Interferon Alfa

(BAN, rINN)
Synonyms: IFNInterferon alpha; Interferoni alfa; Interferonialfa; Interferonum Alfa; Ro-22-8181 (interferon alfa-2a); Sch-30500 (interferon alfa2b).
Cyrillic synonym: Интерферон Альфа.

💊 Chemical information

CAS — 74899-72-2 (interferon alfa); 76543-88-9 (interferon alfa-2a); 99210-65-8 (interferon alfa-2b); 11839030-0 (interferon alfacon-1); 198153-51-4 (peginterferon alfa-2a); 215647-85-1 (peginterferon alfa-2b).
ATC — L03AB01 (natural); L03AB04 (2a); L03AB05 (2b); L03AB06 (n1); L03AB09 (alfacon-1); L03AB10 (peginterferon alfa-2b); L03AB11 (peginterferon alfa-2a).
ATC Vet — QL03AB01 (natural); QL03AB04 (2a); QL03AB05 (2b); QL03AB06 (n1); QL03AB09 (alfacon-1); QL03AB10 (peginterferon alfa-2b); QL03AB11 (peginterferon alfa-2a).

Pharmacopoeias.

Chin. includes monographs for recombinant human alfa-2a and alfa-2b. Eur. includes Interferon Alfa-2 Concentrated Solution.

Ph. Eur. 6.2

(Interferon Alfa-2 Concentrated Solution; Interferoni Alfa-2 Solutio Concentrata). It is produced by a method based on recombinant DNA technology using bacteria as host cells. It is a clear, colourless or slightly yellowish liquid. Store in airtight containers at a temperature of −20° or below. Protect from light.

Nomenclature.

Interferon alfa may be derived from leucocytes or lymphoblasts, or produced by recombinant DNA technology. Sub-species of the human alfa gene may produce interferon alfa with protein variants or a mixture of proteins. The protein variants may be designated by a number (as in interferon alfa-2) which may be further qualified by a letter to indicate the amino-acid sequences at positions 23 and 34:
interferon alfa-2a has lysine at 23 and histidine at 34
interferon alfa-2b has arginine at 23 and histidine at 34
interferon alfa-2c has arginine at both positions In the case of a mixture of proteins an alphanumeric designation is given (as in interferon alfa-n1). Interferon alfacon-1 varies from interferon alfa-2 in 20 of 166 amino acids. The name may be further elaborated on the label by approved sets of initials in parentheses to indicate the method of production: (rbe) indicates production from bacteria (Escherichia coli) genetically modified by recombinant DNA technology; (lns) indicates production from cultured lymphoblasts from the Namalwa cell line that have been stimulated by a Sendai virus; (bls) indicates production from leucocytes from human blood that have been stimulated by a Sendai virus. 1. Finter NB. The naming of cats—and alpha-interferons. Lancet 1996; 348: 348–9.

💊 Adverse Effects and Treatment

The adverse effects of interferon are varied and the natural products appear to be less toxic than the pure synthetic compounds. The frequency and severity of adverse effects of peginterferon alfa appear to be similar to those for interferon alfa although dose-related neutropenia and thrombocytopenia and injection site reactions are more common. Clinical experience suggests that interferons beta and gamma have similar adverse effects. Adverse effects are generally mild and reversible at doses less than 5 million international units/day. The majority of patients on interferon treatment have ‘flulike’ symptoms such as loss of appetite, fever, chills, fatigue, headache, malaise, myalgia, arthralgia, and sweating. These symptoms tend to be dose-related, are most likely to occur at the start of treatment, and mostly respond to paracetamol (but for a possible interaction with paracetamol, see Interactions, below). Other common adverse effects are alopecia, asthenia, weight loss, anxiety, depression, dermatitis, diarrhoea, irritability, nausea, nervousness, neutropenia, pruritus, sleep disturbances, taste alteration, and vomiting. Serious adverse effects reported include neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, and suicide) and neurological disturbances (confusion, coma, and seizures), severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anaemia), cardiovascular disorders (hypo- or hypertension, supraventricular arrhythmias and myocardial infarction), endocrine disorders (such as thyroid disorders and diabetes mellitus), pulmonary disorders (dyspnoea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic or ischaemic colitis), pancreatitis, and ophthalmologic disorders (such as decrease or loss of vision, retinopathy including macular oedema and retinal thrombosis or haemorrhages, optic neuritis and papilloedema). Hypersensitivity reactions, including anaphylaxis, have occurred, and interferon therapy may cause or exacerbate auto-immune disorders (such as idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, SLE, rheumatoid arthritis, and interstitial nephritis). Hypertriglyceridaemia, sometimes severe, has been seen. High doses may cause electrolyte disturbances including decreased calcium concentrations. There may be signs of altered liver function and hepatitis has been reported. Renal failure and nephrotic syndrome have also occurred. Interferons may impair fertility and menstrual irregularities have been reported, particularly with interferon beta. Subcutaneous injection may produce a reaction at the injection site, predominantly mild inflammation or erythema, but pain, hypersensitivity, and other non-specific reactions have been reported. The reaction is reported frequently with interferon beta, which can produce severe reactions including local necrosis. Adverse effects of peginterferon alfa (alone or with ribavirin) reported in patients co-infected with hepatitis C virus and HIV, are similar to those reported in patients infected only with hepatitis C virus. Although haematological adverse effects such as neutropenia, thrombocytopenia, and anaemia occurred more often in co-infected patients, most patients could be managed by dose adjustments. Other adverse effects reported in co-infected patients given peginterferon and ribavirin include apathy, raised blood amylase, chapped lips, chromaturia, raised gamma-glutamyltransferase and hepatitis, influenza, lactic acidosis (including hyperlactacidaemia), lipodystrophy, mood alteration, pain in the pharynx, larynx, back, and limbs, pneumonia, and tinnitus. Peginterferon treatment was associated with decreases in CD4+ cell counts within the first 4 weeks that were reversible when the dose was reduced or stopped; no negative impact was noted on the control of HIV viraemia during treatment or follow-up. Nasal dosage may produce mucosal irritation and damage.
1. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50
2. Pardo M, et al. Risks and benefits of interferon-α in the treatment of hepatitis. Drug Safety 1995; 13: 304–16
3. Kirkwood JM, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20: 3703–18
4. Sleijfer S, et al. Side effects of interferon-alpha therapy. Pharm World Sci 2005; 27: 423–31.

Effects on the blood.

Interferon alfa has myelosuppressive effects and the commonest haematological adverse effects associated with its use are dose-related leucopenia, neutropenia, and thrombocytopenia; anaemia is rarely reported. Other reported effects associated with interferon alfa include immune haemolytic anaemia1 and immune thrombocytopenia.2,3 Haemorrhage occurred in a patient with immune thrombocytopenic purpura treated with interferon alfa,4 and it was thought prudent to use interferons with caution, if at all, in this condition.3,4 Reports of clotting disorders are rare; bleeding associated with induction of factor VIII inhibitor has been seen in a patient given interferon alfa to enhance hydroxycarbamide therapy for chronic myeloid leukaemia.5 Thrombosis associated with interferon alfa has also been reported.6 Restoration of bone-marrow function after marrow transplantation was delayed in 3 patients given a human interferon alfa preparation.7 Laboratory results showed an inhibition of granulocyte colony growth by human leucocyte interferon alfa. It was considered that interferon alfa was contra-indicated in patients with severe bone-marrow insufficiency and should not be given to marrow transplant patients before the graft was fully functional. However, in another 5 patients recombinant interferon alfa did not affect bone marrow transplants, although 3 patients experienced fever and chills, 4 had more than a 60% reduction in absolute peripheral granulocyte counts, and 4 had a 37 to 80% reduction in absolute platelet counts.8 Lymphocytes were increased in all patients; blood counts returned to normal when interferon therapy stopped. Interferon alfa produced a decline in CD4+ Tlymphocytes resulting in opportunistic infections in 2 HIV-positive patients being treated for chronic hepatitis C.9
1. Akard LP, et al. Alpha-interferon and immune hemolytic anemia. Ann Intern Med 1986; 105: 306
2. McLaughlin P, et al. Immune thrombocytopenia following α-interferon therapy in patients with cancer. JAMA 1985; 254: 1353–4
3. Färkkilä M, Iivanainen M. Thrombocytopenia and interferon. BMJ 1988; 296: 642
4. Matthey F, et al. Bleeding in immune thrombocytopenic purpura after alpha-interferon. Lancet 1990; 335: 471–2
5. English KE, et al. Acquired factor VIII inhibitor in a patient with chronic myelogenous leukaemia receiving interferon-alfa therapy. Ann Pharmacother 2000; 34: 737–9
6. Durand JM, et al. Thrombosis and recombinant interferon-α. AmJ Med 1993; 95: 115
7. Nissen C, et al. Toxicity of human leucocyte interferon preparations in human bone-marrow cultures. Lancet 1977; i: 203–4
8. Winston DJ, et al. Safety and tolerance of recombinant leukocyte A interferon in bone marrow transplant recipients. Antimicrob Agents Chemother 1983; 23: 846–51
9. Pesce A, et al. Opportunistic infections and CD4 lymphocytopenia with interferon treatment in HIV-1 infected patients. Lancet 1993; 341: 1597.

Effects on the cardiovascular system.

Hypotension or hypertension, tachycardia, and distal cyanosis are the most commonly reported cardiovascular adverse effects. Other reported cardiac complications include cardiac arrhythmias, atrioventricular block, symptoms of ischaemic heart disease, including myocardial infarction and sudden death, congestive heart failure, acute dyspnoea, pericardial effusion,1,2 and cardiomyopathy.1,3,4Cardiac toxicity was not related to the daily or cumulative total dose, or duration of treatment and is usually reversible on stopping interferon treatment.1 Peripheral vascular complications such as Raynaud’s syndrome5-9 have been associated with interferon alfa therapy and other types of interferon.
1. Sonnenblick M, Rosin A. Cardiotoxicity of interferon. A review of 44 cases. Chest 1991; 99: 557–61
2. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50
3. Angulo MP, et al. Reversible cardiomyopathy secondary to αinterferon in an infant. Pediatr Cardiol 1999; 20: 293–4
4. Kuwata A, et al. A case of reversible dilated cardiomyopathy after α-interferon therapy in a patient with renal cell carcinoma. Am J Med Sci 2002; 324: 331–4
5. Bachmeyer C, et al. Raynaud’s phenomenon and digital necrosis induced by interferon-alpha. Br J Dermatol 1996; 135: 481–3
6. Linden D. Severe Raynaud’s phenomenon associated with interferon-β treatment for multiple sclerosis. Lancet 1998; 352: 878–9
7. Kruit WH, et al. Interferon-α induced Raynaud’s syndrome. Ann Oncol 2000; 11: 1501–2
8. Schapira D, et al. Interferon-induced Raynaud’s syndrome. Semin Arthritis Rheum 2002; 32: 157–62
9. Iorio R, et al. Severe Raynaud’s phenomenon with chronic hepatitis C disease treated with interferon. Pediatr Infect Dis J 2003; 22: 195–7.

Effects on the endocrine system.

Both hypothyroidism1,2and hyperthyroidism2,3 have been associated with interferon alfa therapy. Thyroid disorders are usually minor and regress on stopping the interferon (with or without other specific treatment). However a case of long-lasting ophthalmopathy as a result of interferon alfa-induced Graves’ disease has been reported in a patient being treated for hepatitis C.4 The development of type 1 diabetes has also been associated with interferon alfa therapy,5-8 and exacerbation of existing type 2 diabetes has been reported.9,10 Reversible hypopituitarism has been reported in patients receiving interferon alfa.11,12 Recombinant interferon gamma was reported not to affect thyroid function.13
1. Fentiman IS, et al. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet 1985; i: 1166
2. Burman P, et al. Autoimmune thyroid disease in interferontreated patients. Lancet 1985; ii: 100–1
3. Schultz M, et al. Induction of hyperthyroidism by interferon-α2b. Lancet 1989; i: 1452
4. Binaghi M, et al. Ophtalmopathie de Basedow sévère liée à l’interféron alpha. J Fr Ophtalmol 2002; 25: 412–15
5. Fabris P, et al. Development of type 1 diabetes mellitus during interferon alfa therapy for chronic HCV hepatitis. Lancet 1992; 340: 548
6. Guerci A-P, et al. Onset of insulin-dependent diabetes mellitus after interferon-alfa therapy for hairy cell leukaemia. Lancet 1994; 343: 1167–8
7. Gori A, et al. Reversible diabetes in patient with AIDS-related Kaposi’s sarcoma treated with interferon α-2a. Lancet 1995; 345: 1438–9
8. Murakami M, et al. Diabetes mellitus and interferon-α therapy. Ann Intern Med 1995; 123: 318
9. Campbell S, et al. Rapidly reversible increase in insulin requirement with interferon. BMJ 1996; 313: 92
10. Lopes EPA, et al. Exacerbation of type 2 diabetes mellitus during interferon-alfa therapy for chronic hepatitis B. Lancet 1994; 343: 244. Correction. ibid.: 680
11. Sakane N, et al. Reversible hypopituitarism after interferon-alfa therapy. Lancet 1995; 345: 1305.
12. Concha LB, et al. Interferon-induced hypopituitarism. Am J Med 2003; 114: 161–3
13. Bhakri H, et al. Recombinant gamma interferon and autoimmune thyroid disease. Lancet 1985; ii: 457.

Effects on the eyes.

The most typical ocular adverse effect associated with interferon alfa treatment is retinopathy, which is characterised by cotton wool spots and superficial retinal haemorrhages. Reports of interferon-associated retinopathy have been reviewed.1,2 Reduced vision or complete visual loss is rare or limited and is usually reversible after stopping treatment. In a study of 43 patients with chronic hepatitis given interferon alfa, retinopathy developed in 11 of 37 non-diabetic patients and in 3 of 6 diabetic patients after about 8 to 10 weeks of therapy.3 None of the patients had had retinopathy before treatment; the condition was reversible in the non-diabetic patients on stopping therapy. Visual acuity remained unchanged. Subconjunctival haemorrhage occurred in a further 3 of the non-diabetic patients. Severe irreversible loss of vision has been reported in a non-diabetic patient given interferon alfa.4 A prospective study5 of 156 patients treated with interferon alfa or peginterferon alfa (with or without ribavirin) reported signs of retinopathy in 24% of the patients; 29 patients developed cotton-wool spots, 7 developed retinal haemorrhage, and 2 patients developed both lesions during treatment; none of the patients had retinopathy before starting treatment. The lesions remained asymptomatic and resolved in all the patients. Patient age above 45 years, hypertension, and the use of pegylated alpha-interferon were identified as risk factors for retinopathy. Neurovisual impairment was present in 31 patients before interferon treatment and in 74 patients during treatment. Another study6 of 19 patients reported that 8 patients developed asymptomatic retinopathy while on treatment with interferon alfa (with or without ribavirin); patients who had previously failed to respond to interferon monotherapy seemed more likely to develop retinopathy when given combined therapy than patients who had responded and then relapsed. The changes were transient and sometimes disappeared while the patients were still on treatment. Retinopathy has been reported in patients being treated with interferon beta for the management of multiple sclerosis.7,8 Symptoms also resolved after stopping treatment. Pain in one eyeball leading to exophthalmos and complete visual loss has been reported in a patient given interferon alfa;9 despite withdrawal of interferon and instigation of antibacterial and corticosteroid treatment, the eyeball subsequently ruptured necessitating ophthalmectomy. Other severe ocular effects reported during interferon alfa treatment include a disorder resembling VogtKoyanagi-Harada disease, central retinal vein occlusion, central retinal artery occlusion, and bilateral ischaemic optic neuropathy with severe visual impairment.10
1. Hayasaka S, et al. Interferon associated retinopathy. Br J Ophthalmol 1998; 82: 323–5
2. Savant V, Gillow T. Interferon-associated retinopathy. Eye 2003; 17: 534–6
3. Hayasaka S, et al. Retinopathy and subconjunctival haemorrhage in patients with chronic viral hepatitis receiving interferon alfa. Br J Ophthalmol 1995; 79: 150–2
4. Lohmann CP, et al. Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma. Lancet 1999; 353: 1326
5. d’Alteroche L, et al. Ophthalmologic side effects during alphainterferon therapy for viral hepatitis. J Hepatol 2006; 44: 56–61
6. Jain K, et al. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. Br J Ophthalmol 2001; 85: 1171–3
7. Saito H, et al. Retinopathy in a multiple sclerosis patient undergoing interferon-therapy. Multiple Sclerosis 2007; 13: 939–40
8. Longmuir R, et al. Cotton wool spots associated with interferon beta-1 alpha therapy. Semin Ophthalmol 2007; 22: 49–53
9. Yamada H, et al. Acute onset of ocular complications with interferon. Lancet 1994; 343: 914
10. Sène D, et al. Intraocular complications of IFN-alpha and ribavirin therapy in patients with chronic viral hepatitis C. World J Gastroenterol 2007; 13: 3137–40.

Effects on the gast

rointestinal tract. Mild and transient gastrointestinal adverse effects such as nausea, diarrhoea, vomiting, and anorexia occur in about 30 to 40% of patients being treated with interferon alfa. There have been reports1-4 of the onset of coeliac disease during treatment of hepatitis C with interferon or peginterferon alfa, in some cases used with ribavirin. Symptoms generally resolved after interferon was stopped and a gluten-free diet started. A case5 of eosinophilic enteritis has been reported in a patient, with no history of digestive disorders, after 12 weeks of recombinant interferon alfa-2b treatment; symptoms resolved after stopping interferon and on treatment with prednisolone. New6,7 or exacerbated8 cases of ulcerative colitis have been reported in patients on interferon or peginterferon alfa treatment (with or without ribavirin). Treatment with interferon was usually stopped7,8 and symptoms tended to resolve or improve with appropriate therapy (such as mesalazine and/or corticosteroids).6-8 Cases of ischaemic colitis associated with interferon or peginterferon alpha have been reported rarely.9
1. Bardella MT, et al. Celiac disease during interferon treatment. Ann Intern Med 1999; 131: 157–8
2. Cammarota G, et al. Onset of coeliac disease during treatment with interferon for chronic hepatitis C. Lancet 2000; 356: 1494–5
3. Bourlière M, et al. Onset of coeliac disease and interferon treatment. Lancet 2001; 357: 803–4
4. Martins EV, Gaburri AK. Celiac disease onset after pegylated interferon and ribavirin treatment of chronic hepatitis C. Arq Gastroenterol 2004; 41: 132–3
5. Kakumitsu S, et al. Eosinophilic enteritis observed during alphainterferon therapy for chronic hepatitis C. J Gastroenterol 2000; 35: 548–51
6. Mavrogiannis C, et al. Ulcerative colitis associated with interferon treatment for chronic hepatitis C. J Hepatol 2001; 34: 964–5
7. Sprenger R, et al. Acute ulcerative colitis during successful interferon/ribavirin treatment for chronic hepatitis. Gut 2005; 54: 438–9
8. Watanabe T, et al. A case of exacerbation of ulcerative colitis induced by combination therapy with PEG-interferon alpha-2b and ribavirin. Gut 2006; 55: 1682–3
9. Leung Y, et al. Ischemic colitis during pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Can J Gastroenterol 2006; 20: 661–3.

Effects on the hair.

Excessive temporary loss of telogen hair causing moderate and reversible alopecia occurs in about 7 to 30% of patients on interferon or peginterferon alfa treatment. Alopecia areata1-3 and alopecia universalis4,5 have occasionally been reported; complete regrowth of the hair usually occurs on completing interferon treatment. A report of marked greying of the hair in a patient beginning after 5 months of treatment with interferon alfa for metastatic malignant melanoma; on completion of interferon therapy the hair regrowth returned to its normal colour.6 Marked straightening of scalp and body hair has been reported in 2 patients after combined treatment with interferon alfa-2b or peginterferon alfa-2b and ribavirin for chronic hepatitis C.7 In the first patient, there was also diffuse thinning of scalp hair, change in hair texture, increased greying of the hair, and eyebrow lengthening; the original curly hair began to regrow 6 months after stopping treatment, but the hair abnormalities recurred on rechallenge despite switching from interferon alfa-2b to peginterferon alfa-2b. In the second patient, treatment with peginterferon alfa-2b and ribavirin was associated with straightening of scalp hair, eyebrow hair, and pubic hair.7 Lengthening and thickening of eyelashes has also been reported with interferon alfa therapy.8,9 A case of eyelid and eyebrow trichomegaly has also been reported10 in a patient treated with peginterferon alfa and ribavirin.
1. Radny P, et al. Alopecia areata induced by adjuvant treatment with alpha-interferon in malignant melanoma? Dermatology 2004; 209: 249–50
2. Agesta N, et al. Alopecia areata during interferon alpha-2b/ribavirin therapy. Dermatology 2002; 205: 300–1
3. Kernland KH, Hunziker T. Alopecia areata induced by interferon alpha? Dermatology 1999; 198: 418–19
4. Taliani G, et al. Reversible alopecia universalis during treatment with PEG-interferon and ribavirin for chronic hepatitis C. J Chemother 2005; 17: 212–14
5. Kartal ED, et al. Reversible alopecia universalis secondary to PEG-interferon alpha-2b and ribavirin combination therapy in a patient with chronic hepatitis C virus infection. Eur J Gastroenterol Hepatol 2007; 19: 817–20
6. Fleming CJ, MacKie RM. Alpha interferon-induced hair discolouration. Br J Dermatol 1996; 135: 337–8
7. Bessis D, et al. Straight hair associated with interferon-alfa plus ribavirin in hepatitis C infection. Br J Dermatol 2002; 147: 392–3
8. Hernández-Núñez A, et al. Trichomegaly following treatment with interferon alpha-2b. Lancet 2002; 359: 1107
9. Dikici B, et al. Interferon alpha and hypertrichosis of eyelashes. Pediatr Infect Dis J 2002; 21: 448–9
10. Howaizi M. Pegylated interferon-induced eyelid and eyebrow trichomegaly during chronic hepatitis C. J Gastroenterol Hepatol 2005; 20: 1945–6.

Effects on hearing.

Sensorineural hearing loss, mostly unilateral, has been rarely reported in patients treated with interferon or peginterferon. A prospective study1 reported sensorineural hearing loss in 18 of 49 patients and tinnitus in 14 of 49 patients given interferons. The authors reported that effects were more common in those given interferon beta than in those given interferon alfa, and resolved in all patients on stopping therapy. A report2 of 6 patients who experienced sudden hearing loss while on treatment with peginterferon alfa plus ribavirin found that hearing loss did not fully resolve after stopping treatment; but neither did it worsen in those who continued their treatment. A case report3 of a patient who had acute sensorineural hearing loss 2 months after starting treatment with peginterferon alfa and ribavirin found that when treatment was re-started 4 months after stopping, the patient did not experience further hearing loss and hearing on the left-side was unaffected. In another case report4 a patient who developed hearing loss 22 weeks after starting treatment with peginterferon alfa, continued with treatment and symptoms did not worsen. Hearing loss resolved within 2 weeks of stopping treatment.
1. Kanda Y, et al. Sudden hearing loss associated with interferon. Lancet 1994; 343: 1134–5
2. Formann E, et al. Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin. Am J Gastroenterol 2004; 99: 873–7
3. Wong VK, et al. Acute sensorineural hearing loss associated with peginterferon and ribavirin combination therapy during hepatitis C treatment: outcome after resumption of therapy. World J Gastroenterol 2005; 11: 5392–3
4. Elloumi H, et al. Sudden hearing loss associated with peginterferon and ribavirin combination therapy during hepatitis C treatment. World J Gastroenterol 2007; 13: 5411–12.

Effects on the kidneys.

Renal adverse effects associated with interferon alfa are usually limited to mild, asymptomatic proteinuria and moderate increases in serum creatinine in 15 to 20% of patients. Dose-related asymptomatic proteinuria has been reported with interferon gamma treatment.1 Acute renal failure and nephrotic syndrome associated with interferon alfa treatment is rare and has mostly been reported in patients with underlying renal disease, or malignancies,2-5 and in those receiving high doses.6 Cases have also been reported in patients receiving interferon or peginterferon alfa treatment for chronic hepatitis C.7-9Nephrotic syndrome has also occurred after use of interferon beta.10-12 Renal dysfunction usually resolves after stopping treatment, but incomplete resolution and fatalities have been reported.5,8
1. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50
2. Averbuch SD, et al. Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte A interferon therapy for mycosis fungoides. N Engl J Med 1984; 310: 32–5
3. Selby P, et al. Nephrotic syndrome during treatment with interferon. BMJ 1985; 290: 1180
4. Herrman J, Gabriel F. Membranoproliferative glomerulonephritis in a patient with hairy-cell leukemia treated with alpha-II interferon. N Engl J Med 1987; 316: 112–13
5. Colovic M, et al. Interferon alpha sensitisation induced fatal renal insufficiency in a patient with chronic myeloid leukaemia: case report and review of literature. J Clin Pathol 2006; 59: 879–81
6. Kramer P, et al. Recombinant leucocyte interferon A induces steroid-resistant acute vascular rejection episodes in renal transplant recipients. Lancet 1984; i: 989–90
7. Endo M, et al. Appearance of nephrotic syndrome following interferon-α therapy in a patient with hepatitis B virus and hepatitis C virus coinfection. Am J Nephrol 1998; 18: 439–43
8. Fisher ME, et al. A woman with chronic hepatitis C infection and nephrotic syndrome who developed multiple renal lesions after interferon alfa therapy. Am J Kidney Dis 2004; 44: 567–73
9. Couto CA, et al. Life-threatening thrombocytopenia and nephrotic syndrome due to focal segmental glomerulosclerosis associated with pegylated interferon alpha-2b and ribavirin treatment for hepatitis C. Liver Int 2006; 26: 1294–7
10. Nakao K, et al. Minimal change nephrotic syndrome developing during postoperative interferon-beta therapy for malignant melanoma. Nephron 2002; 90: 498–500
11. Auty A, Saleh A. Nephrotic syndrome in a multiple sclerosis patient treated with interferon beta 1a. Can J Neurol Sci 2005; 32: 366–8
12. Kumasaka R, et al. Nephrotic syndrome associated with interferon-beta-1b therapy for multiple sclerosis. Clin Exp Nephrol 2006; 10: 222–5.

Effects on lipids.

Cases1-3 of reversible hypertriglyceridaemia (with or without elevation of total cholesterol level) have been reported in association with interferon alfa treatment. Hypertriglyceridaemia more often occurs with longer treatment durations and does not appear to be related to pre-existing cardiovascular disorders or baseline dyslipidaemia; frequency and severity are not dose dependent. Lifestyle modifications and drug treatment with a fibrate or statin are usually needed to reduce triglyceride levels. A small study4 reported that taking omega-3 fatty acid supplements (3 g daily for 6 months) reduced serum triglyceride levels in patients on interferon alfa for the management of chronic hepatitis C.
1. Graessle D, et al. Alpha-interferon and reversible hypertriglyceridemia. Ann Intern Med 1993; 118: 316–17
2. Junghans V, Rünger TM. Hypertriglyceridaemia following adjuvant interferon-α treatment in two patients with malignant melanoma. Br J Dermatol 1999; 140: 183–4
3. Wong SF, et al. Management of hypertriglyceridemia in patients receiving interferon for malignant melanoma. Ann Pharmacother 2004; 38: 1655–9
4. Malaguarnera M, et al. Fish oil treatment of interferon-alphainduced dyslipidaemia: study in patients with chronic hepatitis C. BioDrugs 1999; 11: 285–91.

Effects on the liver.

Mild hepatotoxicity with an asymptomatic and reversible rise in serum aminotransferases has been reported in about 25 to 30% of patients receiving interferon alfa; severe hepatotoxicity is rare1 but cases of fatal liver failure have been reported,2-5 sometimes due to severe exacerbation of chronic hepatitis B and/or C infection.4,5 An analysis of the toxicity of adjuvant high-dose interferon alfa in 40 patients being treated for melanoma reported hepatotoxicity in 39 patients, with 26 patients experiencing grade 3 to 4 hepatotoxicity.6 Cases7,8 of peginterferon alfa-induced auto-immune hepatitis have been reported in patients receiving treatment for chronic hepatitis C. Raised serum-alanine aminotransferase values have been reported in about 37% of patients given interferon beta therapy for the treatment of multiple sclerosis, with grade 3 to 4 hepatotoxicity being reported in about 1.4% of patients.9
1. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50
2. Durand JM, et al. Liver failure due to recombinant alpha interferon. Lancet 1991; 338: 1268–9
3. Wandl UB, et al. Liver failure due to recombinant alpha interferon for chronic myelogenous leukaemia. Lancet 1992; 339: 123–4
4. Marcellin P, et al. Fatal exacerbation of chronic hepatitis B induced by recombinant alpha-interferon. Lancet 1991; 338: 828
5. Janssen HLA, et al. Fatal hepatic decompensation associated with interferon alfa. BMJ 1993; 306: 107–8
6. Jonasch E, et al. Adjuvant high-dose interferon alfa-2b in patients with high-risk melanoma. Cancer J 2000; 6: 139–45
7. Kogure T, et al. Fulminant hepatic failure in a case of autoimmune hepatitis in hepatitis C during peg-interferon-alpha 2b plus ribavirin treatment. World J Gastroenterol 2007; 13: 4394–7
8. Kontorinis N, et al. Pegylated interferon-induced immune-mediated hepatitis post-liver transplantation. Liver Transpl 2006; 12: 827–30
9. Byrnes V, et al. Drug induced liver injury secondary to interferon-beta (IFN-beta) in multiple sclerosis. Ann Hepatol 2006; 5: 56–9.

Effects on the nervous system and mental state.

Neurological adverse effects have been reported in association with interferon alfa treatment for chronic hepatitis C virus or for malignant diseases;1-5 notably, an acute confusional state may develop rapidly after starting high-dose interferon alfa treatment and a depressive syndrome may develop more slowly over weeks to months of treatment. Less commonly a manic condition, usually characterised by extreme irritability and agitation but also occasionally by euphoria, may occur. Acute interferon alfa-induced confusional states are typically characterised by disorientation, lethargy, difficulties with speaking and writing, parkinsonism, psychomotor retardation, psychotic symptoms (such as hallucinations), and somnolence. Depression5-9 occurs in about 16 to 58% of patients receiving interferon alfa. Patients considered to be at risk for developing depression are those with pre-existing symptoms of mood and anxiety disorders, those with a history of major depression, and those receiving higher doses of interferon alfa or on long treatment regimens. SSRIs have been used successfully to both treat patients with interferon-associated depression, thus allowing therapy to be continued,10,11 and as pretreatment to prevent its occurrence.12 Should manic symptoms13 occur, interferon alfa and antidepressant treatment should be stopped and a mood stabiliser given. Interferon alfa-induced mood disorders may also consist of an overlap between depressive and manic symptoms. A prospective study14 of 93 patients treated with peginterferon alfa plus ribavirin for chronic hepatitis C reported that mood disorders occurred in 30 patients; 3 cases of mania, 15 cases of irritable hypomania, and 12 cases of mixed depressive states. The distinction between the 2 states is important in terms of management as depressionspecific symptoms respond well to SSRIs, whereas antidepressants may worsen manic or hypomanic states. Seizures15-17 attributed to interferon alfa have been described. Cases of neurological toxicity have been reported in patients receiving interferon beta,1,18 although interferon beta is considered to be slightly less neurotoxic. Chronic hepatitis C virus infection may be complicated by the development of systemic vasculitis caused by mixed cryoglobulinemia or of a non-cryoglobulinemic vasculitis resembling polyarteritis nodosa. Successful treatment of the hepatitis infection with interferon alfa usually results in the improvement of vasculitic symptoms, including neuropathy. However, vasculitis may also be precipitated or exacerbated by treatment with interferon (including peginterferon alfa)19-21 resulting in development of vasculitic neuropathy; cases of apparently non-vasculitic peripheral neuropathy have also been reported.20-22 Others23 have reported no association between peginterferon alfa and peripheral neuropathy. In most cases symptoms improved on treatment with corticosteroids or spontaneously, but fatal exacerbations of vasculitis have occurred despite stopping the interferon treatment and giving immunosuppressants.21
1. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50
2. Dieperink E, et al. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry 2000; 157: 867–76
3. Malek-Ahmadi P. Mood disorders associated with interferon treatment: theoretical and practical considerations. Ann Pharmacother 2001; 35: 489–95
4. Van Gool AR, et al. Neuropsychiatric side effects of interferonalfa therapy. Pharm World Sci 2003; 25: 11–20
5. Raison CL, et al. Neuropsychiatric adverse effects of interferonalpha: recognition and management. CNS Drugs 2005; 19: 105–23
6. Janssen HLA, et al. Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994; 21: 241–3
7. Renault PF, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987; 147: 1577–80
8. Adverse Drug Reactions Advisory Committee (ADRAC). Depression with interferon. Aust Adverse Drug React Bull 1999; 18: 6
9. Capuron L, Ravaud A. Prediction of the depressive effects of interferon alfa therapy by the patient’s initial affective state. N Engl J Med 1999; 340: 1370
10. Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-α. Am J Gastroenterol 1993; 88: 760–1
11. Schramm TM, et al. Sertraline treatment of interferon-alfa-induced depressive disorder. Med J Aust 2000; 173: 359–61
12. Musselman DL, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001; 344: 961–6
13. Kingsley D. Interferon-alpha induced ‘tertiary mania’. Hosp Med 1999; 60: 381–2
14. Constant A, et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry 2005; 66: 1050–7
15. Janssen HLA, et al. Seizures associated with low-dose α-interferon. Lancet 1990; 336: 1580
16. Brouwers PJ, et al. Photosensitive seizures associated with interferon alpha-2a. Ann Pharmacother 1999; 33: 113–14
17. Ameen M, Russell-Jones R. Seizures associated with interferon-
α treatment of cutaneous malignancies. Br J Dermatol 1999;
141: 386–7
18. Goeb JL, et al. Psychiatric side effects of interferon-beta in multiple sclerosis. Eur Psychiatry 2006; 21: 186–93
19. Batisse D, et al. Sustained exacerbation of cryoglobulinaemiarelated vasculitis following treatment of hepatitis C with peginterferon alfa. Eur J Gastroenterol Hepatol 2004; 16: 701–3
20. Boonyapisit K, Katirji B. Severe exacerbation of hepatitis Cassociated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review. Muscle Nerve 2002; 25: 909–13
21. Beuthien W, et al. Vasculitic complications of interferon-alpha treatment for chronic hepatitis C virus infection: case report and review of the literature. Clin Rheumatol 2005; 24: 507–15
22. Gastineau DA, et al. Severe neuropathy associated with lowdose recombinant interferon-alpha. Am J Med 1989; 87: 116
23. Briani C, et al. Peripheral neurotoxicity of pegylated interferon alpha: a prospective study in patients with HCV. Neurology 2006; 67: 781–5.

Effects on the oral mucosa.

Painful oral ulcers, necessitating withdrawal of interferon alfa therapy, have occurred in a patient treated for chronic hepatitis.1 Interferon alfa treatment has been reported to exacerbate pre-existing lichen planus associated with chronic hepatitis C.2,3 New cases of oral lichen planus have been reported in patients receiving interferon alfa treatment for malignant diseases4 and chronic hepatitis.5
1. Qaseem T, et al. A case report of painful oral ulcerations associated with the use of alpha interferon in a patient with chronic hepatitis due to non-A non-B non-C virus. Mil Med 1993; 158: 126–7
2. Areias J, et al. Lichen planus and chronic hepatitis C: exacerbation of the lichen under interferon-alpha-2a therapy. Eur J Gastroenterol Hepatol 1996; 8: 825–8
3. Nagao Y, et al. Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C. Int J Mol Med 2005; 15: 237–41
4. Kütting B, et al. Oropharyngeal lichen planus associated with interferon-
α treatment for mycosis fungoides: a rare side-effect
in the therapy of cutaneous lymphomas. Br J Dermatol 1997; 137: 836–7
5. Guijarro Guijarro B, et al. Aparición de un liquen plano erosivo durante el tratamiento con interferón alfa-2a por una hepatitis C crónica. Med Oral 2001; 6: 358–63.

Effects on the respiratory system.

Pulmonary adverse effects have occasionally been reported in association with interferon or peginterferon alfa treatment. A literature review1 found that the most commonly reported adverse effect was interstitial pneumonitis, followed by a sarcoid-like reaction with non-caseating granuloma formation. Other, less commonly reported events were asthma exacerbation, pleural effusion, bronchiolitis obliterans with organizing pneumonia, and a case of fatal acute respiratory distress-like syndrome.
1. Midturi J, et al. Spectrum of pulmonary toxicity associated with the use of interferon therapy for hepatitis C: case report and review of the literature. Clin Infect Dis 2004; 39: 1724–9.

Effects on skeletal muscle.

Myalgia is one of the ‘flu-like’ symptoms frequently associated with interferons. Rhabdomyolysis1-3 has occurred in patients being treated with interferon alfa and proved fatal when associated with multiple organ failure in a patient receiving adjuvant high-dose interferon alfa for multiple myeloma.1 Rhabdomyolysis has also been reported in a patient receiving interferon beta for the treatment of multiple sclerosis.4
1. Reinhold U, et al. Fatal rhabdomyolysis and multiple organ failure associated with adjuvant high-dose interferon alfa in malignant melanoma. Lancet 1997; 349: 540–1
2. Gabrielli M, et al. Acute reversible rhabdomyolysis during interferon alpha2b therapy for hepatitis C. Am J Gastroenterol 2003; 98: 940
3. Ozdag F, et al. Acute rhabdomyolysis during the treatment of scleromyxedema with interferon alfa. J Dermatolog Treat 2001; 12: 167–9
4. Lünemann JD, et al. Rhabdomyolysis during interferon-beta 1a treatment. J Neurol Neurosurg Psychiatry 2002; 72: 274. Correction. ibid.; 73; 354.

Effects on the skin.

Dermatological adverse effects such as dryness, erythema, rash, or urticaria, have been reported in about 5 to 12% of patients given interferon alfa; severe events occur rarely.1 Exacerbation or development of psoriasis was reported in patients given recombinant interferon alfa2-4 and peginterferon alfa.5 However, no such effect was seen in 7 patients given interferon gamma.6 Both vitiligo and psoriasis developed in a 10year-old girl with chronic hepatitis B infection given interferon alfa; the skin conditions did not improve on stopping the interferon treatment.7 A case8 of vitiligo occurring during the third month of treatment for chronic hepatitis C with peginterferon alfa and ribavirin has been reported; the condition persisted after treatment with peginterferon was completed. Exacerbation of lichen planus has also been reported9 during interferon alfa treatment (see also Effects on the Oral Mucosa, above). Cases of cutaneous sarcoidosis have been reported in patients with chronic hepatitis C being treated with interferon or pegylated interferon alfa plus ribavirin; skin lesions are usually benign and treatment with interferon alfa may sometimes be continued with resolution of the skin lesions occurring spontaneously or within a few months of completing treatment.10,11 Cutaneous vascular lesions with punctate telangiectasias were noted in 18 of 44 patients treated with interferon alfa-2a; lesions did not appear at the injection site.12 Severe necrotising cutaneous lesions were reported at injection sites in a patient given recombinant interferon beta-1b; the lesions healed when interferon alfa-n3 was substituted.13However, cutaneous necrosis has also been associated with interferon alfa14,15 and peginterferon alfa.16 Five cases17 of a self-resolving cutaneous lesion at the injection site of interferon, mimicking lupus erythematosus, have been reported; 3 of them involved interferon alfa therapy for malignant melanoma and the other 2 patients were being given interferon beta for multiple sclerosis. Fatal paraneoplastic pemphigus developed in a patient given interferon alfa-2a.18 Hyperpigmentation of the skin and tongue has been described19 in 2 dark-skinned patients during treatment with interferon alfa and ribavirin.
1. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Safety 1994; 10: 115–50
2. Quesada JR, Gutterman JU. Psoriasis and alpha-interferon. Lancet 1986; i: 1466–8
3. Funk J, et al. Psoriasis induced by interferon-α. Br J Dermatol 1991; 125: 463–5
4. Taylor C, et al. Extensive psoriasis induced by interferon alfa treatment for chronic hepatitis C. Postgrad Med J 2000; 76: 365–6
5. Ketikoglou I, et al. Extensive psoriasis induced by pegylated interferon alpha-2b treatment for chronic hepatitis B. Eur J Dermatol 2005; 15: 107–9
6. Schulze H-J, Mahrle G. Gamma interferon and psoriasis. Lancet 1986; ii: 926–7
7. Seçkin D, et al. Concomitant vitiligo and psoriasis in a patient treated with interferon alfa-2a for chronic hepatitis B infection. Pediatr Dermatol 2004; 21: 577–9
8. Tomasiewicz K, et al. Vitiligo associated with pegylated interferon and ribavirin treatment of patients with chronic hepatitis C: a case report. Adv Therapy 2006; 23: 139–42
9. Protzer U, et al. Exacerbation of lichen planus during interferon alfa-2a therapy for chronic active hepatitis C. Gastroenterology 1993; 104: 903–5
10. Eberlein-König B, et al. Cutaneous sarcoid foreign body granulomas developing in sites of previous skin injury after systemic interferon-alpha treatment for chronic hepatitis C. Br J Dermatol 1999; 140: 370–2
11. Hurst EA, Mauro T. Sarcoidosis associated with pegylated interferon alfa and ribavirin treatment for chronic hepatitis C: a case report and review of the literature. Arch Dermatol 2005; 141: 865–8
12. Dreno B, et al. Alpha-interferon therapy and cutaneous vascular lesions. Ann Intern Med 1989; 111: 95–6
13. Sheremata WA, et al. Severe necrotizing cutaneous lesions complicating treatment with interferon beta-1b. N Engl J Med 1995; 332: 1584
14. Shinohara K. More on interferon-induced cutaneous necrosis. N Engl J Med 1995; 333: 1222
15. Sasseville D, et al. Interferon-induced cutaneous necrosis. J Cutan Med Surg 1999; 3: 320–3
16. Bessis D, et al. Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient. Eur J Dermatol 2002; 12: 99–102
17. Arrue I, et al. Lupus-like reaction to interferon at the injection site: report of five cases. J Cutan Pathol 2007; 34 (suppl 1): 18–21
18. Kirsner RS, et al. Treatment with alpha interferon associated with the development of paraneoplastic pemphigus. Br J Dermatol 1995; 132: 474–8
19. Willems M, et al. Hyperpigmentation during interferon-alpha therapy for chronic hepatitis C virus infection. Br J Dermatol 2003; 149: 390–4.

Shock.

Fatal non-cardiogenic shock occurred after the third dose of interferon alfa-2b in a patient with malignant melanoma.1There were similarities to a fatal reaction reported in another patient with malignant melanoma (see under Effects on Skeletal Muscle, above).
1. Carson JJ, et al. Fatality and interferon α for malignant melanoma. Lancet 1998; 352: 1443–4.

💊 Precautions

Interferons should be used with caution or avoided altogether in patients with depression or psychiatric disorders, epilepsy or other CNS diseases, severe renal or hepatic impairment, chronic hepatitis with advanced, decompensated hepatic disease or cirrhosis of the liver, auto-immune hepatitis, cardiac disorders, myelosuppression, poorly controlled thyroid dysfunction, pulmonary disease, diabetes mellitus, auto-immune diseases, coagulation disorders, or a history of these conditions. All patients receiving interferons should be closely monitored for any signs or symptoms of psychiatric disorders; if psychiatric symptoms continue or worsen, or suicidal ideation is identified, then interferon therapy should be stopped. Interferon treatment is not advised for patients whose hypoglycaemia, hyperglycaemia and/or diabetes mellitus is not effectively controlled; patients who develop these conditions during treatment and cannot be controlled with medication should stop interferon treatment. Standard blood and biochemical laboratory tests (including thyroid function) should be done before starting treatment with interferon and then periodically during therapy. Interferon should be used with caution in patients also receiving other potentially myelosuppressive agents. Assessment of cardiac function is advised before treatment is started in patients with pre-existing cardiac abnormalities and if there is any deterioration of cardiovascular status interferon should be suspended or stopped. Hepatic and renal function should be monitored during treatment with interferons. Interferon treatment should be stopped in patients who develop evidence of liver decompensation during treatment. Treatment should also be stopped in those patients who despite the dose of interferon being reduced still have progressive and clinically significant increases in serum-alanine aminotransferase. Patients receiving interferons who have visual disturbances should undergo eye examination. A baseline ocular examination is recommended before treatment, and periodic eye examinations should be performed throughout treatment in patients predisposed to retinopathy, such as those with diabetes mellitus or hypertension; treatment should be stopped in patients who develop new or worsening ophthalmologic disorders. Patients with psoriasis or sarcoidosis have been reported to experience exacerbations during interferon alfa therapy. Patients should receive adequate fluids to maintain hydration during treatment with interferon alfa since hypotension related to fluid depletion has been seen in some patients. Interferons may affect the ability to drive or operate machinery. Antibodies may develop to exogenous interferon that reduce its activity.

Asthma.

For a report of severe exacerbation of asthma in patients receiving interferon alfa, see Effects on the Respiratory System, above.

Breast feeding.

The American Academy of Pediatrics1 states that there have been no reports of any clinical effect on the infant associated with the use of interferon alfa by breast-feeding mothers, and that therefore it may be considered to be usually compatible with breast feeding. It has been suggested that interferons are too large in molecular weight to transfer into breast milk in clinically relevant amounts.2
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 12/06/08
2. Kumar AR, et al. Transfer of interferon alfa into human breast milk. J Hum Lact 2000; 16: 226–8.

Psychiatric disorders.

For comment on the risk of mood disorders in patients with a history of such disorders, see Effects on the Nervous System and Mental State, above.

💊 Interactions

Interactions involving interferons have not been fully evaluated, but it is known that they can inhibit hepatic oxidative metabolism via cytochrome P450 enzymes; the clinical relevance of this interaction is unclear and thus caution should be exercised during use with drugs metabolised in this way. Studies with peginterferon alfa showed increased activity of the cytochrome P450 isoenzymes CYP2C8/9 and CYP2D6; caution is advised when giving peginterferon alfa with drugs that are metabolised by these isoenzymes, such as warfarin, phenytoin, and flecainide. Interferon and peginterferon alfa have been shown to inhibit the metabolism of theophylline which is metabolised via the cytochrome P450 isoenzyme CYP1A2. Drugs likely to exacerbate the haematological effects of interferons, such as ribavirin and zidovudine, should also be used with caution. Interferons may also increase the neurotoxic and cardiotoxic effects of other drugs.

ACE inhibitors.

For a report of possible synergistic haematological toxicity in patients receiving interferon alfa and ACE inhibitors.

Anticoagulants.

For reference to potentiation of acenocoumarol or warfarin necessitating dosage reduction in patients also receiving interferon alfa.

Antineoplastics.

For reduction in the area under the plasma concentration-time curve for melphalan in patients receiving interferon alfa.

Antivirals.

For a report of synergistic bone-marrow toxicity with interferon alfa and zidovudine.

Paracetamol.

Three patients had increases in liver enzyme values when given paracetamol 1 g two or three times daily on the same three days each week as interferon alfa; vinblastine was also given every third week.1 Paracetamol has also been found to enhance the antiviral effect of interferon alfa in healthy subjects.2
1. Kellokumpu-Lehtinen P, et al. Hepatotoxicity of paracetamol in combination with interferon and vinblastine. Lancet 1989; i: 1143
2. Hendrix CW, et al. Modulation of α-interferon’s antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteers. Antiviral Res 1995; 28: 121–31.

Thalidomide.

For reports of toxicity associated with interferons and thalidomide.

Theophylline.

For reference to reduced clearance of theophylline in patients receiving interferon alfa.

💊 Antiviral Action

Interferons are naturally occurring proteins produced by eukaryotic cells in response to viral infection and other biological inducers that confer protection on uninfected cells of the same species. They are cytokines that affect many cell functions and have, in addition to their antiviral activity, antiproliferative and immunoregulatory properties. Three major classes have been identified: alfa, beta and gamma. Interferon alfa and beta are classified as Type I interferons and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinct biological activities; interferon gamma in particular is a potent macrophagestimulating factor. Interferons exert their biological effect by binding to specific receptors on the surface of human cells. After binding, a cascade of intracellular events, including the induction of certain enzymes, occurs. This process is thought to be responsible for the various cellular responses to interferon, including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Pegylated interferons have similar, but possibly slightly weaker, actions to the native forms. Studies have shown interferons to have benefit in infections with hepatitis B virus, hepatitis C virus, herpes simplex viruses, varicella-zoster virus, CMV, rhinoviruses, and papillomaviruses.

💊 Pharmacokinetics

Interferons are not absorbed from the gastrointestinal tract. More than 80% of a subcutaneous or intramuscular dose of interferon alfa is absorbed. After intramuscular injection, interferon alfa produced by recombinant techniques and that from cultured leucocytes produce similar plasma concentrations although there is a large interindividual variation. Plasma concentrations are dose-related; and peak concentrations are usually reached within 4 to 8 hours returning to baseline by 16 to 24 hours. After intravenous doses, serum interferon levels decline at a slightly faster rate than after subcutaneous or intramuscular use and are undetectable 4 hours after infusion. After systemic use low levels of interferon are detected in respiratory secretions, CSF, eye, and brain. The elimination half-life of interferon alfa is about 2 to 7 hours after subcutaneous or intramuscular injections and 2 hours after intravenous infusion. Interferon alfa undergoes renal catabolism and negligible amounts of interferons are excreted in the urine; biliary excretion and liver metabolism are minor pathways of elimination. The attachment of interferon to large inert macrogol (polyethylene glycol; PEG) molecules, termed pegylation, substantially reduces the rate of absorption and excretion of interferon and increases the plasma concentration. After a subcutaneous dose of peginterferon alfa-2b the maximum serum concentration is attained in about 15 to 44 hours and high concentrations are sustained for 48 to 72 hours; the mean elimination halflife is approximately 40 hours. The maximum serum concentration of peginterferon alfa-2a is attained about 72 to 96 hours after subcutaneous dosing and the mean terminal half-life is approximately 160 hours. The absolute bioavailability of peginterferon alfa-2a is 84% and is similar to that of unmodified interferon alfa-2a.
1. Zeuzem S, et al. Pharmacokinetics of peginterferons. Semin Liver Dis 2003; 23 (suppl 1): 23–8
2. Pedder SC. Pegylation of interferon alfa: structural and pharmacokinetic properties. Semin Liver Dis 2003; 23 (suppl 1): 19–22
3. Caliceti P. Pharmacokinetics of pegylated interferons: what is misleading? Dig Liver Dis 2004; 36 (suppl 3): S334–9.

💊 Uses and Administration

The interferons are cytokines that have a range of activities. In addition to their action against viruses they are active against malignant neoplasms and have an immunomodulating effect. Several alfa interferons are available: interferon alfa-2a (rbe), interferon alfa-2b (rbe), alfa-n3 (bls), alfacon-1 (rbe), and the pegylated interferons peginterferon alfa-2a (rbe) and peginterferon alfa-2b (rbe). Alfa interferons are used in chronic hepatitis B (alfa-2a and its pegylated form and alfa-2b) and chronic hepatitis C (alfa-2a and its pegylated form, alfa-2b and its pegylated form, and alfacon-1); in several malignant neoplasms including AIDS-related Kaposi’s sarcoma (alfa-2a and alfa-2b), hairy-cell leukaemia (alfa-2a and alfa-2b), chronic myeloid leukaemia (alfa-2a and alfa-2b), follicular lymphoma (alfa-2a and alfa-2b), cutaneous T-cell lymphoma (alfa-2a), carcinoid tumours (alfa-2b), melanoma (alfa-2a and alfa-2b), multiple myeloma (alfa-2b), and renal cell carcinoma (alfa-2a); and in condylomata acuminata (alfa-2b and alfa-n3). ADMINISTRATION AND DOSAGE. Dosage regimens for alfa interferons are as follows:
Chronic active hepatitis B. Interferon alfa-2a is given in a dose of 2.5 to 5 million units/m 2 three times weekly by subcutaneous injection for 4 to 6 months. Peginterferon alfa-2a is given in a dose of 180 micrograms once weekly subcutaneously for 48 weeks. Interferon alfa-2b is given in a dose of 5 to 10 million units three times weekly for 4 to 6 months, or 5 million units daily for 16 weeks, by subcutaneous or intramuscular injection.
Chronic hepatitis C. Interferon alfa-2a is given in a dose of 3 to 4.5 million units three times weekly by subcutaneous injection for 6 months when it is used with ribavirin. In patients unable to tolerate ribavirin, interferon alfa-2a monotherapy is given either in an initial dose of 3 to 6 million units three times weekly for 6 months followed by 3 million units three times weekly for an additional 6 months, or in a dose of 3 million units three times weekly for 12 months, by subcutaneous injection. Peginterferon alfa-2a is given in a dose of 180 micrograms once weekly subcutaneously, with ribavirin or as monotherapy, for 24 to 48 weeks (depending on genotype). Interferon alfa-2b is given in a dose of 3 million units three times weekly for 6 to 12 months (depending on genotype) with ribavirin or, when given as monotherapy, for 6 to 18 months, or for up to 24 months (depending on genotype), by subcutaneous or intramuscular injection. Peginterferon alfa-2b is given subcutaneously in a dose of 1.5 micrograms/kg once weekly for 24 to 48 weeks with ribavirin, or in a dose of 0.5 or 1 microgram/kg once weekly for 24 to 48 weeks when given as monotherapy. Interferon alfacon-1 is given in a dose of 9 micrograms three times weekly by subcutaneous injection for 24 weeks followed by 15 micrograms three times weekly for up to 48 weeks if necessary.
AIDS-related

Kaposi’s sarcoma.

Interferon alfa-2a is usually given in an escalating dose of 3 million units daily for 3 days, 9 million units daily for 3 days, 18 million units daily for 3 days, and 36 million units daily, if tolerated, on days 10 to 84, by subcutaneous injection; thereafter the maximum tolerated dose (up to 36 million units) may be given three times weekly. Interferon alfa-2b is given in a dose of 30 million units/m 2 three times weekly, by subcutaneous or intramuscular injection.
Hairy-cell leukaemia. Interferon alfa-2a is given in an initial subcutaneous dose of 3 million units daily for 16 to 24 weeks, then the same dose three times weekly, by subcutaneous injection. Treatment has continued for up to 24 months. Interferon alfa-2b is given in a dose of 2 million units/m 2 three times weekly by subcutaneous or intramuscular injection for up to 6 months or more.
Chronic myeloid leukaemia. Interferon alfa-2a is given by subcutaneous injection in an escalating dose of 3 million units daily for 3 days, 6 million units daily for 3 days, and 9 million units daily thereafter. Patients showing a response after 12 weeks should continue treatment until a complete haematological response is achieved or for a maximum of 18 months; those who achieve a complete haematological response should continue on 9 million units daily (or a minimum of 9 million units three times weekly) in order to achieve a cytogenetic response. Interferon alfa-2b is given in a dose of 4 to 5 million units/m 2 daily by subcutaneous injection, continuing at the maximum tolerated dose to maintain remission (usually 4 to 5 million units/m 2 daily). Published November 29, 2018.