Interferon alfa adverse effects

Elderly Treatment with alpha interferons, including peginterferon alfa-2b, is associated with CNS, cardiac, and systemic (flu-like) adverse effects. Because these adverse reactions may be more severe in the elderly, exercise caution in the use of interferon alfa-2b in this population. 

Interferon gamma is an activator of macrophages. Its anti-viral activity is limited compared to that of interferon alfa. Human recombinant interferon gamma restores, at least in part, macrophage cytotoxicity and with that decreases the incidence of infections in patients with chronic granulomatous diseases. Its adverse effects consist mainly of flu-like syndrome skin rashes may occur. 

The adverse effects of interferon alfa-2b include fever and a fiulike syndrome of muscle ache, fatigue, headache, anorexia, and nausea. Other less common side effects include leukopenia, diarrhea, dizziness, and skin rash. 

Since the original 1988 report of hypothyroidism in patients with breast cancer receiving leukocyte-derived interferon alfa (498), numerous investigators have provided clear clinical and biological data on thyroid disorders induced by different forms of interferon in patients with various diseases (499,500-503). Two of these reports also mentioned associated adverse effects that developed concomitantly, namely myelosuppression and severe proximal myopathy (Hoffmann s syndrome). 

A middle-aged woman developed subacute thyroiditis by the sixth month of treatment with interferon alfa (508). She also had the classic symptoms of hyperthyroidism, although it is clear that these could easily have been mistaken for adverse effects of interferon alfa itself, for example weakness, weight loss, and palpitation. 

Drug(s) Biologic response modifiers Interferons Interferon alfa-2a [Roferon-A] Interferon alfa-2b [Intron-A] Primary Antineoplastic Indication(s) Hairy-cell leukemia Kaposi sarcoma chronic myelocytic leukemia renal and bladder cancers Common Adverse Effects Flulike syndrome [mild fever, chills, malaise]... 

Typical side effects are constitutional in nature, including a flu-like syndrome within 6 hours after dosing in more than 30% of patients that tends to resolve upon continued administration. Other potential adverse effects include thrombocytopenia, granulocytopenia, elevation in serum aminotransferase levels, induction of autoantibodies, nausea, fatigue, headache, arthralgias, rash, alopecia, anorexia, hypotension, and edema. Severe neuropsychiatric side effects may occur. Absolute contraindications to therapy are psychosis, severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and a history of organ transplantation (other than liver). Alfa interferons are abortifacient in primates and should not be administered in pregnancy. 

Neuropsychiatric complications of interferon alfa were recognized in the early 1980s and represent one of the most disturbing adverse effects of interferon alfa (SED-13, 1091 SEDA-20, 327 SEDA-22, 400). Reviews have provided comprehensive analysis of the large amount of experimental and clinical data that have accumulated since 1979 (321,322). 

Several mechanisms involved in the pathogenesis of interferon alfa-induced psychiatric adverse effects have been hypothesized (Loftis 175), but the mechanisms by which interferon alfa enters the brain to produce neurotransmitter changes are unclear. In a prospective study in 48 patients who received adjuvant interferon alfa for malignant melanoma there was a positive correlation between the increase in serum concentration of soluble ICAM-1 and depression scores the authors suggested that induction of soluble ICAM-1 by interferon alfa increased the permeability of the blood-brain barrier, allowing the drug to enter the brain more readily (358). 

Cognitive defects, depression, and mania can occur in patients taking interferon alfa. Interferon alfa-induced psychiatric adverse effects and their recommended management have been comprehensively reviewed (383,384,385). 

Pariante CM, Landau S, Carpiniello BCagliari Group. Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis. N Engl J Med 2002 347(2) 148-9. 

In a phase III trial in 190 patients with metastatic melanoma, sequential chemotherapy with dacarbazine, cisplatin, and vinblastine plus interferon alfa and aldesleukin modestly increased the response rates and produced considerably more frequent and severe adverse effects than chemotherapy alone (128). In particular, severe episodes of anemia and thrombocytopenia that required blood or platelet transfusions were 2-6 times more frequent in the chemotherapy group. 

However, treatment withdrawal is more frequent in practice. In a retrospective analysis of 441 consecutive patients treated with interferon alfa and ribavirin, 25% of patients discontinued treatment because of adverse effects... 

In a randomized comparison of recombinant interferon alfa-2b and interferon alfa n-3 (9 MU/week for 1 year) in 168 naive patients with chronic hepatitis C, there was no significant difference in clinical outcomes and the incidence or type of adverse effects between the groups (9). There was a non-significant trend toward more severe leukopenia and a higher incidence of severe thyroid disorders in patients who received recombinant interferon alfa-2b. 

In 1530 patients with chronic hepatitis C, pegylated interferon alfa-2b had a similar profile of adverse effects to unmodified interferon alfa-2b, but with more frequent dose-hmiting neutropenia (10). No particular adverse effect has emerged since the use of this new formulation. 

The adverse effects of interferon alfa have mostly been reported after systemic administration, as intranasal use was not associated with more frequent adverse effects than placebo (13). Almost aU patients treated with interferon alfa have experienced adverse effects, most of which are mild to moderate in intensity and easily manageable without withdrawal of treatment (14). The incidence and profile of adverse effects reported with the available tjfpes... 

Although the adverse effects profiles of the currently available formulations of interferon alfa are very similar, patients who have adverse effects with one formulation can be successfully re-treated with another type of interferon alfa. This has been shown in 22 patients in whom lymphoblastoid interferon alfa was withdrawn because of severe adverse effects (leukopenia, thrombocytopenia, thyroid disorders, and psychiatric disturbances) and were successfully re-treated with similar dosages of leukocyte interferon alfa (22). Only one of these patients had severe leukopenia again. 

Hypotension or hypertension, benign sinus or supraventricular tachycardia, and rarely distal cyanosis, have been reported within the first days of treatment in 5-15% of patients receiving high-dose interferon alfa (20). These adverse effects are usually benign, except in high-risk patients with a previous history of dysrhythmias, coronary disease, or cardiac dysfunction. 

Similar, but anecdotal reports were also described in patients without evidence of previous cardiac disease and receiving low-dose interferon alfa (SEDA-20, 326). In chronic viral hepatitis, only seven of 11 241 patients had severe cardiac adverse effects (16). The exact risk of such cardiovascular adverse effects is unknown. In patients with chronic viral hepatitis, cardiovascular test results were not modified when patients were re-examined after at least 6 months of treatment, even where there was an earlier cardiac history (26), but there was a potentially critical reversible reduction in left ventricular ejection of more than 10% in another prospective study (27). 

The respiratory adverse effects of interferon alfa include interstitial pneumonitis (38), which is rare. Since the first description of interstitial pneumonitis associated with interferon alfa in Japanese patients who also used the popular Sho-saiko-t herbal formulation, similar cases have been described in Western patients, suggesting that interferon alfa can be the sole cause in some patients (SED-13,1091) (SEDA-20, 326) (SEDA-21, 370) (39,40). 

Although the mechanism of this adverse effect was purely speculative, it was suggested that interferon alfa might have induced a reaction similar to the immunopathologi-cal mechanism involved in serositis associated with systemic lupus erythematosus. 

Other adverse liver effects reported with interferon alfa include primary biliary cirrhosis (SEDA-20, 329) and granulomatous hepatitis (SEDA-20, 329) (SEDA-21, 372) (259). 

Injection-site alopecia has been reported in three patients, affecting the thighs in two patients and the abdomen in one (307). A reversible focal telogen effluvium secondary to high local concentrations of interferon alfa was the most likely cause, indicating that rotating injection sites are needed to prevent this adverse effect. 

Sexual complaints attributed to interferon alfa, namely decreased hbido, impotence, or erectile failure, are usually concomitant to other neuropsychiatric symptoms, and cases of reversible impotence are anecdotal (315). The mechanisms accounting for these adverse effects are unclear, and changes in sex hormone concentrations have not been consistently reported. In one study in healthy women, interferon alfa produced falls in serum progesterone and estradiol concentrations (316), but neither impairment of libido nor impairment of fertility has apparently been reported in women. No evidence of gonadal toxicity or sexual dysfunction was found in 43 men with hairy cell leukemia who received interferon alfa for 2-12 months compared with 33 patients who... 

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