Interferon dosage

Haug E, Bell H. Thyroid dysfunction during treatment of chronic hepatitis C with interferon alpha no association with either interferon dosage or efficacy of therapy. J Intern Med 2002 251(5) 400-6. 

The type and incidence of adverse effects associated with unmodified interferon and pegylated interferon are comparable. Approximately 10% to 30% of patients receiving interferon and/or ribavirin require a dosage reduction or treatment discontinuation to minimize side effects. Patients should be screened for uncommon adverse effects and laboratory abnormalities prior to starting interferon and ribavirin because treatment may exacerbate or worsen some medical conditions. 

About 10% to 25% of patients treated with interferon and ribavirin require dosage reductions when hemoglobin levels decrease or they develop intolerable symptoms such as shortness of breath or severe fatigue. If warranted, erythropoietin may be used as adjunctive therapy for ribavirin-induced hemolytic anemia.45... 

PEGylated interferons Covalent attachment of PEG increases interferon half-life from 3 h to some 24 h, thereby generating a product whose dosage schedule requires once-weekly as opposed to daily administration 8... 

IFN-x is currently generating considerable clinical interest. It induces effects similar to type I interferon, but it appears to exhibit significantly lower toxicity. Thus, it may prove possible to use this interferon safely at dosage levels far greater than the maximum dosage levels applied to currently used type I interferons. This, however, can only be elucidated by future clinical trials. 

Zidovudine should be used cautiously with any other agent that causes bone marrow suppression, such as interferon-a, trimethoprim-sulfamethoxazole, dap-sone, foscarnet, flucytosine, ganciclovir, and valganci-clovir. Probenecid and interferon-p inhibit the elimination of zidovudine therefore, a dosage reduction of zidovudine is necessary when the drugs are administered concurrently. Ribavirin inhibits the phosphorylation reactions that activate zidovudine, and zidovudine similarly inhibits the activation of stavudine thus, the coadministration of zidovudine with ribavirin or stavudine is contraindicated. 

Recommended dosage and monitoring requirements The recommended dose of Roferon-A for chronic hepatitis C is 3 million international units (MIU) three times a week for 12 months. The recommended dose for CML is 9 MIU daily optimal duration of therapy has not been determined. The recommended dose for hairy cell leukemia is 3 MIU daily for 16 to 24 weeks. The recommended dose for AIDS-related Kaposi s sarcoma is 36 MIU daily for 10 to 12 weeks. There are five types of interferon alfa currently available in the United States interferon alfa-2a, peginterferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and interferon alfa n3. Doses are not consistent for these preparations. 

Dosage form Avonex is formulated as a sterile, lyophilized powder for injection after reconstitution with supplied diluent or sterile water for injection. Each 1.0ml of reconstituted Avonex contains 30 pg of interferon beta-la. 

Dosage form Betaseron is available as a sterile, lyophihzed powder for injection. After reconstitution with accompanying diluent, Betaseron vials contain 0.25 mg interferon beta-lb per ml of solution. 

Dosage form Actimmune is a sterile solution filled in single-dose vials. Each 0.5 ml of Actimmune contains interferon gamma-lb 100 pg. 

Dosage form Rebif is formulated as a sterile solution in a graduated prelilled syringe. Each 0.5 ml of Rebif contains interferon beta-la, either 44pg or 22pg, and excipients. 

The use of pegylated interferon alfa-2a and pegylated interferon alfa-2b, as a result of slower clearance resulting in substantially longer terminal half-lives and steadier drug concentrations, allows for less frequent dosing in patients with chronic HCV infection. Renal elimination accounts for about 30% of clearance, and clearance is approximately halved in subjects with impaired renal function dosage must therefore be adjusted. 

Imatinib is administered orally and is well absorbed it is highly protein-bound in plasma. The drug is metabolized in the liver, and elimination of metabolites occurs mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior interferon- therapy. Imatinib is effective also for treatment of gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. Dosage and toxicities are listed in Table 55-6. 

Therapeutic formulations contain a recombinant form of IFN-a (either interferon alfa-2a or interferon alfa-2b). These are available as powders for reconstitution or as prefilled injection pens. The drug is administered by subcutaneous injection (or intravenous for reconstituted powder formulations) and intramuscular injection. The dosage is usually stated as units per millilitre (refer to BNF for various preparations and dosages). Powder formulations of interferon alfa-2b also contain glycine, sodium phosphate (mono- and dibasic) and human albumin prefilled pens contain sodium chloride, edetate disodium, polysorbate 80 and m-cresol as a preservative. 

The reported side-effects of interferon alfa include cardiovascular problems such as arrhythmia, tachycardia and hypotension in the absence of history of such conditions, severe myelosuppression, depression and suicidal behaviour, opthalmic disorders, anorexia and flu-like symptoms and hypersensitivity reactions. Mr JJ should be advised of these and of the actions to be taken. The patient should be informed that under no circumstances should he switch treatments as different formulations may contain different dosages. Furthermore, he should be made aware of the proper disposal of used pens/syringes and to take extra care if blood enters the dispensers, as described in the product literature. Hepatitis B support groups are available. Dietary advice may be offered as cytokine-based treatments often cause reduced appetite. 

CrCl < 50 mL/min Accumulation of PEG-interferon a-2a may occur close monitoring for adverse reactions requiring dosage reduction is recommended... 

Moderate depression Decrease dose by 50%. If condition remains stable, continue reduced dosage. If symptoms improve and are stable for > 4 weeks, continue reduced dosage regimen or return to normal dose Severe depression Discontinue PEG-interferon a-2b permanently White blood cell count neutrophil count <750/mm or platelet count <80,000/mm Decrease dose by 50%... 

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. 

In one study in 119 patients treated with interferon alfa and ribavirin for chronic hepatitis C, in whom neutropenia was not considered as a cause for exclusion or dosage modification, the neutrophil count fell by an average of 34% (31-74%) (226). During the course of treatment, 32 patients had at least one neutrophil count below 1 X 10 /1, 11 had a neutrophil count below 0.75 x 10 /1, and 2 had a neutrophil count below 0.5 x 10 /1 however, none of these patients required dosage modification because of neutropenia. None of the 22 patients who developed documented or suspected bacterial infections... 

A review of 15 other available reports of renal insufficiency and proteinuria in patients with chronic myeloid leukemia or other malignancies confirmed that the histological spectrum of renal lesions associated with interferon alfa is varied, and includes membranous glomerulonephritis, minimal change glomerulonephritis, acute interstitial nephritis, hemolytic-uremic sjmdrome, and thrombotic microangiopathy. Renal comphcations were reversible in nine patients three patients had persistent proteinuria, and four had persistent renal dysfunction, of whom three required chronic hemodialysis. Two-thirds of the patients developed renal comphcations within 1 month of treatment with interferon alfa, and one-third had received a relatively low dosage of interferon alfa (9-15 MU/week). 

Meyerson s phenomenon, multiple focal and transient eczematous eruptions around melanocjdic nevi, has been reported in a 24-year-old man when the dosage of interferon alfa for Behqet s disease was doubled (303). 

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