Pharmacy World and Science

, 27:423 | Cite as

Side Effects of Interferon-α Therapy

  • Stefan SleijferEmail author
  • Marjolein Bannink
  • Arthur  R.  Van Gool
  • Wim  H. J. Kruit
  • Gerrit Stoter
Review Article



Interferon-α (IFN-α) has been extensively explored for its efficacy in various disease conditions and is currently used as a standard treatment in several of these. Its use is accompanied by a wide variety of possible side effects. These side-effects may hamper reaching and maintaining the dose needed for maximal therapeutic effect while their occurrence can outweigh clinical benefit of IFN-α treatment. This review addresses the toxicity profile of IFN-α, the presumed pathophysiology of the different side effects and the strategies to handle these.


Computerized searches were used and cross-references of articles and books were checked.


Adverse effects due to IFN-α have been described in almost every organ system. Many side-effects are clearly dose-dependent. Taken together, occurrence of flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue, and psychiatric sequelae are the most frequently encountered. Although insight in the mechanisms accounting for IFN-α-related toxicities has improved in recent years, much remains to be elucidated. Guidelines on the management of these untoward sequelae are mostly based on clinical experience, while many side-effects can only be adequately handled by dose adjustment or cessation of treatment.


Further research on the mechanisms underlying both therapeutic effects and adverse events is warranted. Hopefully, this will lead to better identification of those patients who are likely to benefit from treatment without experiencing severe toxicities.


Hepatitis Interferon-α Melanoma Pathophysiology Renal cell carcinoma Side effects 


  1. 1.
    Kirkwood, JM, Ibrahim, JG, Sondak, VK, Richards, J, Flaherty, LE, Ernstoff, MS,  et al. 2000High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190J Clin Oncol18244458PubMedGoogle Scholar
  2. 2.
    Kirkwood, JM, Bender, C, Agarwala, S, Tarhini, A, Shipe-Spotloe, J, Smelko, B,  et al. 2002Mechanisms and management of toxicities associated with high-dose Interferon Alfa-2b therapyJ Clin Oncol20370318PubMedGoogle Scholar
  3. 3.
    Messing, EM, Manola, J, Wilding, G, Propert, K, Fleischmann, J, Crawford, ED,  et al. 2003Phase III study of interferon alfa as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup TrialJ Clin Oncol21121422CrossRefPubMedGoogle Scholar
  4. 4.
    Hancock, BW, Wheatley, K, Harris, S, Ives, N, Harrison, G, Horsman, JM,  et al. 2004Adjuvant interferon in high-risk melanoma: the AIM HIGH Study-United Kingdom Coordinating Committee on Cancer Research Randomized study of adjuvant low-dose extended-duration interferon alfa-2a in high-risk resected malignant melanomaJ Clin Oncol222361Google Scholar
  5. 5.
    Saper, CB, Breder, CD 1994The neurologic basis of feverN Engl J Med33018806CrossRefPubMedGoogle Scholar
  6. 6.
    Dinarello, CA, Bernheim, HA, Duff, GW, Le, HV, Nagabhushan, TL, Hamilton, NC,  et al. 1984Mechanisms of fever induced by recombinant interferonJ Clin Invest7490613PubMedCrossRefGoogle Scholar
  7. 7.
    Hendrix, CW, Petty, BG, Woods, A, Kuwahara, SK, Witter, FR, Soo, W,  et al. 1995Modulation of alpha-interferon’s antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteersAntiviral Res2812131CrossRefPubMedGoogle Scholar
  8. 8.
    Munoz, AE, Levi, D, Podesta, A, Gorin, JM, Gonzalez, J, Bartellini, MA, Munne, MS, Cabanne, A, Flichman, D, Terg, R 2000Interferon-alpha 2b combined with daily ketoprofen administration improves virological response in chronic hepatitis C: a prospective and randomised trialGut4642731CrossRefPubMedGoogle Scholar
  9. 9.
    Cameron, DA, Cornbleet, MC, Mackie, RM, Hunter, JA, Gore, M, Hancock, B,  et al. 2001Adjuvant interferon alpha 2b in high risk melanoma – the Scottish studyBr J Cancer8411469CrossRefPubMedGoogle Scholar
  10. 10.
    Negrier, S, Escudier, B, Lasset, C, Douillard, JY, Savary, J, Chevreau, C,  et al. 1998Recombinant human interleukin-2, recombinant interferon alfa-2a, or both in metastatic renal-cell carcinomaN Engl J Med33812728CrossRefPubMedGoogle Scholar
  11. 11.
    Motzer, R, Murphy, BA, Bacik, J,  et al. 2000Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinomaJ Clin Oncol18297280PubMedGoogle Scholar
  12. 12.
    Verma, DS, Spitzer, G, Zander, AR, Gutterman, JU, McCredie, KB, Dicke, KA,  et al. 1981Human leucocyte interferon preparation-mediated block of granulopoietic differentiation in vitroExp Hematol96376PubMedGoogle Scholar
  13. 13.
    Ortega, JA, Ma, A, Shore, NA, Dukes, PP, Merigan, TC,  et al. 1979Suppressive effect of interferon on erythroid cell proliferationExp Hematol71459PubMedGoogle Scholar
  14. 14.
    Chakrabarti, D, Hultgren, B, Stewart, TA 1996IFN-alpha induces autoimmune T cells through the induction of intracellular adhesion molecule-1 and B72J Immunol1575228PubMedGoogle Scholar
  15. 15.
    Nishiwaki, H, Ogura, Y, Miyamoto, K, Matsuda, N, Honda, Y 1996Interferon alfa induces leucocyte capillary trapping in rat retinal microcirculationArch Ophthalmol11472630PubMedGoogle Scholar
  16. 16.
    Gutman, H, Schachter, J, Stopel, E, Gutman, R, Lahav, J 2002Impaired platelet aggregation in melanoma patients treated with interferon-alpha-2b adjuvant therapyCancer947805CrossRefPubMedGoogle Scholar
  17. 17.
    Kontorinis, N, Agarwal, K, Dieterich, DT 2004Current status of the use of growth factors and other adjuvant medications in patients receiving peginterferon and ribavirinRev Gastroenterol Disord4S3947PubMedGoogle Scholar
  18. 18.
    Ariad, S, Song, E, Cohen, R, Bezwoda, WR 1992Interferon-alpha induced autoimmune hepatitis in a patient with Philadelphia chromosome-positive chronic myeloid leukemia with cytogenetically normal T-lymphocytesMol Biother413942PubMedGoogle Scholar
  19. 19.
    Islam, M, Frye, RF, Richards, TJ, Sbeitan, I, Donnelly, SS, Glue, P,  et al. 2002Differential effect of IFNalpha-2b on the cytochrome P450 enzyme system: a potential basis of IFN toxicity and its modulation by other drugsClin Cancer Res824807PubMedGoogle Scholar
  20. 20.
    Gralla, RJ, Osoba, D, Kris, MG, Kirkbride, P, Hesketh, PJ, Chinnery, LW,  et al. 1999Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical OncologyJ Clin Oncol17297194PubMedGoogle Scholar
  21. 21.
    Plata-Samalán, CR 2001Cytokines and feedingInt J Obes25S4S52Google Scholar
  22. 22.
    Dieperink, E, Willenbring, M, Ho, SB 2000Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a reviewAm J Psychiatr15786776CrossRefPubMedGoogle Scholar
  23. 23.
    Gool, AR, Kruit, WH, Engels, FK, Stoter, G, Bannink, M, Eggermont, AM 2003Neuropsychiatric side effects of interferon-alfa therapyPharm World Sci251120PubMedGoogle Scholar
  24. 24.
    Adams, F, Fernandez, F, Mavligit, G 1988Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalitiesJ Neurooncol63559CrossRefPubMedGoogle Scholar
  25. 25.
    Merimsky, O, Reider-Groswasser, I, Inbar, M, Chaitchik, S 1990Interferon-related mental deterioration and behavioral changes in patients with renal cell carcinomaEur J Cancer26596600PubMedGoogle Scholar
  26. 26.
    Schaefer, M, Schwaiger, M, Pich, M, Lieb, K, Heinz, A 2003Neurotransmitter changes by interferon-alpha and therapeutic implicationsPharmacopsychiatry36S2036PubMedGoogle Scholar
  27. 27.
    Suzuki, E, Yagi, G, Nakaki, T, Kanba, S, Asai, M 2001Elevated plasma nitrate levels in depressive statesJ Affect Disord632214PubMedGoogle Scholar
  28. 28.
    Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatr 2004 Oct 19; [Epub ahead of print]Google Scholar
  29. 29.
    Capuron, L, Miller, AH 2004Cytokines and psychopathology: lessons from interferon-α Biol Psychiatr5681924CrossRefGoogle Scholar
  30. 30.
    Licino, J, Kling, MA, Hauser, P 1998Cytokines and brain function: relevance to interferon-α-induced mood and cognitive changesSemin Oncol25308Google Scholar
  31. 31.
    Fried, MW 2002Side effects of therapy of hepatitis C and their managementHepatology36S23744PubMedGoogle Scholar
  32. 32.
    Lucía, A, Earnest, C, Pérez, M 2003Cancer-related fatigue: can exercise physiology assist oncologists?Lancet Oncol461625PubMedGoogle Scholar
  33. 33.
    Reinhold, U, Hartl, C, Hering, R, Hoeft, A, Kreysel, HW 1997Fatal rhabdomyolysis and multiple organ failure associated with adjuvant high-dose interferon alfa in malignant melanomaLancet3495401CrossRefPubMedGoogle Scholar
  34. 34.
    Londen, GJ, Mascarenhas, B, Kirkwood, JM 2001Rhabdomyolysis, when observed with high-dose interferon-alfa (HDI) therapy, does not always exclude resumption of HDIJ Clin Oncol193794PubMedGoogle Scholar
  35. 35.
    Gabrielli, M, Santarelli, L, Serricchio, M, Leo, D, Pola, P, Gasbarrini, A 2003Acute reversible rhabdomyolysis during interferon alpha2B therapy for hepatitis CAm J Gastroenterol98940PubMedGoogle Scholar
  36. 36.
    Shakil, AO, Bisceglie, AM, Hoofnagle, JH 1996Seizures during alpha interferon therapyJ Hepatol244851CrossRefPubMedGoogle Scholar
  37. 37.
    Anthoney, DA, Bone, I, Evans, TR 2000Inflammatory demyelinating polyneuropathy: a complication of immunotherapy in malignant melanomaAnn Oncol1111972000CrossRefPubMedGoogle Scholar
  38. 38.
    Meriggioli, MN, Rowin, J 2000Chronic inflammatory demyelinating polyneuropathy after treatment with interferon-alphaMuscle Nerve234335CrossRefPubMedGoogle Scholar
  39. 39.
    Maeda, M, Ohkoshi, N, Hisahara, S, Mizusawa, H, Shoji, S 1995Mononeuropathy multiplex in a patient receiving interferon alpha therapy for chronic hepatitis CRinsho Shinkeigaku35104850PubMedGoogle Scholar
  40. 40.
    Tunca, A, Erbayrak, M, Aytac, S, Turkay, C 2004Axonal neuropathy and hearing loss associated with alpha interferon treatment in chronic hepatitis B: a case reportTurk J Gastroenterol15979PubMedGoogle Scholar
  41. 41.
    Ogundipe, O, Smith, M 2000Bell’s palsy during interferon therapy for chronic hepatitis C infection in patients with haemorrhagic disordersHaemophilia61102CrossRefPubMedGoogle Scholar
  42. 42.
    Fukumoto, Y, Shigemitsu, T, Kajii, N, Omura, R, Harada, T, Okita, K 1994Abducent nerve paralysis during interferon alpha-2a therapy in a case of chronic active hepatitis CIntern Med3363740PubMedGoogle Scholar
  43. 43.
    Kataoka, I, Shinagawa, K, Shiro, Y, Okamoto, S, Watanabe, R, Mori, T,  et al. 2002Multiple sclerosis associated with interferon-alpha therapy for chronic myelogenous leukemiaAm J Hematol7014953CrossRefPubMedGoogle Scholar
  44. 44.
    Matsuo, T, Takabatake, R 2002Multiple sclerosis-like disease secondary to alpha interferonOcul Immunol Inflamm10299304PubMedCrossRefGoogle Scholar
  45. 45.
    Batocchi, AP, Evoli, A, Servidei, S, Palmisani, MT, Apollo, F, Tonali, P 1995Myasthenia gravis during interferon alfa therapyNeurology453823PubMedGoogle Scholar
  46. 46.
    Mase, G, Zorzon, M, Biasutti, E, Vitrani, B, Cazzato, G, Urban, F,  et al. 1996Development of myasthenia gravis during interferon-alpha treatment for anti-HCV positive chronic hepatitisJ Neurol Neurosurg Psychiatr603489PubMedGoogle Scholar
  47. 47.
    Rohde, D, Sliwka, U, Schweizer, K, Jakse, G 1996Oculo-bulbar myasthenia gravis induced by cytokine treatment of a patient with metastasized renal cell carcinomaEur J Clin Pharmacol504713CrossRefPubMedGoogle Scholar
  48. 48.
    Bailly, F, Mattei, A, SiAhmed, SN, Trepo, C 1997Uncommon side-effects of interferonJ Viral Hepat48994PubMedGoogle Scholar
  49. 49.
    Kanda, Y, Shigeno, K, Kinoshita, N, Nakao, K, Yano, M, Matsuo, H 1994Sudden hearing loss associated with interferonLancet34311345CrossRefPubMedGoogle Scholar
  50. 50.
    Quesada, JR, Talpaz, M, Rios, A, Kurzrock, R, Gutterman, JU 1986Clinical toxicity of interferons in cancer patients: a reviewJ Clin Oncol423443PubMedGoogle Scholar
  51. 51.
    Wilson, RA 2002Nephrotoxicity of interferon-alfa-ribavarin therapy for chronic hepatitis CJ Clin Gastroenterol358992Google Scholar
  52. 52.
    Sonnenblick, M, Rosin, A 1991Cardiotoxicity of interferon. A review of 44 casesChest9955761PubMedGoogle Scholar
  53. 53.
    Kondo, Y, Yukinaka, M, Nomura, M, Nakaya, Y, Ito, S 2000Early diagnosis of interferon-induced myocardial disorder in patients with chronic hepatitis C: evaluation by myocardial imaging with 123I-BMIPPJ Gastroenterol3512735CrossRefPubMedGoogle Scholar
  54. 54.
    Salman, H, Bergman, M, Bessler, H, Alexandrova, S, Djaldetti, M 1999The effect of interferon on mouse myocardial capillaries: an ultrastructural studyCancer8513759CrossRefPubMedGoogle Scholar
  55. 55.
    Fernandez-Miranda, C, Castellano, G, Guijarro, C, Fernandez, I, Schoebel, N,  et al. 1998Lipoprotein changes in patients with chronic hepatitis C treated with interferon-α Am J Gastroenterol9319014CrossRefPubMedGoogle Scholar
  56. 56.
    Kruit, WHJ, Eggermont, AMM, Stoter, G 2000Interferon-α induced Raynaud’s syndromeAnn Oncol1115012CrossRefPubMedGoogle Scholar
  57. 57.
    Al-Zahrani, H, Gupta, V, Minden, MD, Messner, HA, Lipton, JH 2003Vascular events associated with alpha interferon therapyLeuk Lymphoma444715CrossRefPubMedGoogle Scholar
  58. 58.
    Kawano, T, Shigehira, M, Uto, H, Nakama, T, Kato, J, Hayashi, K,  et al. 1996Retinal complications during interferon therapy for chronic hepatitis CAm J Gastroenterol9130913PubMedGoogle Scholar
  59. 59.
    Dvorak, HF, Gresser, I 1989Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in miceJ Natl Cancer Inst81497502PubMedGoogle Scholar
  60. 60.
    Anderson, P, Höglund, M, Rödjer, S 2003Pulmonary side-effects of interferon-alpha therapy in patients with hematological malignanciesAm J Hematol73548CrossRefPubMedGoogle Scholar
  61. 61.
    Ogata, K, Koga, T, Yagawa, K 1994Interferon-related bronchiolitis obliterans organizing pneumoniaChest1066123PubMedGoogle Scholar
  62. 62.
    Takeda, A, Ikegame, K, Kimura, Y, Ogawa, H, Kanazawa, S, Nakamura, H 2000Pleural effusion during interferon treatment for chronic hepatitis CHepatogastroenterology4714315PubMedGoogle Scholar
  63. 63.
    Fabris, P, Floreani, A, Tositti, G, Vergani, D, Lalla, F, Betterle, C 2003Type 1 diabetes mellitus in patients with chronic hepatitis C before and after interferon therapyAliment Pharmacol Ther1854958CrossRefPubMedGoogle Scholar
  64. 64.
    Gisslinger, H, Svoboda, T, Clodi, M, Gilly, B, Ludwig, H, Havelec, L,  et al. 1993Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitroNeuroendocrinology5748995PubMedGoogle Scholar
  65. 65.
    Koivisto, VA, Pelkonen, R, Cantell, K 1989Effect of interferon on glucose tolerance and insulin sensitivityDiabetes386417PubMedGoogle Scholar
  66. 66.
    Ito, Y, Takeda, N, Ishimori, M, Akai, A, Miura, K, Yasuda, K 1999Effects of long-term interferon-alpha treatment on glucose tolerance in patients with chronic hepatitis CJ Hepatol3121520CrossRefPubMedGoogle Scholar
  67. 67.
    Corssmit, EP, Endert, E, Sauerwein, HP, Romijn, JA 2000Acute effects of interferon-alpha administration on testosterone concentrations in healthy menEur J Endocrin1433714CrossRefGoogle Scholar
  68. 68.
    Concha, LB, Carlson, HE, Heimann, A, Lake-Bakaar, GV, Paal, AF 2003Interferon-induced hypopituitarismAm J Med1141613CrossRefPubMedGoogle Scholar
  69. 69.
    Sakane, N, Yoshida, T, Yoshioka, K, Umekawa, T, Kondo, M, Shimatsu, A 1995Reversible hypopituitarism after interferonalfa therapyLancet3451305CrossRefPubMedGoogle Scholar
  70. 70.
    Weijl, NI, Harts, D, Brand, A, Kooy, Y, Luxemburg, S, Schroder, J,  et al. 1993Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatmentJ Clin Oncol11137683PubMedGoogle Scholar
  71. 71.
    Bell, TM, Bansal, AS, Shorthouse, C, Sandford, N, Powell, EE 1999Low-titre auto-antibodies predict autoimmune disease during interferon-alpha treatment of chronic hepatitis CJ Gastroenterol Hepatol1441922CrossRefPubMedGoogle Scholar
  72. 72.
    Watanabe, U, Hashimoto, E, Hisamitsu, T, Obata, H, Hayashi, N 1994The risk factor for development of thyroid disease during interferon-alpha therapy for chronic hepatitis CAm J Gastroenterol89399403PubMedGoogle Scholar
  73. 73.
    Vial, T, Descotes, J 1995Immune-mediated side-effects of cytokines in humansToxicology1053157CrossRefPubMedGoogle Scholar
  74. 74.
    Lahat, N, Sheinfeld, M, Sobel, E, Kinarty, A, Kraiem, Z 1992Divergent effects of cytokines on human leucocyte antigen-DR antigen expression of neoplastic and non-neoplastic human thyroid cellsCancer691799807PubMedGoogle Scholar
  75. 75.
    You, X, Teng, W, Shan, Z 1999Expression of ICAM-1, B7.1 and TPO on human thyrocytes induced by IFN-alphaChin Med J112616PubMedGoogle Scholar
  76. 76.
    Kakizaki, S, Takagi, H, Murakami, M, Takayama, H, Mori, M 1999HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis CJ Hepatol30794800CrossRefPubMedGoogle Scholar
  77. 77.
    Carella, C, Mazziotti, G, Morisco, F, Manganella, G, Rotondi, M, Tucillo, C,  et al. 2001Long-term outcome of interferon-alpha-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatmentJ Clin Endocrinol Metab8619259CrossRefPubMedGoogle Scholar
  78. 78.
    Guillot, B, Blazquez, L, Bessis, D, Dereure, O, Guilhou, JJ 2004A prospective study of cutaneous adverse events induced by low-dose alpha-interferon treatment for malignant melanomaDermatology2084954CrossRefPubMedGoogle Scholar
  79. 79.
    Dalekos, GN, Hatzis, J, Tsianos, EV 1998Dermatologic disease during interferon-alpha therapy for chronic viral hepatitisAnn Intern Med12840910PubMedGoogle Scholar
  80. 80.
    Asnis, LA, Gaspari, AA 1995Cutaneous reactions to recombinant cytokine therapyJ Am Acad Dermatol33393410CrossRefPubMedGoogle Scholar
  81. 81.
    Rowan, PJ, Tabasi, S, Abdul-Latif, M, Kunik, ME, El-Serag, HB 2004Psychosocial factors are the most common contraindications for antiviral therapy at initial evaluation in veterans with chronic hepatitis CJ Clin Gastroenterol385304PubMedGoogle Scholar
  82. 82.
    Loftis, JM, Hauser, P 2004The phenomenology and treatment of interferon-induced depressionJ Affect Disord8217590CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Stefan Sleijfer
    • 1
    Email author
  • Marjolein Bannink
    • 2
  • Arthur  R.  Van Gool
    • 2
  • Wim  H. J. Kruit
    • 1
  • Gerrit Stoter
    • 1
  1. 1.Department of Medical OncologyErasmus University Medical Center – Daniel den Hoed Cancer CenterRotterdamThe Netherlands
  2. 2.Department of PsychiatryErasmus University Medical Center – Daniel den Hoed Cancer CenterRotterdamThe Netherlands

Personalised recommendations