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Itraconazole interacts with felodipine
134
Journal of the American Academy of Dermatology July 1995
Brief communications
15. Hung W, August GP. A "collagen like" syndrome associated with antithyroid therapy. J Pediatr 1973;82:852-4. 16. Amrhein JA, Kenny FM, Ross D. Granulocytopenia, lupus-like syndrome, and other complicationsof propylthiouracil therapy. J Pediatr 1970;76:54-63. 17. GriswoldWR, Mendoza SA, Johnston W. Vasculitisassociated with propylthiouracil:evidencefor immune complex patbogenesis and response to therapy. West J Med 1978; 128:543-6. 18. Shigemasa C, Noguchi T, Onoyama S, et al. Side effectsof antithyroid drugs. Nippon Naibunpi Gakkai Zasshi 1983; 59:1160-7. 19. Baker B, Shapiro B, Fig IM, et al. Unusual complications of antithyroid drug therapy:four case reports and reviewof literature. Thyroidol Clin Exp 1989;1:17-26. 20. Caplan RH, Webster SR, Hartigan JM. Vesiculareruption in newborns secondary to maternal propylthiouraciltherapy: report of two cases. Wis Med J 1977;76:988-90. 21. Zegarelli DJ, Zegarelli EV. lntraoral pemphigus vulgaris. Oral Surg Oral Med Oral Pathol 1977;44:384-93. 22. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:117-20. 23. Cotran RS, Kumar V, Robbins SL. Robbins pathologic
24. 25. 26. 27. 28. 29. 30. 31.
basis of disease. 4th ed. Philadelphia: WB Saunders, 1989:1304. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:120. Arnold HL Jr, Odom RB, James WD. Andrew's diseases of the skin. 8th ed. Philadelphia: WB Saunders, 1990:536-7. Fitzpatrick TB, Eisen AZ, Wolff K, et al. Dermatologyin general medicine.4th ed. New York: McGraw-Hill, 1993: 607. Cotran RS, Kumar V, Robbins SL. Robbins pathologic basis of disease. 4th ed. Philadelphia:WB Saunders, 1989: 1336. Cotran RS, Kumar V, Robbins SL. Robbins pathologic basis of disease. 4th ed. Philadelphia:WB Saunders, 1989: 1224. Fitzpatrick TB, Eisen AZ, Wolff K, et al. Dermatologyin general medicine. 4th ed. New York: McGraw-Hill, 1993:608. Schaehner LA, Hansen RC. Pediatric dermatology.New York: Churchill Livingstone,1988:797. Laskaris G, Stoufi E. Oral pemphigusvulgaris in a 6-yearold girl. Oral Surg Oral Med Oral Pathol 1990;69:609-13.
Itraconazole interacts with felodipine Pertti J. Neuvonen, MD, and Raimo Suhonen, M D Helsinki and Mikkeli, Finland
Felodipine, a dihydropyridine calcium antagonist, is extensively metabolized presystemically by the isoenzyme CYP3A4, resulting in a bioavailability of about 15% after oral administration. Felodipine in a dose-dependent manner causes ankle swelling from precapillary vasodilatation. Itraconazole is a potent inhibitor of C Y P 3 A 4 and can seriously interact with some substrates of C Y P 3 A 4 such as terfenadine and midazolam.1, 2 W e report two cases that indicate that itraconazole m a y also interact with felodipine.
CASE REPORTS Case 1 A 52-year-old woman had taken felodipine (Plendil), 10 rag/day, for hypertension for 1 year without any problems. Because of tinea pedis, itraconazole (SporanFrom the Department of Clinical Pharmacology, Universityof Helsinki, and the Department of Dermatology, Mikkeli Central Hospital, Mikkeli. Reprints not available from authors. J AM ACAD DERMATOL 1995;33:134-5. Copyright ® 1995 by the American Academy of Dermatology, Inc. 0190-9622/95 $3.00 + 0 16/54/63652
ox), 100 mg/day, was then initiated. She observed an increasing swelling of the lower extremities during the first week of treatment. When she stopped itraconazole, the edema subsided within 2 to 4 days. Treatment with felodipine is continuing without further problems.
Case 2 A 53-year-old woman had taken felodipine, 5 mg/day, for hypertension without any side effects for 1 year until itraconazole, 200 mg twice daily, was given for onychomycosis. Within days she noticed swelling of her legs. Felodipine was stopped on the fifth day of concomitant treatment, ltraconazole was given for 7 days monthly during the next 3 months, without any side effects.
Felodipine challenges Three felodipine challenges were performed in case 2. The first challenge was performed 2 weeks after the cessation of the first itraconazole treatment, the second on the seventh day of the third itraconazole treatment, and the third challenge 3 weeks after the end of the last itraconazole treatment. The patient always took a single oral 5 mg dose of felodipine at 7 AM.Blood samples were taken 1,2, 4 (except during the first challenge), and 6 hours after felodipine ingestion, for the determination of plasma
Journal of the AmericanAcademyof Dermatology Volume 33, Number 1
concentrations of felodipine by gas chromatography3 and itraconazole by high-performance liquid chromatography.4 During the second challenge the patient reported a slight swelling in the ankles in the evening of the challenge day. The edema disappeared the next day. No swelling occurred during the first or third challenges (i.e., without itraconazole). Plasma concentrations of felodipine were considerably higher when felodipine was ingested with itraconazole than without itraconazole (Fig. 1). The area under the plasma felodipine concentration-time curve (AUCo_6hr) was at least four times higher with itraconazole (40.9 #g/L X hour) than without it (3.2 #g/L x hour) and 10.9 #g/L X hour). During the second challenge the peak concentration of itraconazole in plasma at 4 hours was 2.04 mg/L.
Brief communications
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DISCUSSION Our cases show that the concomitant use of itraconazole and felodipine can cause a swelling of the ankles and legs within a few days. Ankle swelling is a typical side effect of dihydropyridine calcium antagonists when their plasma concentrations are high. Ankle edema has also been reported as an unusual compfication of itraconazole therapy. 5 After an oral ingestion dihydropyridine calcium antagonists are metabolized in the gut wall and liver by CYP3A enzymes that are inhibited by itraconazole. The inhibition of this first-pass metabolism seems to explain the observed pharmacokinetic interaction. A fourfold to 10-fold increase in the A U C of felodipine by itraconazole, observed in case 2, is of the same magnitude as the 10-fold increase in the A U C of midazolam caused by itraconazole. 2 The threefold difference in the AUC0.6 hr of felodipine without itraconazole may be caused by a variation in the absorption of felodipine and by a limited number of plasma samples. It is probable that the interaction between itraconazole and calcium antagonists is not limited to felodipine only. In fact, we have seen an additional patient in whom considerable ankle swelling developed within 1 week when itraconazole (200 mg twice daily) was added to her ongoing isradipine (5 mg/day) therapy. Rosen 5 has also recently described a patient in whom massive pitting edema of both lower extremities developed when itraconazole (! 00 nag twice daily) was added to her other medications, including nifedipine. The possibility of drug interaction was not considered, however.5 Care should be taken when itraconazole is used concomitantly with felodipine. The observed inter-
-t2) 0
0
2
4
6
Time (h)
Fig. 1. Case 2. Plasma concentrations of felodipine after single doses of 5 mg during three challenges. Solid squares, During itraconazole therapy; open symbols, without itraconazole.
action of itraconazole may be shared by some other antifungals of the azole family6 and that of felodipine by some other calcium antagonists. REFERENCES
1. Pohjola-SintonenS, ViitasaloM, ToivonenL, et al. Itraconazole preventsterfenadinemetabolismand increasesrisk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993;45:191-3. 2. OlkkolaKT, BackmanJ, NeuvonenPJ. Midazolamshould be avoided in patients receivingthe systemicantimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55:481-5. 3. AhnoffM. Determinationof felodipinein plasma by capillary gas chromatographywith electroncapture detection.J Pharm BiomedAnal 1984;2:5l 9-26. 4. AllenmarkS, EdeboA, LindgrenK. Determinationof itraconazolein serumwithhigh-performanceliquidchromatography. J Chromatogr 1990;532:203-6. 5. Rosen T. Debilitating edema associated with itraconazole therapy. Arch Dermatol 1994;130:260-1. 6. Gupta AK, Sauder DN, Shear NH. Antifungalagents: an overview.Part II. J AM ACADDERMATOL1994;30:911-33.
Journal of the American Academy of Dermatology July 1995
Brief communications
15. Hung W, August GP. A "collagen like" syndrome associated with antithyroid therapy. J Pediatr 1973;82:852-4. 16. Amrhein JA, Kenny FM, Ross D. Granulocytopenia, lupus-like syndrome, and other complicationsof propylthiouracil therapy. J Pediatr 1970;76:54-63. 17. GriswoldWR, Mendoza SA, Johnston W. Vasculitisassociated with propylthiouracil:evidencefor immune complex patbogenesis and response to therapy. West J Med 1978; 128:543-6. 18. Shigemasa C, Noguchi T, Onoyama S, et al. Side effectsof antithyroid drugs. Nippon Naibunpi Gakkai Zasshi 1983; 59:1160-7. 19. Baker B, Shapiro B, Fig IM, et al. Unusual complications of antithyroid drug therapy:four case reports and reviewof literature. Thyroidol Clin Exp 1989;1:17-26. 20. Caplan RH, Webster SR, Hartigan JM. Vesiculareruption in newborns secondary to maternal propylthiouraciltherapy: report of two cases. Wis Med J 1977;76:988-90. 21. Zegarelli DJ, Zegarelli EV. lntraoral pemphigus vulgaris. Oral Surg Oral Med Oral Pathol 1977;44:384-93. 22. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:117-20. 23. Cotran RS, Kumar V, Robbins SL. Robbins pathologic
24. 25. 26. 27. 28. 29. 30. 31.
basis of disease. 4th ed. Philadelphia: WB Saunders, 1989:1304. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:120. Arnold HL Jr, Odom RB, James WD. Andrew's diseases of the skin. 8th ed. Philadelphia: WB Saunders, 1990:536-7. Fitzpatrick TB, Eisen AZ, Wolff K, et al. Dermatologyin general medicine.4th ed. New York: McGraw-Hill, 1993: 607. Cotran RS, Kumar V, Robbins SL. Robbins pathologic basis of disease. 4th ed. Philadelphia:WB Saunders, 1989: 1336. Cotran RS, Kumar V, Robbins SL. Robbins pathologic basis of disease. 4th ed. Philadelphia:WB Saunders, 1989: 1224. Fitzpatrick TB, Eisen AZ, Wolff K, et al. Dermatologyin general medicine. 4th ed. New York: McGraw-Hill, 1993:608. Schaehner LA, Hansen RC. Pediatric dermatology.New York: Churchill Livingstone,1988:797. Laskaris G, Stoufi E. Oral pemphigusvulgaris in a 6-yearold girl. Oral Surg Oral Med Oral Pathol 1990;69:609-13.
Itraconazole interacts with felodipine Pertti J. Neuvonen, MD, and Raimo Suhonen, M D Helsinki and Mikkeli, Finland
Felodipine, a dihydropyridine calcium antagonist, is extensively metabolized presystemically by the isoenzyme CYP3A4, resulting in a bioavailability of about 15% after oral administration. Felodipine in a dose-dependent manner causes ankle swelling from precapillary vasodilatation. Itraconazole is a potent inhibitor of C Y P 3 A 4 and can seriously interact with some substrates of C Y P 3 A 4 such as terfenadine and midazolam.1, 2 W e report two cases that indicate that itraconazole m a y also interact with felodipine.
CASE REPORTS Case 1 A 52-year-old woman had taken felodipine (Plendil), 10 rag/day, for hypertension for 1 year without any problems. Because of tinea pedis, itraconazole (SporanFrom the Department of Clinical Pharmacology, Universityof Helsinki, and the Department of Dermatology, Mikkeli Central Hospital, Mikkeli. Reprints not available from authors. J AM ACAD DERMATOL 1995;33:134-5. Copyright ® 1995 by the American Academy of Dermatology, Inc. 0190-9622/95 $3.00 + 0 16/54/63652
ox), 100 mg/day, was then initiated. She observed an increasing swelling of the lower extremities during the first week of treatment. When she stopped itraconazole, the edema subsided within 2 to 4 days. Treatment with felodipine is continuing without further problems.
Case 2 A 53-year-old woman had taken felodipine, 5 mg/day, for hypertension without any side effects for 1 year until itraconazole, 200 mg twice daily, was given for onychomycosis. Within days she noticed swelling of her legs. Felodipine was stopped on the fifth day of concomitant treatment, ltraconazole was given for 7 days monthly during the next 3 months, without any side effects.
Felodipine challenges Three felodipine challenges were performed in case 2. The first challenge was performed 2 weeks after the cessation of the first itraconazole treatment, the second on the seventh day of the third itraconazole treatment, and the third challenge 3 weeks after the end of the last itraconazole treatment. The patient always took a single oral 5 mg dose of felodipine at 7 AM.Blood samples were taken 1,2, 4 (except during the first challenge), and 6 hours after felodipine ingestion, for the determination of plasma
Journal of the AmericanAcademyof Dermatology Volume 33, Number 1
concentrations of felodipine by gas chromatography3 and itraconazole by high-performance liquid chromatography.4 During the second challenge the patient reported a slight swelling in the ankles in the evening of the challenge day. The edema disappeared the next day. No swelling occurred during the first or third challenges (i.e., without itraconazole). Plasma concentrations of felodipine were considerably higher when felodipine was ingested with itraconazole than without itraconazole (Fig. 1). The area under the plasma felodipine concentration-time curve (AUCo_6hr) was at least four times higher with itraconazole (40.9 #g/L X hour) than without it (3.2 #g/L x hour) and 10.9 #g/L X hour). During the second challenge the peak concentration of itraconazole in plasma at 4 hours was 2.04 mg/L.
Brief communications
135
12
10
m
E 133
"u o
DISCUSSION Our cases show that the concomitant use of itraconazole and felodipine can cause a swelling of the ankles and legs within a few days. Ankle swelling is a typical side effect of dihydropyridine calcium antagonists when their plasma concentrations are high. Ankle edema has also been reported as an unusual compfication of itraconazole therapy. 5 After an oral ingestion dihydropyridine calcium antagonists are metabolized in the gut wall and liver by CYP3A enzymes that are inhibited by itraconazole. The inhibition of this first-pass metabolism seems to explain the observed pharmacokinetic interaction. A fourfold to 10-fold increase in the A U C of felodipine by itraconazole, observed in case 2, is of the same magnitude as the 10-fold increase in the A U C of midazolam caused by itraconazole. 2 The threefold difference in the AUC0.6 hr of felodipine without itraconazole may be caused by a variation in the absorption of felodipine and by a limited number of plasma samples. It is probable that the interaction between itraconazole and calcium antagonists is not limited to felodipine only. In fact, we have seen an additional patient in whom considerable ankle swelling developed within 1 week when itraconazole (200 mg twice daily) was added to her ongoing isradipine (5 mg/day) therapy. Rosen 5 has also recently described a patient in whom massive pitting edema of both lower extremities developed when itraconazole (! 00 nag twice daily) was added to her other medications, including nifedipine. The possibility of drug interaction was not considered, however.5 Care should be taken when itraconazole is used concomitantly with felodipine. The observed inter-
-t2) 0
0
2
4
6
Time (h)
Fig. 1. Case 2. Plasma concentrations of felodipine after single doses of 5 mg during three challenges. Solid squares, During itraconazole therapy; open symbols, without itraconazole.
action of itraconazole may be shared by some other antifungals of the azole family6 and that of felodipine by some other calcium antagonists. REFERENCES
1. Pohjola-SintonenS, ViitasaloM, ToivonenL, et al. Itraconazole preventsterfenadinemetabolismand increasesrisk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993;45:191-3. 2. OlkkolaKT, BackmanJ, NeuvonenPJ. Midazolamshould be avoided in patients receivingthe systemicantimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55:481-5. 3. AhnoffM. Determinationof felodipinein plasma by capillary gas chromatographywith electroncapture detection.J Pharm BiomedAnal 1984;2:5l 9-26. 4. AllenmarkS, EdeboA, LindgrenK. Determinationof itraconazolein serumwithhigh-performanceliquidchromatography. J Chromatogr 1990;532:203-6. 5. Rosen T. Debilitating edema associated with itraconazole therapy. Arch Dermatol 1994;130:260-1. 6. Gupta AK, Sauder DN, Shear NH. Antifungalagents: an overview.Part II. J AM ACADDERMATOL1994;30:911-33.