Lack of Methemoglobinemia with Flutamide

Oncology

Lack of Methemoglobinemia with Flutamide Martin Schulz, Achim Schmoldt, Folkert Donn, and Hermann Becker

OBJECTIVE: To determine whether the nonsteroidal antiandrogenic drug flutamide is a clinically relevant inducer of methemoglobinemia in patients with prostatic cancer. METHODS: Fifty consecutive outpatients with prostatic cancer stage D2 entered the study (age 71.1 ± 7.3 y). Five patients were lost to follow-up; the remaining 45 patients received the recommended oral dose of flutamide 250 mg three times daily. Total hemoglobin (Hb) and methemoglobin (Met-Hb) concentrations were measured on varying days using an ultraviolet/visible-spectrophotometric method with an intra- and interday variability 70% may be rapidly fatal.8-12 Acquired methemoglobinemia is generally due to exposure to certain drugs or toxins including dapsone, benzocaine, lidocaine, prilocaine, nitrites, metoclopramide, phenacetin, sulfonamides, and primaquine8-12; however, it is rarely clinically relevant with these drugs. Persons with Met-Hb reductase deficiency, such as cytochrome b5 reductase, reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase, or glucose-6-phosphate dehydrogenase (G6PD) deficiency, may exhibit severe effects.8,9 These patients are generally aware of this condition and should not be treated with Met-Hb–inducing drugs; therefore, our patients were not tested for these deficiencies. This could account, at least in part, for the negative findings in this study.

2001 January, Volume 35

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Since flutamide and 2-hydroxyflutamide are nitroaromatic anilide derivatives (Figure 1; A and B), methemoglobinemia is a potential concern. After reduction of the aromatic nitro group to the hydroxylamine, they may function for the catalytic co-oxidation of Hb to the ferric (Fe3+) derivative Met-Hb. In addition, rapid hydrolysis of the amide moiety may produce 3-trifluoromethyl- 4-nitroaniline (Figure 1; C), another potential inducer of methemoglobinemia. However, controlled clinical trials with flutamide do not suggest a higher incidence of methemoglobinemia.2,3,22 Even though drug labeling of flutamide13 points to the possible occurrence of methemoglobinemia, according to an extensive literature search in MEDLINE, EMBASE, Biosis, Cancerlit, Derwent, IPA, and Scisearch in October 2000, only four cases have been published.23-26 Khan et al.26 reported a Met-Hb concentration of 4.5% in an 82-year-old man with a history of smoking and emphysema who developed progressive dyspnea but was not cyanotic. The Met-Hb concentration decreased slowly after discontinuation of flutamide. Since the patient’s pulmonary status remained unaffected, flutamide therapy was resumed. The arterial Met-Hb content increased and reached a concentration of 3.6% within one week. In another report,24 a 73-year-old patient receiving flutamide 750 mg/d for two years developed a Met-Hb concentration of 5.5% and signs of cyanosis, which was detected during cardiopulmonary bypass surgery. The Met-Hb concentration one day later was 3.2%. Flutamide treatment was not restarted

postoperatively. In both cases, no specific therapy (e.g., with methylene blue) was considered necessary. Kouides et al.25 reported marked sulfhemoglobinemia (15%, normal 0 –1% of total Hb) in a 70-year-old white

Table 1. Percent of Methemoglobin in 12 Patients Before and During Treatment with Flutamide 750 mg/d % Met-Hb Before

During Flutamidea

1

1.1

2.5

2

1.3

2.9

3

0.4

0.4

4

1.3

2.5

5

5.9

2.7

6

2.1

2.3

7

2.9

2.7

8

0.8

0.8

9

3.0

2.4

10

1.4

2.1

18

0.8

0.7

20

1.3

1.9

Mean ± SD

1.9 ± 1.5

2.0 ± 0.9

Patient

Met-Hb = methemoglobin. Number of measurements: 4.8 ± 3.1 (mean ± SD, range 1–10); p = 0.332. a

Figure 2. Percentage of methemoglobin in 45 patients with prostatic cancer during flutamide therapy. Each point refers to a measurement at different days.

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M Schulz et al.

man taking flutamide 150 mg three times daily. The patient developed cyanosis, dyspnea, anemia, and a Met-Hb concentration of 5%. This is the only reference found where flutamide has been associated with sulfhemoglobinemia. The only published case report23 of severe methemoglobinemia during flutamide therapy described an 80-year-old white man with severe cyanosis of the lips and proximal extremities and moderate dyspnea. He was successfully treated with discontinuation of flutamide and administration of intravenous ascorbic acid 3 g/d. A limitation of our study is the use of a relatively small, nonrandomized sample for measuring Met-Hb concentrations before and after initiating flutamide therapy. In addition, we were not able to establish a specific time schedule for obtaining blood samples. Our intraindividual data (Table 1) show that Met-Hb increased in six of 12 patients after initiating flutamide therapy; however, the highest increase was only 1.6%. In contrast, the Met-Hb concentration in one patient (no. 5) decreased from 5.9% to 2.7%. We do not have a sufficient explanation for the high concentration in this patient before initiating flutamide. The average Met-Hb concentration of 1.9% (Figure 2) is within the upper range of normal, and we found no clinical signs of cyanosis in our patients. An asymptomatic increase of 1.5–2.0% of Met-Hb seems acceptable for a drug used in cancer therapy. Summary This study found no clinically relevant increase of MetHb concentrations in elderly patients with prostatic cancer

during chronic treatment with flutamide. However, clinicians should be aware that flutamide-induced methemoglobinemia may occur in rare cases. Flutamide should not be administered to patients with known hereditary methemoglobinemia. Martin Schulz PhD, Head, Center for Drug Information and Pharmacy Practice, ABDA — Federal Union of German Associations of Pharmacists, Eschborn, Germany Achim Schmoldt MD, Professor and Vice-Director, Institute of Legal Medicine, University of Hamburg, University Hospital Eppendorf, Hamburg, Germany Folkert Donn MD, Associate Professor, Department of Urology, Marienkrankenhaus, Hamburg, Germany Hermann Becker MD, Professor and Head, Department of Urology, Marienkrankenhaus Reprints: Martin Schulz PhD, Center for Drug Information and Pharmacy Practice, ABDA, Carl-Mannich-Strasse 26, 65760 Eschborn, Germany, FAX 49 6196 928-140, E-mail [email protected]

References 1. Derman MA, Figg WD. Flutamide (drug evaluations). In: Hutchison TA, Shahan DR, Anderson ML, eds. DRUGDEX system. Englewood, CO: MICROMEDEX, Inc. (edition expired 12/31/00). 2. Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, et al. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology 1997;50:330-6. 3. Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339:1036-42. 4. Greenway BA. Effect of flutamide on survival in patients with pancreatic cancer: results of a prospective, randomized, double blind, placebo controlled trial. BMJ 1998;316:1935-8. 5. Schulz M, Schmoldt A, Donn F, Becker H. The pharmacokinetics of flu-

Figure 3. Percentage of methemoglobin during continuous dosing of flutamide 750 mg /d ( ⇑ ) and 2-hydroxyflutamide plasma concentrations at 0800 (days 2–7) in a 71-year-old man with prostatic cancer. Each small arrow (↑) corresponds to an oral dose of flutamide 250 mg.

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tamide and its major metabolites after a single oral dose and during chronic treatment. Eur J Clin Pharmacol 1988;34:633-6. Shet MS, McPhaul M, Fisher CW, Stallings NR, Estabrook RW. Metabolism of the antiandrogenic drug (flutamide) by human CYP1A2. Drug Metab Dispos 1997;25:1298-303. Katchen B, Buxbaum S. Disposition of a new, nonsteroid, antiandrogen, α,α,α-trifluoro-2-methyl-4´-nitro-m-propionotoluidide (flutamide), in men following a single oral 200 mg dose. J Clin Endocrinol Metab 1975; 41:373-9. Curry S. Methemoglobinemia. Ann Emerg Med 1982;11:214-21. Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia. Treatment issues. Drug Saf 1996;14:394-405. Ward KE, McCarthy MW. Dapsone-induced methemoglobinemia. Ann Pharmacother 1998;32:549-53. Tush GM, Kuhn RJ. Methemoglobinemia induced by an over-thecounter medication. Ann Pharmacother 1996;30:1251-4. Guerriero SE. Methemoglobinemia caused by topical benzocaine. Pharmacotherapy 1997;17:1038-40. Package insert. Fugerel. P (flutamide). Munich, Germany: Essex Pharma, November 1999. Siggaard-Andersen O, Nørgaard-Pedersen B, Rem J. Hemoglobin pigments. Spectrophotometric determination of oxy-, carboxy-, met-, and sulfhemoglobin in capillary blood. Clin Chim Acta 1972;42:85-100. Evelyn KA, Malloy HT. Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in a single sample of blood. J Biol Chem 1938;126:655-62. SAS. SPSS version 10.0.5. Chicago: SPSS, November 1999. Brogden RN, Clissold SP. Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer. Drugs 1989;38:185-203. Goldspiel BR, Kohler DR. Flutamide: an antiandrogen for advanced prostate cancer. DICP 1990;24:616-23. Møller S, Iversen P, Franzman MB. Flutamide-induced liver failure. J Hepatol 1990;10:346-9. Pirmohamed M, Madden S, Park BK. Idiosyncratic drug reactions. Metabolic bioactivation as a pathogenic mechanism. Clin Pharmacokinet 1996;31:215-30. Berson A, Wolf C, Chachaty C, Fisch C, Fau D, Eugene D, et al. Metabolic activation of the nitroaromatic antiandrogen flutamide by rat and human cytochromes P-450, including forms belonging to the 3A and 1A subfamilies. J Pharmacol Exp Ther 1993;265:366-72. Sogani PC, Vagaiwala MR, Whitmore WF. Experience with flutamide in patients with advanced prostatic cancer without prior endocrine therapy. Cancer 1984;54:744-50. Schott AM, Vial T, Gozzo I, Chareyre S, Delmas PD. Flutamide-induced methemoglobinemia. DICP 1991;25:600-1. Jackson SH, Barker SJ. Methemoglobinemia in a patient receiving flutamide. Anesthesiology 1995;82:1065-7. Kouides PA, Abboud CN, Fairbanks VF. Flutamide-induced cyanosis refractory to methylene blue therapy. Br J Haematol 1996;94:73-5. Khan AM, Singh NT, Bilgrami S. Flutamide induced methemoglobinemia. J Urol 1997;157:1363.

MÉTODOS:

Cincuenta pacientes ambulatorios con cáncer de próstata estadío D2 participaron del estudio. Cinco pacientes se retiraron del estudio por falta de seguimiento. Los 45 pacientes restantes recibieron flutamida en dosis de 250 mg tres veces al día. Los niveles de la hemoglobina total y la methemoglobina (Met-Hb) fueron medidos durante varios días por el método de UV/VIS-espectrofotometría. En 12 pacientes, Met-Hb fue analizada antes y después de iniciada la terapia con flutamida. RESULTADOS: En promedio, se analizó 2.6 muestras de sangre por persona con un valor promedio de Met-Hb de 1.9% de la hemoglobina total (Hb). Solo se detectó niveles promedios de Met-Hb mayores o igual a 3% en seis pacientes (13%). Los datos de los 12 pacientes en los que se midió los niveles de Met-Hb antes y después de iniciado la flutamida no demostraron diferencias significativas. No se observó ni reportó signos clínicos de methemoglobinemia durante el período estudiado. CONCLUSIONES: Este estudio no encontró aumentos clínicamente significativos en los niveles de Met-Hb en pacientes de edad avanzada con cáncer de próstata en tratamiento oral crónico de flutamida. Sin embargo, es importante reconocer la posibilidad de methemoglobinemia inducida por flutamida en casos raros. Mitchell Nazario PharmD RÉSUMÉ OBJECTIF:

Déterminer si l’antiandrogène non stéroïdien flutamide est un inducteur cliniquement significatif de méthémoglobinémie chez des patients atteints de cancer de la prostate. MÉTHODES: Cinquante patients ambulatoires consécutifs atteints de cancer de la prostate de grade 2 ont participé à l’étude. Cinq ont été perdus de vue. Les 45 patients restants ont reçu la dose orale recommandée de flutamide trois fois par jour. Les taux d’hémoglobine totale et de méthémoglobine (Met-Hb) ont été mesurés certains jours par une méthode spectrophotométrique UV/visible ayant une variabilité inter et intrajournalière inférieure à 8%. Chez 12 patients, la Met-Hb a été mesurée avant le début du traitement par flutamide et après son instauration. RÉSULTATS: En moyenne, 2.6 prélèvements de sang veineux par patient ont été mesurés, avec un taux moyen de Met-Hb de 1.9% du taux d’Hb totale. Chez seulement 6 patients (13%), des taux moyens ≥3% ont été détectés. Les résultats des 12 patients évalués avant et après l’instauration du traitement par flutamide ne présentaient pas de différences significatives. Durant l’étude, aucun signe clinique de méthémoglobinémie n’a été signalé ni observé. CONCLUSIONS: Cette étude n’a trouvé aucune augmentation cliniquement significative des taux de Met-Hb chez des patients atteints de cancer de la prostate au cours d’un traitement chronique par flutamide. Cependant, les cliniciens devraient être au courant de la possibilité de survenue de méthémoglobinémie induite par le flutamide dans de très rares cas. Michel Le Duff

EXTRACTO OBJETIVO:

Determinar si flutamida, un fármaco antiandrogénico noesteroidal, es un inductor relevante de la methemoglobinemia en pacientes con cáncer de próstata.

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