Haemolytic anaemia induced by flutamide: a case report
Yu Sun, Suyan Zhu ®, Qi Hu, Ping Xu İD
Department of Pharmacy, Ningbo City First Hospital, Ningbo, Zhejiang, China
Correspondence to Ping Xu, Pharmacy, Ningbo City First Hospital, Ningbo 315010, China; pxu2004@ 126.com
Received 15 June 2021 Accepted 12 July 2021 Published Online First 2 August 2021
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@ European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.
To cite: Sun Y, Zhu S, Hu Q, et al. Eur J Hosp Pharm 2023;30:e109-e111.
SUMMARY
Flutamide-induced haemolytic anaemia is rare but can be fatal. We describe the case of an 88-year-old man with prostatic carcinoma who, in addition to clinically obvious jaundice, developed haemolytic anaemia after undergoing treatment with flutamide for 5 days. When flutamide was replaced with temporary adrenocortical hormone treatment and blood transfusion, the blood indices and liver function of the patient improved gradually. We emphasise the need for routine monitoring of blood counts for patients undergoing flutamide treatment, and highlight the importance of discontinuing flutamide immediately when haemolytic anaemia occurs.
BACKGROUND
Flutamide is a non-steroidal anti-androgen that was first designed and synthesised by Schering- Plough.1 2 Flutamide exerts its anti-androgenic effect by inhibiting androgen uptake and preventing androgen binding.3 Although drug-induced haemo- lytic anaemia is rare, it can be fatal.4 5 Immune- mediated destruction of red blood cells (RBCs) is the predominant cause of drug-induced haemolytic anaemia.6 Several drugs have been reported to induce haemolytic anaemia including piperacillin,’ cefotetan8 9 and ceftriaxone. 10
It is difficult to identify drug-induced haemolytic anaemia symptomatically. Thus, reporting clinical cases of this anaemia is crucial.11 Based on recent investigations, haemolytic anaemia is rarely caused by flutamide.2 12 We report the case of a patient who developed flutamide-induced haemolytic anaemia and recovered after flutamide discontinuation.
CASE PRESENTATION
An 88-year-old man was admitted to the emergency department complaining of disconnected syncope three times in 6hours. Concomitant symptoms of the patient included dizziness, incontinence, nausea and vomiting. His body temperature was 36.9ºC, heart rate 78 beats/min and blood pressure 152/70 mmHg. The patient had undergone treat- ment with flutamide for 5 days at a dose of 0.25 g orally three times daily in combination with goser- elin acetate, a gonadotrophin-releasing hormone analogue.
The patient was diagnosed originally with differ- entiated adenocarcinoma in the prostate and was treated with 3.6 mg of goserelin acetate subcutane- ously for 28 days, combined with a 50 mg bicalut- amide tablet orally per day as maintenance therapy since July 2015. However, the prostate-specific antigen level continued to escalate so bicalutamide
was replaced with flutamide 5 days prior to admission.
Haemolysis-related laboratory values are shown in figure 1. The patient had a reduced RBC count (2.28×1012/L), haemoglobin (Hb) level (66.0g/L) and haematocrit (HCT) level (21.4%). Further- more, the D-dimer level (651ng/ml) and white blood cell (WBC) count (11.74×109/L) were elevated. The platelet (PLT) count and troponin level of the patient were within normal limits. Blood gas analysis indicated an elevated blood lactic acid level (3.4 mmol/L), reduced partial pres- sure of oxygen (19 mmHg) and a mildly reduced HCO3- concentration (19.9 mmol/L). However, the partial pressure of carbon dioxide and pH were within normal limits. The liver function test revealed elevated concentrations of total bilirubin (TBIL) (148.9 µmol/L), direct bilirubin (DBIL) (22.4 µmol/L) and indirect bilirubin (IBIL) (126.5 umol/L). The albumin concentration was mildly reduced (34.9 g/L). However, alanine aminotrans- ferase (ALT), aspartate aminotransferase (AST), y-glutamyl transpeptidase (y-GT), alkaline phos- phatase (ALP) and total protein (TP) were within normal limits. The anaemia and obvious jaundice continued to worsen, leaving the patient in a crit- ical condition. Further examinations including CT revealed no abnormalities so bleeding disorders were ruled out. For the above reasons, we diag- nosed the patient with haemolytic anaemia.
INVESTIGATIONS
Consultation with the haematology department suggested that the haemolytic anaemia was prob- ably induced by flutamide, as prostate cancer progression rarely causes a significant reduction in Hb levels in such a short period. Therefore, flut- amide was discontinued immediately. Both direct and indirect Coombs tests returned negative results. Although coagulation function was normal, the reticulocyte count was elevated (6.77%; normal range 2.00-2.50%). Moreover, the faecal occult blood test was negative. No further haemolysis- related tests were conducted.
The clinical pharmacist assessed causality of the adverse drug reaction using the Naranjo algorithm. This revealed a score of 6, indicating a probable adverse drug reaction (table 1). This adverse reac- tion was submitted to the pharmacovigilance centre by the clinical pharmacist.
TREATMENT
Flutamide was discontinued as it was suspected to have caused the haemolytic anaemia, and the goserelin acetate sustained-release depot implant
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Case report
Hb
HCT
RBC
100
40-
4-
75.
30
3.
Hb(g/L)
HCT(%)
RBC(1012/L)
50
20
2
25
10-
1.
0
5d ago
Day 1
Day 2
Day 4
Day 6
0
5d ago
Day 2
Day 4
Day 6
0
Day 1
5d ago
Day 1
Day 2
Day 4
Day 6
ALT
AST
Y-GT
15
30-
25.
20
ALT(U/L)
10
AST(U/L)
20
V-GT(U/L)
15
5.
10
10
5.
0
5d ago
Day 1
Day 2
Day 4
Day 6
0
5d ago
Day 1
Day 2
Day 4
Day 6
0
5d ago
Day 1
Day 2
Day 4
Day 6
ALP
TBIL
DBIL
100
150
40
80
60
100
30
ALP(U/L)
TBIL(µmol/L)
DBIL(µmol/L)
20
40
50
20
10
0
0
5d ago
Day 1
Day 2
Day 4
Day 6
5d ago
Day 1
Day 2
Day 4
Day 6
0
5d ago
Day 1
Day 2
Day 4
Day 6
was maintained for the treatment of prostatic carcinoma. Because the patient also complained of dizziness, nausea and vomiting, omeprazole was administered at a dose of 20mg per day. However, the RBC, Hb and HCT levels fell further to 1.28 ×1012/L, 37g/L and 20.5%, respectively. Temporary adre- nocortical hormone treatment was applied. Consequently, two units of RBC suspension and four units of washed RBCs were administered immediately.
OUTCOME AND FOLLOW-UP
After treatment for 5 days, the Hb and HCT levels increased to 86 g/L and 27.1%, respectively. The liver function also improved considerably (ALT: 12U/L, AST: 17U/L, Y-GT: 20U/L, ALP: 45 U/L, TBIL: 26.41 µmol/L, DBIL: 16.50 µmol/L, IBIL: 9.91 umol/L, albumin: 23.9 g/L and TP: 69.4 g/L). The jaundice disap- peared along with the dizziness, nausea and vomiting. Thus, the
overall condition of the patient improved. Changes in the Hb level during flutamide treatment are shown in figure 1. Further, the Hb level increased to 109.0 g/L after a month.
DISCUSSION
Considering the previous medication history of the patient and the development of anaemia, flutamide was suspected to have caused an adverse drug reaction and was therefore discontinued instantly. On re-examining the blood after flutamide discon- tinuation, the Hb level and liver function returned to normal within a short period, indicating the importance of discontin- uing the suspected drug immediately and introducing glucocor- ticoid therapy and blood transfusion in drug-induced haemolytic anaemia. Although both direct and indirect Coombs tests were negative, immune-mediated haemolytic anaemia could not be completely ruled out, and the possibility of drug-induced
| Table 1 Assessment using the Naranjo algorithm (adverse drug reaction probability scale) | ||||
|---|---|---|---|---|
| Yes | No | Do not know | Score | |
| 1. Are there previous conclusive reports on this reaction? | +1 | 0 | 0 | 1 |
| 2. Did the adverse event appear after the suspected drug was administered ? | +2 | -1 | 0 | 2 |
| 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? | +1 | 0 | 0 | 1 |
| 4. Did the adverse reaction reappear when the drug was re-administered? | +2 | -1 | 0 | 0 |
| 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? | -1 | +2 | 0 | 2 |
| 6. Did the reaction reappear when a placebo was given? | -1 | +1 | 0 | 0 |
| 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? | +1 | 0 | 0 | 0 |
| 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? | +1 | 0 | 0 | 0 |
| 9. Did the patient have a similar reaction on the same or similar drugs in any previous exposure? | +1 | 0 | 0 | 0 |
| 10. Was the adverse event confirmed by any objective evidence? | +1 | 0 | 0 | 0 |
| Total score | 6 | |||
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haemolytic anaemia was considered as the time sequence was reasonable. Moreover, previous studies on flutamide-associated hepatotoxicity showed that patients suffered liver damage. 2 13 14 CT and other examinations ruled out other disorders including hepatic metastases.
Haemolysis may occur at the beginning of drug treatment or after a few weeks or months, along with black urine, fatigue, low Hb, dizziness or renal failure.13 The patient in this study presented with yellowing of the face and dizziness after taking flutamide for 5 days. Elevated bilirubin is predominantly associ- ated with DBIL. Because Hb is converted to bilirubin in the haem recycling process, jaundice and elevated bilirubin are attributable to haemolytic anaemia.
No significant drug interaction has been reported between flut- amide and goserelin acetate sustained-release depot implants. The Naranjo algorithm assessment revealed a score of 6, indicating probable flutamide-induced haemolytic anaemia in this patient.16 16
One of the metabolites of flutamide, 4-nitro-3-F-methylaniline, may cause a severe toxic reaction by activating an acute haemo- lytic reaction in susceptible individuals.17
In patients undergoing flutamide treatment, Hb and HCT levels, liver function, reticulocyte counts and other examina- tions should be monitored routinely in addition to Coombs tests to avoid potential adverse reactions. When symp- toms including jaundice, liver damage and change in urine colour occur, all medicines associated with haemolysis must be discontinued immediately. In addition, adrenocortical hormone therapy and blood transfusion may be initiated if necessary, as severe haemolysis could be life-threatening in the short term. In summary, generating clinical awareness of potential haemolytic anaemia induced by flutamide is critical.
Learning points
⇒ Haemolytic anaemia associated with flutamide is fatal but rarely reported.
⇒ The relationship between haemolytic anaemia and flutamide was probable according to the Naranjo algorithm assessment; this adverse reaction was submitted to the pharmacovigilance centre by the clinical pharmacist.
⇒ Discontinuing flutamide immediately and administering glucocorticoid therapy and blood transfusion is crucial in treating flutamide-induced haemolytic anaemia.
Contributors Conception or design of the work: YS, PX. Acquisition of data: SZ, QH. Analysis of data: YS, PX.
Funding This study was funded by Natural Science Foundation of Ningbo (2019A610299).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
Data availability statement All data relevant to the study are included in the article.
ORCID iDs
Suyan Zhu http://orcid.org/0000-0001-6704-3193 Ping Xu http://orcid.org/0000-0003-4166-042X
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