Utilisation and Safety of Deferasirox: Results from an Observational Cohort Study in England Vicki Osborne1,3
•
Miranda Davies1,2 • Deborah Layton1,2 • Saad A. W. Shakir1,2
Springer International Publishing AG 2017
Abstract Introduction Deferasirox (EXJADE, Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. Objective The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. Method A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers C 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. Results The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2–17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior
measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. Conclusion These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.
Key Points Deferasirox is mostly being prescribed according to the licensed indications and at licensed doses within the UK. Events reported after treatment initiation, including raised serum creatinine, are consistent with the known safety profile.
1 Introduction Electronic supplementary material The online version of this article (doi:10.1007/s40264-017-0606-2) contains supplementary material, which is available to authorized users. & Saad A. W. Shakir [email protected] 1
Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton SO31 1AA, UK
2
School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK
3
Department of Epidemiology, University of Florida, Gainesville, FL, USA
Iron overload is a condition that occurs when iron is deposited in multiple organs and serum ferritin value is greater than 1000 lg/L [1]. It can be caused by both regular blood transfusions and genetic conditions such hereditary haemochromatosis [1, 2]. Many rare anaemias such as sickle cell anaemia or beta thalassaemia are treated with regular red blood cell (RBC) transfusions, since there can be a decrease in RBC production or increase in cell destruction with these disorders [3]. Such chronic blood transfusions will usually lead to chronic iron overload and so patients with these rare anaemias often require iron
V. Osborne et al.
chelation therapy [3]. The aim of this therapy is to maintain safe iron levels for the patient [4]. Three iron-chelating medications are currently available for the treatment of iron overload: deferoxamine, deferasirox and deferiprone [4]. Deferasirox (EXJADE, Novartis, UK) is an oral medication indicated for the treatment of chronic iron overload due to frequent blood transfusions (C 7 mL/kg/month of packed RBCs) in patients with beta thalassaemia major aged 6 years and older [5]. It is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy (another iron-chelating agent) is contraindicated or inadequate in the following patient groups: •
•
•
aged 2–5 years with beta thalassaemia major and overload due to frequent blood transfusions (C 7 kg/month of packed RBCs); aged C 2 years with beta thalassaemia major and overload due to infrequent blood transfusions (\ 7 kg/month of packed RBCs); aged C 2 years with other anaemias [5].
iron mL/ iron mL/
Deferasirox is also indicated for the treatment of chronic iron overload requiring chelating therapy in situations whereby deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older [5]. Deferasirox is to be taken at an initial dose of 20 mg/kg body weight, with a maximum dose of 40 mg/kg [5]. It provides 24-h chelation for both intra- and extracellular excess iron in the body including in the heart, liver, reticuloendothelial system and the circulation [6]. Randomised controlled trials in the pre-marketing phase included 1005 patients with transfusional iron overload in various diseases (beta thalassemia, rare anaemias, sickle cell disease) of whom 652 received deferasirox and 353 deferoxamine [6]. The safety issues that were identified with deferasirox during these studies included increases in serum creatinine of [ 30 to [ 90% that occurred mainly during the first month of treatment, hepatobiliary disorders and increases in liver transaminases that occurred within a few months of starting deferasirox, skin rash (though these resolved spontaneously for most cases) and, as with other iron-chelating agents such as deferoxamine, high-frequency hearing loss and lenticular opacities (early cataracts) [6]. In order to study the safety and utilisation of deferasirox in the post-marketing phase, an observational single exposure cohort study was conducted using PrescriptionEvent Monitoring (PEM). PEM studies provide active surveillance of targeted medicines on a national scale in England [7]. These studies can provide information on the safety and utilisation of medicines in the real-world setting to contribute to the post-marketing information of a
product [7]. The overall aim of this study was to examine the utilisation and safety of deferasirox used in general medical practice in England.
2 Methods 2.1 Study Design An observational post-marketing cohort study (PEM) was conducted to monitor the safety and utilisation of deferasirox as used in general practice in England. A detailed description of PEM is published elsewhere [7]. Briefly, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for deferasirox, supplied to the Drug Safety Research Unit (DSRU) in confidence by the National Health Service Business Services Authority (NHSBSA). All patients who were dispensed a script, written by a GP for deferasirox in England during the study period, would have been identified using data from the NHSBSA. The GPs were sent a short postal questionnaire (see Electronic Supplementary Material 1) at least 6 months following the date of the first prescription for deferasirox for each individual patient between September 2006 and September 2014, requesting information including reason for prescribing, initial dose, maintenance dose, start and stop dates of treatment (if stopped), age, gender, reasons for stopping deferasirox and details of events1 experienced by patients after starting therapy. GPs were also asked whether serum creatinine was measured prior to commencing treatment and, if so, the measurement and date obtained. Questionnaires were sent in monthly batches and processed as soon as they were returned to the DSRU. In order to maximise the GP response rate, a second questionnaire was posted to GPs relating to specific patient(s) for whom they had not responded, within 2 months of the date the initial questionnaire was sent. A flow diagram of the study methodology is provided in Fig. 1. Reason for prescribing deferasirox was captured through tick boxes since the indications were highly specific to the product; however, a free-text option remained. The information provided for these patients was coded onto a database; events and free-text reasons for prescribing were extracted according to MedDRA (v17). Analyses were performed using STATA v12 (StataCorp, TX, USA).
1
An ‘event’ in PEM is defined as ‘‘any new diagnosis, any reason for referral to a consultant or admission to hospital, any unexpected deterioration (or improvement) in a concurrent illness, any alteration of clinical importance in laboratory values, or any other complaint that was considered of sufficient importance to enter in the patient’s notes.’’
Utilisation and Safety of Deferasirox Fig. 1 Flow diagram of study methodology. DRSU Drug Safety Research Unit, GP General Practitioner, NHSBSA National Health Service Business Services Authority, PEM Prescription-Event Monitoring
2.2 Inclusion and Exclusion Criteria For this study, eligible subjects were those patients who received a prescription from a GP for deferasirox in the primary care setting and for whom deferasirox was subsequently dispensed at an NHS contracted pharmacy in England. Thus, patients were identified from prescription data for deferasirox. Patients were admitted to the study regardless of the strength or frequency of administration of deferasirox and irrespective of whether any medicines were concurrently administered. Those patients for whom any of the following applied were excluded from the final evaluable cohort: questionnaire was returned with no information (blank), the GP reported that the patient did not take, and had never been prescribed, deferasirox, the GP reported that the patient was no longer registered with the practice and no information was provided (where information was available up to a specific date it was included). 2.3 Analysis Summary descriptive statistics were calculated. All percentages were calculated using a denominator of the total cohort size for each stratum. Missing data were defined as non-response to a specific question or where the GP specified that the answer was not known. These numbers are provided in the tables, where applicable. 2.4 Quality Assurance in Prescription-Event Monitoring (PEM) Good data management is a high priority in all PEM studies, including for deferasirox. A number of strategies were used to minimise biased results. Data quality was assured through a number of methods such as operator training, on-screen validation during data entry, adoption of and adherence to study-specific data coding conventions,
coding and convention meetings, double entry (10%) with error reporting, data cleaning using logical checks and analysis of outliers.
3 Results The final evaluable study cohort consisted of 122 patients (Fig. 2). 3.1 Age and Gender The median age of the whole cohort was 23 years (interquartile range [IQR] 11–61 years). The median age for male patients was 21 years (IQR 9–64); and for female patients the median age was 26 years (IQR 13–58). Seventy-one patients (58.2% of cohort) were male. In total, 12 patients (9.8% of cohort) were aged 2–5 years, 17 patients (13.9% of cohort) were aged 6–9 years and 22 patients (18.0% of cohort) were aged 10–17 years. No patients were younger than 2 years of age. Summary characteristics for the cohort are provided in Table 1. 3.2 Reasons for Prescribing Deferasirox GPs were asked to report the reasons for prescribing deferasirox, which may have been reported as the clinical condition leading to the need for blood transfusions, but could also have been reported as laboratory findings (e.g. iron overload, increased serum ferritin). More than one reason for prescribing could have been reported and these were coded as primary, secondary and tertiary reasons for prescribing. A primary reason for prescribing deferasirox was reported for 103 patients (84.4% of total cohort). The most frequently reported primary reasons for prescribing were sickle cell anaemia (n = 27, 22.1%) and beta thalassaemia (n = 26, 21.3%), respectively. Of the patients with beta thalassaemia, 14 patients had frequent blood
V. Osborne et al. Fig. 2 Cohort flow diagram
transfusions (as indicated by C 7 mL/kg/month of packed RBCs); three patients had reported infrequent blood transfusions (packed RBC \ 7 mL/kg/month). For nine patients with beta thalassaemia, it was unknown if they had frequent or infrequent blood transfusions. 3.3 Initiation of Treatment For 103 (84.4%) of the 122 patients in the cohort, it was specified whether a ‘specialist’ or a GP initiated the patient’s treatment. Treatment was initiated by a specialist for 100 patients (82.0%) and by their GP for only three patients (2.5%). 3.4 Initial Dose and Maintenance Dose of Deferasirox The initial dose at start of treatment with deferasirox was reported for 51 (41.8%) of the 122 patients in the cohort. For 23 patients the initial dose was 10 mg/kg/day (18.9%). There were a further 20 patients prescribed deferasirox at a starting dose of 20 mg/kg/day (16.4%). For 40 patients in the cohort, the maintenance dose was specified. Twenty-eight of the 40 patients for whom maintenance dose was specified also had a reported initial dose. Of the 28 patients for whom this information was available, the majority of patients increased their daily dose from start of treatment to maintenance dose (n = 17, 60.7% where initial dose and
maintenance dose were specified). Eight patients remained on the same dose for maintenance as the initial dose at start of treatment (28.6% where initial dose and maintenance dose were specified) and three patients had a lower maintenance dose than their initial starting dose (10.7% where initial dose and maintenance dose were specified). 3.5 Serum Creatinine Levels Prior to Starting Treatment Prescribing guidelines for deferasirox recommend that serum creatinine should be measured in duplicate prior to initiating therapy, due to observed increases in serum creatinine levels during clinical trials [5]. A tick box question was included on the questionnaire to ask whether serum creatinine was measured and if so, the date of measurement and the value. Of the 18 patients for whom prior serum creatinine levels were provided, the median value was 69 lmol/L (IQR 51–95; reference range 60–110 lmol/L [male], 45–90 lmol/L [female]) [8]. Four values were above the upper limit of normal; 95–139 lmol/L in two male and two female patients, respectively; however, the initial starting dose was not provided for any of these patients. Events reported in these four patients included raised ferritin, renal function decline, ear wax and cellulitis of the leg; one patient was also noted to have been started on warfarin for atrial fibrillation.
Utilisation and Safety of Deferasirox Table 1 Cohort characteristics
Characteristicsa
Total cohort N = 122
Aged 2–5 years N = 12
Aged 6–9 years N = 17
Aged 10–17 years N = 22
Age at start of treatment (years), n (%) 2–5
12 (9.8)
6–9
17 (13.9)
10–17
22 (18.0)
18–64
44 (36.1)
C 65
27 (22.1)
Median age (IQR)
23 (11, 61)
Not known
0
Sex, n (%) Males
71 (58.2)
8 (66.7)
11 (64.7)
12 (54.5)
Females Not known
51 (41.8) 0 (0.0)
4 (33.3) 0 (0.0)
6 (35.3) 0 (0.0)
10 (45.5) 0 (0.0)
Reasons for prescribing, n (%) Beta thalassaemia
26 (21.3)
5 (41.7)
2 (11.8)
6 (27.3)
Sickle cell anaemia
27 (22.1)
5 (41.7)
10 (58.8)
6 (27.3)
Myelodysplastic syndrome
13 (10.7)
0 (0.0)
0 (0.0)
0 (0.0)
Congenital aplastic anaemia
8 (6.6)
1 (8.3)
2 (11.8)
2 (9.1)
Other
29 (23.8)
1 (8.3)
1 (5.9)
4 (18.2)
Not known
19 (15.6)
0 (0.0)
2 (11.8)
4 (18.2)
100 (82.0)
11 (91.7)
15 (88.2)
15 (68.2)
3 (2.5)
0 (0.0)
0 (0.0)
2 (9.1)
19 (15.6)
1 (8.3)
2 (11.8)
5 (22.7)
10 mg/kg/day
23 (18.9)
2 (16.7)
1 (5.9)
3 (13.6)
20 mg/kg/day
20 (16.4)
4 (33.3)
2 (11.8)
2 (9.1)
30 mg/kg/day Other
3 (2.5) 5 (4.1)
1 (8.3) 0 (0.0)
1 (5.9) 1 (5.9)
0 (0.0) 3 (13.6)
71 (58.2)
5 (41.7)
12 (70.6)
14 (63.6)
10 mg/kg/day
4 (3.3)
0 (0.0)
0 (0.0)
0 (0.0)
20 mg/kg/day
10 (8.2)
2 (16.7)
1 (5.9)
2 (9.1)
30 mg/kg/day
9 (7.4)
0 (0.0)
2 (11.8)
2 (9.1)
Other
17 (13.9)
3 (25.0)
2 (11.8)
5 (22.7)
Not known
82 (67.2)
7 (58.3)
12 (70.6)
13 (59.1)
Initial prescriber, n (%) Specialist GP Not known Initial dose, n (%)
Not known Maintenance dose, n (%)
a
All percentages are % of total
3.6 Serum Creatinine Levels After Starting Treatment Of the 11 patients for whom serum creatinine values were provided following the start of treatment, seven patients (two male, five female) had values which exceeded the upper limit of normal. The two male patients were aged 24 and 40 years; creatinine values provided were 122 and 137 lmol/L. The only events reported for these two patients were low back pain, prostatism and investigations into loss of weight. The five female patients (aged 38–75 years) had creatinine
values of 96–267 lmol/L, respectively; the value of 267 lmol/L was obtained approximately 18 months following the start of treatment and this patient was reported to have pre-existing renal disease and was on renal dialysis during treatment with deferasirox. Clinical events reported in the other patients included indigestion and heartburn. 3.7 Events Events were collected as free-text responses on the questionnaire and 91 incident (first report) events were reported
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in the cohort. All events where the number reported was two or more are shown in Table 2. There were two reports of increased serum creatinine (MedDRA preferred term: blood creatinine increased) in the cohort, one of which occurred 4 months after starting treatment and the other occurred 6 months after starting treatment. Both events occurred during treatment with deferasirox. Of the 91 events reported in the cohort, 20 of these occurred in patients aged 2–17 years (children and adolescents). One event was reported in a patient aged 2–5 years (refusal of treatment by relative), nine events were reported in patients aged 6–9 years and ten events were reported in patients aged 10–17 years (Table 3). One of the two reported cases of increased serum creatinine in the cohort occurred in a child aged 6–9 years.
patients in total, with 51 patients aged 2–17 years (children and adolescents). Of these 51 patients, 12 were aged 2–5 years, 17 patients were aged 6–9 years and 22 patients were aged 10–17 years. In this study, treatment was initiated by a specialist for 100 patients (82.0%) and by their GP for three patients (2.5%); this information was not specified for the remaining 19 patients. Since it is recommended that treatment with deferasirox is ‘‘initiated and maintained by physicians experienced in the treatment of chronic iron overload due to blood transfusions’’ [5], it is not unexpected that for many of the patients identified in this study their treatment was initiated by hospital specialists. Of the 51 patients (41.8% of cohort) for whom the initial dose at start of treatment with deferasirox was reported in this cohort, the majority of patients (84.3% where specified) were prescribed 10 or 20 mg/kg/day. The recommended initial daily dose of deferasirox is 20 mg/kg body weight or 10 mg/kg/day (in certain circumstances, for example if ‘‘the patient does not require reduction of body iron levels and is receiving \ 7 mL/kg/month of packed red blood cells’’ [5]). As such, this finding is in concordance with the prescribing recommendations for deferasirox. However, due to the large number of patients for whom dose was not reported (n = 71, 58.2% of cohort), any final conclusions on adherence to dosage guidelines cannot be drawn based on these results alone. It is recommended that serum creatinine be assessed in duplicate before initiating therapy, due to the identified risk of raised serum creatinine levels after initiating deferasirox therapy [5]. Only 18 patients were reported to have had a creatinine value measured prior to starting treatment. As such, it appeared that very few patients had their creatinine levels assessed prior to initiating therapy. However, it is possible that creatinine levels were initially assessed under care of a specialist and these results were not available to the GP at the time of completing the questionnaire.
3.8 Reasons for Stopping Deferasirox Treatment with deferasirox had not been stopped for 67 of 102 (65.7%) patients for which definite information was obtained during the observation period. For 20 patients (16.4% of cohort) it was not known if treatment was discontinued. GPs recorded 17 reasons for stopping deferasirox in 14 patients (11.5% of cohort, 40.0% of patients who stopped treatment) (Table 4). Eleven reasons were reported within the first 6 months. Three patients had more than one reason reported for discontinuing deferasirox. Increased serum creatinine was the reason for stopping treatment in two patients.
4 Discussion In this study, we aimed to examine the utilisation and safety of deferasirox used in general medical practice in England. The final evaluable cohort consisted of 122
Table 2 Events reported in total cohort where number of events C 2 (including events reported in both adults and children) MedDRA preferred term
Number reported in month 1
Number reported in months 2–6
Number reported in months 7?
Total number of events reported
Rash
3
1
1
5
Therapy regimen changed Serum ferritin increased
1 2
1 0
2 1
4 3
Pre-existing condition improved
1
1
1
3
Abdominal pain
1
0
1
2
Death
1
1
0
2
Lower respiratory tract infection
1
1
0
2
Arthralgia
0
1
1
2
Blood creatinine increaseda
0
2
0
2
This is the MedDRA preferred term which refers to increased serum creatinine
a
Utilisation and Safety of Deferasirox Table 3 Events reported in children and adolescents (aged 2–17 years)
MedDRA preferred term
Aged 2–5 years Na
Aged 6–9 years N
Abdominal pain
0
0
Abnormal behaviour
Aged 10–17 years N 2
0
1
Blood creatinine increasedb
0
1
0
Endoscopy upper gastrointestinal tract
0
0
1
Gastritis
0
0
1
Gastrointestinal haemorrhage
0
0
1
Lower respiratory tract infection
0
1
0
Pharyngitis
0
1
0
Proteinuria
0
1
0
Rash
0
0
2
Refusal of treatment by relative Renal function test normal
1 0
0 1
0 0
Snoring
0
1
0
Staphylococcal skin infection
0
0
1
Therapy regimen changed
0
0
1
Ultrasound Doppler
0
1
0
Unevaluable eventc
0
2
0
Total
1
9
10
a
Number of events This is the MedDRA preferred term which refers to increased serum creatinine
b c
Reported event terms: drug restarted (n = 1), left practice (n = 1)
Table 4 Reasons for stopping deferasirox Reasons for stopping (MedDRA preferred term)
Total cohort N = 122
Aged 2–5 years N = 12
Aged 6–9 years N = 17
Aged 10–17 years N = 22
Pre-existing condition improved
3
0
0
0
Blood creatinine increaseda
2
0
1
0
Unevaluable eventb
2
0
0
0
Pharyngitis
1
0
1
0
Visual acuity reduced
1
0
0
0
Gastritis
1
0
0
1
Abdominal pain
1
0
0
1
Arthralgia
1
0
0
0
Muscle spasms
1
0
0
0
Death
1
0
0
0
Drug ineffective
1
0
0
0
Refusal of treatment by patient
1
0
0
0
Refusal of treatment by relative
1
1
0
0
17
1
2
2
Total
Multiple reasons for stopping may have been reported per patient This is the MedDRA preferred term which refers to increased serum creatinine
a
b
Reported event terms: ‘‘hospital stopped it’’ (n = 1) and ‘‘only 1 prescription’’ (n = 1)
Increased serum creatinine was an event of interest in the study as the EU Summary of Product Characteristics (SmPC) states that during clinical trials increases in serum creatinine of [ 33% on two or more occasions was
observed in about 36% of patients. Increased blood creatinine is listed as very common in the EU SmPC, though it occurred at a lower frequency in this study (n = 2, 1.6% of cohort) [5]. No events reported in this study were found to
V. Osborne et al.
have occurred at greater frequency than that reported in the EU SmPC [5]. The results of this study are in concordance with a recent systematic review evaluating the safety of oral iron-chelating agents in young patients \ 25 years of age. The review concluded that such therapy is generally safe and other studies have shown that adverse events do not occur at greater frequency than that reported in the EU SmPC [4]. 4.1 Strengths and Limitations of the Study Design In PEM, exposure is based on dispensed prescription data which are more accurate than exposure data based solely on written prescriptions. However, as with many observational studies, the degree of patient compliance in taking the prescribed medication cannot be ascertained. PEM is reliant on the GP confirming the prescription was issued from the patient’s medical records—human error can occur in this process. Data errors are also possible in dispensed prescription data. We excluded questionnaires where the GP could not confirm the prescription was issued. In addition, the amount of information available to the GP to complete the questionnaire is dependent on the amount of information provided to the GP by the specialist, especially in relation to lab test values and previous medications prescribed in secondary care. Since 97% of patients were initiated on treatment by a specialist, it is possible that the study may be limited by the amount of information available in GP notes. The proportion of total scripts issued by general practitioners in England cannot be determined as we do not have data available on prescriptions issued by specialists. However, GP notes should contain all information on events that were reported to the GP. Where events occurred in secondary care, the GP will likely have been made aware of these through communication with secondary care. We acknowledge that non-response bias may have been a potential bias in this study. It is unknown whether the characteristics of patients for whom the GP returned a valid questionnaire may differ to those of patients for whom no response was received from the GP, as such this represents a potential source of selection bias and may impact on the representativeness of patients included in this cohort. However, the response rate in this study (61.3%) is comparable to response rates reported elsewhere for GP postal surveys [9] and higher than the reporting rates of suspected adverse drug reactions (ADRs) in the Yellow Card scheme [10, 11]. Under-reporting may have occurred in this study if events that occurred under the care of the specialist were not communicated to the GP. As such, under-reporting of events including serious or fatal events is possible. Missing data was observed in this study and so the ‘true’ proportions
for some variables may differ from those observed in this study. 4.2 Generalisability This study was based in the primary care setting in England, although deferasirox is usually prescribed by specialists in secondary care. As such, this study would not have identified patients that were started on and stopped treatment in the secondary care setting only. Patients must have been continued on treatment in the primary care setting to be identified in this study. The results of this study in terms of utilisation should be generalisable to patients prescribed deferasirox under shared care arrangements (between specialists and GPs) in England. No conclusions can be drawn on generalisability to other populations.
5 Conclusion The final results of this PEM study show that deferasirox is largely being prescribed for its licensed indications in general practice in England. The results of this study contribute to the post-marketing information on this product. No previously unrecognised ADRs were identified. However, considering the small cohort size and that treatment is more likely to be initiated in secondary care, any conclusions on utilisation or safety of the product from this study should be put into context with results from other post-authorisation studies. Acknowledgements We would like to record our keen appreciation of the co-operation of the general practitioners and numerous other colleagues who have helped in this investigation. We also wish to thank Mr Shayne Freemantle and Mrs Rachel Green for their assistance in the preparation of this paper. Compliance with Ethical Standards Funding The Drug Safety Research Unit (DSRU) has received an unconditional grant from Novartis, the manufacturer of EXJADE (deferasirox) to conduct this study. Conflict of interest The Drug Safety Research Unit (DSRU) is an independent charity (No. 327206), and is an Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth. It receives unconditional grants from pharmaceutical companies; however, the DSRU retains operational, scientific and communications controls. Vicki Osborne, Miranda Davies, Deborah Layton and Saad Shakir have no other conflicts of interest to declare. Ethics This study was conducted in accordance with national and international guidelines [12–14]. In addition, under Section 251 of the NHS Act 2006, the DSRU have received support from the Ethics and Confidentiality Committee of the National Information Governance Board to gain access to and process patient identifiable information without consent for the purposes of medical research (October 2009).
Utilisation and Safety of Deferasirox
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