|September/October 1998In This IssueInfluenza
                  Vaccination:
                  1998-1999*Interferon
                  alpha-2b/Ribavirin (Rebetron®):
                  A Brief Review
                  
                  Drug
                  Information Service
                  Pharmacy Department
                  Warren G. Magnuson Clinical Center
                  National Institutes of Health
                  Bethesda, Maryland 20892-1196
                  Charles E. Daniels, Ph.D.
                  Chief, Pharmacy DepartmentEditor-in-Chief
                  Karim Anton Calis, Pharm.D., M.P.H.
                  Coordinator, Drug Information Service, and
                  Endocrinology Clinical Pharmacy Specialist[email protected]Associate
                  EditorMaryam R.
                  Mohassel, Pharm.D.
                  Specialized Resident in Drug Information Practice
                  and Pharmacotherapy[email protected]
                  
                  Archives
               Influenza Vaccination:
                  1998-1999
                  
                  Each year, infections due
                  to the influenza virus result in substantial
                  morbidity and mortality worldwide. Vaccination
                  offers appreciable protection against the influenza
                  virus for individuals and contributes to improved
                  overall public health.
                  
                  A new trivalent vaccine is
                  now available for the 1998-1999 influenza season.
                  The vaccine is recommended for patients with
                  chronic medical disorders, children with asthma,
                  residents of long-term care facilities, and the
                  elderly. Health-care workers and household contacts
                  of elderly and high-risk patients are also strongly
                  encouraged to receive the vaccine.
                  
                  Protection conferred by
                  the influenza vaccine typically begins two weeks
                  after vaccination and may last for six months or
                  longer. Serum antibodies in some elderly patients
                  can diminish more rapidly to non-protective levels.
                  Because large outbreaks in the United States
                  usually occur between December and early March, the
                  optimal time to receive the vaccination is between
                  October and November. However, administration of
                  the vaccine is appropriate anytime from September
                  to the end of the influenza season.
                  
                  The vaccine formulation is
                  changed annually because of the antigenic
                  variability of the influenza virus. Antigens in the
                  current vaccine are derived from
                  A/Sydney/05/97-like (H3N2), A/Beijing/262/95-like
                  (H1N1), and B/Beijing/184/93-like
                  viruses.
                  
                  Influenza vaccine is
                  produced from inactivated virus grown in chicken
                  eggs. Individuals who have experienced severe
                  hypersensitivity reactions to eggs or egg products
                  should not receive the vaccine. An intramuscular
                  dose of 0.5 mL of the split-virus formulation can
                  be administered (in the deltoid) to adults and
                  children at least three years of age. Recipients of
                  the vaccine may experience soreness at the site of
                  injection, fever, and malaise that may persist for
                  one or two days.
                  
                  Questions about influenza
                  or the vaccine should be directed to the Hospital
                  Epidemiology Service at 6-2209 or the NIH Drug
                  Information Service at 6-2407. For questions about
                  the vaccination schedule, contact the Occupational
                  Medical Service at 6-4411.
                  
                  Interferon
                  alpha-2b/Ribavirin (Rebetron®):
                  A Brief Review
                  
                  Chronic hepatitis C
                  infection is considered the single most common
                  cause of cirrhosis, hepatic carcinoma, and chronic
                  liver disease.Patients with this infection
                  typically present with elevations in serum
                  aminotransferase concentrations (specifically
                  alanine amino-transferase) and positive serum
                  HCV-RNA. Interferon alpha is the principal
                  treatment available to patients with chronic
                  hepatitis C. Interferon alpha-2b, given
                  subqutaneously (SQ) three times a week (TIW) for 12
                  months, can decrease serum aminotransferase
                  concentrations and render serum HCV-RNA
                  undetectable. Once treatment is discontinued,
                  however, the majority of patients relapse, and only
                  20% maintain a sustained response. Ribavirin, a
                  nucleoside analog administered orally, has been
                  used in combination with interferon alpha-2b to
                  improve the overall response rate. Previously,
                  ribavirin was available in the United States only
                  in an aerosol form for the treatment of respiratory
                  syncytial virus infections in infants and young
                  children.1Up to Top
               Description:Intron-A®
                  is Schering Corporation's brand name for interferon
                  alpha-2b, a purified sterile recombinant interferon
                  product. Intron-A® injection is a clear,
                  colorless solution which is available as a 3-MU
                  single-dose vial (3 MU/0.5 ML), an 18-MU multi-dose
                  vial (3 MU/0.5 ML), and an 18-MU multi-dose pen (3
                  MU/0.2 ML). Rebetol® is Schering Corporation's
                  brand name for ribavirin, a nucleoside analog with
                  antiviral activity. Rebetol® capsules consist
                  of a white powder in a white-opaque gelatin
                  capsule. Each capsule contains 200 mg of ribavirin.
                  The combination of interferon and ribavirin is
                  marketed as a package containing a two-week supply
                  of both medications.2
                  
                  Indication:The
                  combination therapy of oral ribavirin and
                  recombinant interferon alpha-2b injection is
                  indicated for the treatment of chronic hepatitis C
                  in patients with compensated liver disease who have
                  relapsed following alpha interferon therapy
                  alone.2
                  
                  
                  
                  Pharmacology:Ribavirin is a
                  nucleoside analog that inhibits the repli-cation of
                  many different RNA and DNA viruses, including some
                  related to HCV. 1, 2 Interferon alpha-2b
                  is a recombinant alpha interferon with both
                  antiviral and immuno-modulatory effects. It blocks
                  viral replication and inhibits viral activity by
                  reducing entry of viruses into cells, impairing
                  viral uncoating, and inhibiting viral mRNA and
                  protein synthesis.3 Approximately 60% of
                  patients with chronic hepatitis C have
                  normalization of serum aminotransferase
                  concentrations during treatment with interferon.
                  Nearly 40% of these patients show undetectable
                  serum HCV-RNA levels. However, the majority of
                  these patients relapse once interferon treatment is
                  discontinued.4
                  
                  Pharmacokinetics:Single- and
                  multiple-dose pharmacokinetic properties of
                  interferon alpha-2b and ribavirin are summarized in
                  Table 1.2
                  
                  Ribavirin is rapidly and
                  extensively absorbed following oral administration.
                  However, the absolute bioavailability is decreased
                  due to first pass metabolism. Both AUC and
                  Cmaxare increased by 70% when ribavirin
                  is administered with high-fat meals. Ribavirin is
                  metabolized via two pathways: a reversible
                  phosphorylation pathway in nucleated cells and a
                  degradative pathway involving deribosylation and
                  amide hydrolysis, yielding a triazole carboxylic
                  acid metabolite. Ribavirin and its triazole
                  carboxamide and triazole carbo-xylic acid
                  metabolites are excreted renally. Following oral
                  administration, approximately 61% of the ribavirin
                  dose is excreted in the urine, and 12% in the
                  feces. In vitro studies suggest little or no
                  cytochrome P-450 enzyme-mediated metabolism of
                  ribavirin. No pharmacokinetic interactions between
                  ribavirin and interferon alpha-2b have been noted.
                  2Up to Top
               Table 1. Mean
                           Pharmacokinetic Parameters for Interferon
                           alpha-2b and RibavirinParameter
                        Interferon
                           alpha-2b
                        RibavirinSingle
                           Dose
                        Multiple
                           Dose
                        Single
                           Dose
                        Multiple
                           Dose3
                           MU
                        3 MU
                           TIW
                        600
                           mg
                        600 mg
                           BIDTmax(h)
                        7
                        5
                        1.7
                        3Cmax*
                        13.9
                        29.7
                        782
                        3680AUC**
                        142
                        333
                        13400
                        228000T1/2(h)
                        6.8
                        6.5
                        43.6
                        298* U/mL for
                           interferon alpha-2b and ng/mL for
                           ribavirin** U.h/mL for
                           interferon alpha-2b and ng.h/mL for
                           ribavirin
                  
                  Selected Clinical
                  Trials:Several
                  clinical trials have investigated the efficacy of
                  interferon/ribavirin combination therapy in the
                  management of chronic hepatitis C. Most of these
                  studies involved patients who have failed to
                  respond or maintain a sustained response to
                  interferon monotherapy. The efficacy of interferon
                  combination therapy has also been compared to that
                  of interferon therapy alone in a number of
                  randomized, double-blind, placebo-controlled
                  clinical trials which included interferon-naive
                  patients.
                  
                  In a Swedish clinical
                  trial, twenty patients with chronic hepatitis C (10
                  with a history of non-sustained response to
                  interferon, and 10 with no response at all) were
                  started on the interferon alpha-2b (3 MU SQ TIW)
                  and ribavirin (1000-1200 mg/day PO)
                  combination.5 All patients had positive
                  HCV-RNA tests and elevated aminotransferase levels
                  for at least six months prior to enrollment.The duration of treatment was 24 weeks, and
                  all patients were monitored for an additional 24
                  weeks after discontinuation of therapy. All 10
                  patients who had previously experienced a
                  non-sustained response with interferon, experienced
                  a sustained response with the combination. These
                  patients developed negative HCV-RNA tests and
                  normal aminotransferase levels upon completion of
                  treatment, with nine maintaining a negative HCV-RNA
                  test at the 24-week follow-up. Of the 10 patients
                  who had experienced no response with interferon,
                  five developed normal aminotransferase levels by
                  the end of therapy, and four had a negative HCV-RNA
                  test. At follow-up, three of these 10 patients
                  continued to have negative HCV-RNA tests and normal
                  aminotransferase levels. Reductions in leukocyte
                  counts and hemoglobin concentrations were the most
                  common adverse effects reported. However, none of
                  the patients discontinued therapy due to adverse
                  reactions. This study was limited by a small sample
                  size (n=20) and the lack of clear
                  inclusion/exclusion criteria. Additionally,
                  patients enrolled in this study had varying degrees
                  of disease severity, including a few with severe
                  liver cirrhosis.
                  
                  Combination therapy with
                  interferon and ribavirin was also evaluated in a
                  clinical trial enrolling 10 patients with chronic
                  hepatitis C (six with a non-sustained response to
                  previous interferon therapy and four with no
                  response).6 Patients were given
                  interferon alpha-2b (3 MU SQ TIW) and ribavirin
                  (1000-1200 mg/day PO) for 24 weeks and were
                  monitored for 24 weeks after discontinuation of
                  therapy. All four non-sustained responders had
                  normal aminotransferase levels at the end of
                  therapy and at follow-up. Among the non-responders,
                  three out of six had normal aminotransferase levels
                  at the end of therapy, but only one at follow-up.
                  All four non-sustained responders developed
                  negative HCV-RNA tests, with three remaining
                  negative at follow-up. In the non-responder group,
                  two patients became HCV-RNA negative and remained
                  negative at follow-up. All patients completed the
                  study. Common adverse drug reactions included mild
                  reductions in hemoglobin, and decreased white blood
                  cell and platelet counts. This study was limited by
                  a small sample size and the lack of clear exclusion
                  criteria. Additionally, it was unclear if all
                  patients enrolled in this study had the same degree
                  of disease severity.
                  
                  The use of
                  interferon/ribavirin combination therapy in
                  interferon-naive patients has also been evaluated.
                  One study compared the efficacy of interferon
                  alpha-2b/ribavirin combination therapy to that of
                  interferon with a placebo capsule. 7
                  This was a randomized, double-blind,
                  placebo-controlled study enrolling 100 patients
                  with chronic hepatitis C. Patients were randomly
                  assigned to treatment with interferon alpha-2b (3
                  MU SQ TIW) and ribavirin (1000-1200 mg/day PO) or
                  interferon (3 MU SQ TIW) and placebo. The duration
                  of treatment was 24 weeks, with an additional
                  24-week follow-up period. An additional follow-up
                  was performed one year after discontinuation of
                  therapy. Thirty-six percent (18/50) in the
                  interferon/ribavirin group had a sustained response
                  vs. 18% (9/50) in the interferon/placebo group. At
                  one-year follow up, 42% of the patients in the
                  interferon/ribavirin group maintained a sustained
                  response vs. 20% of those in the interferon/placebo
                  arm (p=0.03). Common adverse reactions experienced
                  included fatigue, nausea, headache, alopecia, and
                  anemia. A total of seven patients discontinued
                  treatment due to adverse drug effects. This study
                  included a relatively large sample size, and the
                  inclusion/exclusion criteria were clear. In
                  addition, complete patient demographics, including
                  the degree of disease severity, were
                  provided.
                  
                  The use of
                  ribavirin/interferon combination therapy has also
                  been studied in liver transplant recipients with
                  hepatitis C infection. 8 Mazzaferro et
                  al. studied the effects of interferon/ribavirin
                  combination therapy in 21 patients following liver
                  transplant. Combination interferon alpha-2b (3 MU
                  SQ TIW) and ribavirin (10 mg/kg/d PO) therapy was
                  started three weeks after liver transplant in all
                  HCV-RNA positive patients discharged from the ICU
                  on an oral diet. These patients continued on the
                  combination therapy for one year and were followed
                  every two weeks. After the first month and a half
                  of therapy, all patients had normal alanine
                  aminotran-sase serum concentrations. At the
                  one-year follow-up, 20 of the 21 patients were
                  alive, and 8 of these 20 were HCV-RNA negative.
                  Common adverse reactions reported were anemia and
                  asthenia, but none of the patients discontinued
                  treatment because of adverse affects. However, 43%
                  experienced adverse drug reactions (primarily
                  anemia) and required dosage reduction. This study
                  was poorly reported, and limited patient
                  demographics and baseline data were
                  presented.
                  
                  Adverse Effects:The most
                  common adverse effects seen during combi-nation
                  therapy with interferon alpha-2b and ribavirin
                  included flu-like symptoms, headache, fatigue,
                  fever, and myalgia. Other commonly reported side
                  effects were nausea, anorexia, insomnia, alopecia,
                  and irritability. Neutropenia, elevated uric acid
                  levels, and thyroid abnormalities were also
                  reported.2 Ribavirin induces a
                  dose-related hemolysis, and most patients
                  experience a decrease in hemoglobin levels of 1-2
                  g/dL.
                  
                  Drug
                  Interaction:Co-administration of
                  ribavirin with an antacid preparation containing
                  magnesium, aluminum, and simethicone resulted in a
                  14% decrease in mean ribavirin area under the
                  time-concentration curve. The clinical relevance of
                  this interaction is unknown.2
                  
                  Precautions and
                  Contraindications:Combination
                  interferon/ribavirin therapy is categor-ized by the
                  FDA as pregnancy category X. This combination must
                  be avoided in women who are or may become pregnant.
                  Therapy should not be started until pregnancy is
                  ruled out. Interferon/ribavirin combination therapy
                  is contraindicated in patients with autoimmune
                  hepatitis or those with a history of
                  hypersensitivity to interferon or ribavirin. In
                  addition, patients with a history of unstable
                  cardiac disease should not be started on this
                  combination therapy, since anemia associated with
                  this treatment can result in further deterioration
                  of cardiac function. Interferon/ribavirin therapy
                  must also be used with extreme caution in patients
                  with a history of preexisting psychiatric
                  disorders. Severe psychiatric adverse effects
                  including depression and suicidal behavior have
                  been reported with the use of this combination.
                  Because patients have complained of loss of visual
                  acuity while on this therapy, a visual exam is
                  recommended prior to initiation. Combination
                  interferon/ribavirin therapy should be used with
                  caution in patients with creatinine clearance
                  measurements less than 50
                  mL/min.2
                  
                  Dosage and
                  Administration:The recommended dosing
                  guidelines for ribavirin and interferon alpha-2b
                  are provided in Table 2. Since the long-term safety
                  and efficacy of this combination therapy has not
                  been evaluated, treatment should be limited to a
                  period of six months.
                  
                  Table 2.
                           Recommended Dosage
                           GuidelinesBody
                           Weight
                        Interferon
                           alpha-2b
                        Ribavirin< 75
                           Kg
                        3 MU SQ
                           TIW
                        2x200 mg caps AM
                           (PO)3x200 mg caps PM
                           (PO)> 75
                           Kg
                        3 MU SQ
                           TIW
                        3x200 mg caps AM
                           (PO)3x200 mg caps PM
                           (PO)For patients with a
                  history of stable cardiovascular disease, a
                  permanent dose reduction is required if hemoglobin
                  levels decrease by more that 2 g/dL during any
                  four-week period. The dose of ribavirin must be
                  decreased to 600 mg/day in patients with hemoglobin
                  levels less than 10 g/dL. If hemoglobin falls below
                  8.5 g/dL, therapy must be
                  discontinued.2
                  
                  
                  
                  Cost:
                  
                  Table 3. Cost
                           of Rebetron®Patient's
                           Weight
                        Monthly Cost
                           of Therapy> 75
                           Kg
                        $ 910*< 75
                           Kg
                        $ 815**Federal
                           Supply ScheduleUp to Top
               Conclusion:
                  
                  The combination of
                  interferon alpha-2b and ribavirin appears to be
                  effective in patients who have failed to respond or
                  maintain a sustained response to interferon
                  monotherapy.
                  
                  Additional long-term
                  studies and studies in interferon-naive patients
                  are warranted.
                  
                  
                  
                  References:
                  
                  1.Dana F, Becherer
                  PR, Bacon BR. Hepatitis C virus. Postgrad
                  Med 1994; 95 (6):121-130.
                  
                  2.Schering-Plough
                  Corporation. Rebetron® Package Insert,
                  1998.
                  
                  3.Najm W. Viral
                  hepatitis: how to manage type C and D infections.
                  Geriatrics1997; 52 (5): 28-37.
                  
                  4.Wright TL.
                  Chronic hepatitis B and C. Postgrad Med
                  1992; 92 (4): 75-8
                  
                  5.Schvarcz R, Ando
                  Y, Sonnerborg A, Weiland O. Combination treatment
                  with interferon alpha-2b and ribavirin for chronic
                  hepatitis C in patients who have failed to achieve
                  sustained response to interferon alone: Swedish
                  experience. J Hepatol 1995; 23 (Suppl. 2):
                  17-21.
                  
                  6.Schvarez R, Yun
                  ZB, Sonnerborg A, Weiland O. Combined treatment
                  with interferon alpha-2b and ribavirin for chronic
                  hepatitis C in patients with a previous
                  non-response or non-sustained response to
                  interferon alone. J Med Virol 1995; 46:
                  43-47.
                  
                  7.Reichard O,
                  Norkrans G, Fryden A, Braconier J, Sonnerborg A,
                  Weiland O. Randomized, double-blind,
                  placebo-controlled trial of interferon alpha-2b
                  with and without ribavirin for chronic hepatitis C.
                  Lancet 1998; 351: 83-87.
                  
                  8.Mazzaferro V,
                  Regalia E, Pulvirenti A, Tagger A, Andreola S,
                  Pasquali M, et al. Prophylaxis against HCV
                  recurrence after liver transplantation: effects of
                  interferon and ribavirin combination.
                  Transplantation 1997; 29:
                  519-521.
                  
                  9.Bizollon T,
                  Ducerf C, Trepo C. New approaches to the treat-ment
                  of hepatitis C virus infection after liver
                  transplantation using ribavirin. J Hepatol
                  1995; 23 (Suppl. 2): 22-25.
                  
                  
                  
                  Editors'
                  Note
                  
                  We wish to thank
                     Drs. Daryl Lau and Jay Hoofnagle
                     for their comments and helpful suggestions
                     regarding the Rebetron® article.Drug
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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                      | September/October 1998                 | In This IssueInfluenza
                  Vaccination:
                  1998-1999*Interferon
                  alpha-2b/Ribavirin (Rebetron®):
                  A Brief Review
                  
                  Drug
                  Information Service
                  Pharmacy Department
                  Warren G. Magnuson Clinical Center
                  National Institutes of Health
                  Bethesda, Maryland 20892-1196
                  Charles E. Daniels, Ph.D.
                  Chief, Pharmacy DepartmentEditor-in-Chief
                  Karim Anton Calis, Pharm.D., M.P.H.
                  Coordinator, Drug Information Service, and
                  Endocrinology Clinical Pharmacy Specialist[email protected]Associate
                  EditorMaryam R.
                  Mohassel, Pharm.D.
                  Specialized Resident in Drug Information Practice
                  and Pharmacotherapy[email protected]
                  
                  Archives | Influenza Vaccination:
                  1998-1999
                  
                  Each year, infections due
                  to the influenza virus result in substantial
                  morbidity and mortality worldwide. Vaccination
                  offers appreciable protection against the influenza
                  virus for individuals and contributes to improved
                  overall public health.
                  
                  A new trivalent vaccine is
                  now available for the 1998-1999 influenza season.
                  The vaccine is recommended for patients with
                  chronic medical disorders, children with asthma,
                  residents of long-term care facilities, and the
                  elderly. Health-care workers and household contacts
                  of elderly and high-risk patients are also strongly
                  encouraged to receive the vaccine.
                  
                  Protection conferred by
                  the influenza vaccine typically begins two weeks
                  after vaccination and may last for six months or
                  longer. Serum antibodies in some elderly patients
                  can diminish more rapidly to non-protective levels.
                  Because large outbreaks in the United States
                  usually occur between December and early March, the
                  optimal time to receive the vaccination is between
                  October and November. However, administration of
                  the vaccine is appropriate anytime from September
                  to the end of the influenza season.
                  
                  The vaccine formulation is
                  changed annually because of the antigenic
                  variability of the influenza virus. Antigens in the
                  current vaccine are derived from
                  A/Sydney/05/97-like (H3N2), A/Beijing/262/95-like
                  (H1N1), and B/Beijing/184/93-like
                  viruses.
                  
                  Influenza vaccine is
                  produced from inactivated virus grown in chicken
                  eggs. Individuals who have experienced severe
                  hypersensitivity reactions to eggs or egg products
                  should not receive the vaccine. An intramuscular
                  dose of 0.5 mL of the split-virus formulation can
                  be administered (in the deltoid) to adults and
                  children at least three years of age. Recipients of
                  the vaccine may experience soreness at the site of
                  injection, fever, and malaise that may persist for
                  one or two days.
                  
                  Questions about influenza
                  or the vaccine should be directed to the Hospital
                  Epidemiology Service at 6-2209 or the NIH Drug
                  Information Service at 6-2407. For questions about
                  the vaccination schedule, contact the Occupational
                  Medical Service at 6-4411.
                  
                  Interferon
                  alpha-2b/Ribavirin (Rebetron®):
                  A Brief Review
                  
                  Chronic hepatitis C
                  infection is considered the single most common
                  cause of cirrhosis, hepatic carcinoma, and chronic
                  liver disease.Patients with this infection
                  typically present with elevations in serum
                  aminotransferase concentrations (specifically
                  alanine amino-transferase) and positive serum
                  HCV-RNA. Interferon alpha is the principal
                  treatment available to patients with chronic
                  hepatitis C. Interferon alpha-2b, given
                  subqutaneously (SQ) three times a week (TIW) for 12
                  months, can decrease serum aminotransferase
                  concentrations and render serum HCV-RNA
                  undetectable. Once treatment is discontinued,
                  however, the majority of patients relapse, and only
                  20% maintain a sustained response. Ribavirin, a
                  nucleoside analog administered orally, has been
                  used in combination with interferon alpha-2b to
                  improve the overall response rate. Previously,
                  ribavirin was available in the United States only
                  in an aerosol form for the treatment of respiratory
                  syncytial virus infections in infants and young
                  children.1 |  | Up to Top                              | Description:Intron-A®
                  is Schering Corporation's brand name for interferon
                  alpha-2b, a purified sterile recombinant interferon
                  product. Intron-A® injection is a clear,
                  colorless solution which is available as a 3-MU
                  single-dose vial (3 MU/0.5 ML), an 18-MU multi-dose
                  vial (3 MU/0.5 ML), and an 18-MU multi-dose pen (3
                  MU/0.2 ML). Rebetol® is Schering Corporation's
                  brand name for ribavirin, a nucleoside analog with
                  antiviral activity. Rebetol® capsules consist
                  of a white powder in a white-opaque gelatin
                  capsule. Each capsule contains 200 mg of ribavirin.
                  The combination of interferon and ribavirin is
                  marketed as a package containing a two-week supply
                  of both medications.2
                  
                  Indication:The
                  combination therapy of oral ribavirin and
                  recombinant interferon alpha-2b injection is
                  indicated for the treatment of chronic hepatitis C
                  in patients with compensated liver disease who have
                  relapsed following alpha interferon therapy
                  alone.2
                  
                  
                  
                  Pharmacology:Ribavirin is a
                  nucleoside analog that inhibits the repli-cation of
                  many different RNA and DNA viruses, including some
                  related to HCV. 1, 2 Interferon alpha-2b
                  is a recombinant alpha interferon with both
                  antiviral and immuno-modulatory effects. It blocks
                  viral replication and inhibits viral activity by
                  reducing entry of viruses into cells, impairing
                  viral uncoating, and inhibiting viral mRNA and
                  protein synthesis.3 Approximately 60% of
                  patients with chronic hepatitis C have
                  normalization of serum aminotransferase
                  concentrations during treatment with interferon.
                  Nearly 40% of these patients show undetectable
                  serum HCV-RNA levels. However, the majority of
                  these patients relapse once interferon treatment is
                  discontinued.4
                  
                  Pharmacokinetics:Single- and
                  multiple-dose pharmacokinetic properties of
                  interferon alpha-2b and ribavirin are summarized in
                  Table 1.2
                  
                  Ribavirin is rapidly and
                  extensively absorbed following oral administration.
                  However, the absolute bioavailability is decreased
                  due to first pass metabolism. Both AUC and
                  Cmaxare increased by 70% when ribavirin
                  is administered with high-fat meals. Ribavirin is
                  metabolized via two pathways: a reversible
                  phosphorylation pathway in nucleated cells and a
                  degradative pathway involving deribosylation and
                  amide hydrolysis, yielding a triazole carboxylic
                  acid metabolite. Ribavirin and its triazole
                  carboxamide and triazole carbo-xylic acid
                  metabolites are excreted renally. Following oral
                  administration, approximately 61% of the ribavirin
                  dose is excreted in the urine, and 12% in the
                  feces. In vitro studies suggest little or no
                  cytochrome P-450 enzyme-mediated metabolism of
                  ribavirin. No pharmacokinetic interactions between
                  ribavirin and interferon alpha-2b have been noted.
                  2 | Up to Top                              | Table 1. Mean
                           Pharmacokinetic Parameters for Interferon
                           alpha-2b and RibavirinParameter
                        Interferon
                           alpha-2b
                        RibavirinSingle
                           Dose
                        Multiple
                           Dose
                        Single
                           Dose
                        Multiple
                           Dose3
                           MU
                        3 MU
                           TIW
                        600
                           mg
                        600 mg
                           BIDTmax(h)
                        7
                        5
                        1.7
                        3Cmax*
                        13.9
                        29.7
                        782
                        3680AUC**
                        142
                        333
                        13400
                        228000T1/2(h)
                        6.8
                        6.5
                        43.6
                        298* U/mL for
                           interferon alpha-2b and ng/mL for
                           ribavirin** U.h/mL for
                           interferon alpha-2b and ng.h/mL for
                           ribavirin
                  
                  Selected Clinical
                  Trials:Several
                  clinical trials have investigated the efficacy of
                  interferon/ribavirin combination therapy in the
                  management of chronic hepatitis C. Most of these
                  studies involved patients who have failed to
                  respond or maintain a sustained response to
                  interferon monotherapy. The efficacy of interferon
                  combination therapy has also been compared to that
                  of interferon therapy alone in a number of
                  randomized, double-blind, placebo-controlled
                  clinical trials which included interferon-naive
                  patients.
                  
                  In a Swedish clinical
                  trial, twenty patients with chronic hepatitis C (10
                  with a history of non-sustained response to
                  interferon, and 10 with no response at all) were
                  started on the interferon alpha-2b (3 MU SQ TIW)
                  and ribavirin (1000-1200 mg/day PO)
                  combination.5 All patients had positive
                  HCV-RNA tests and elevated aminotransferase levels
                  for at least six months prior to enrollment.The duration of treatment was 24 weeks, and
                  all patients were monitored for an additional 24
                  weeks after discontinuation of therapy. All 10
                  patients who had previously experienced a
                  non-sustained response with interferon, experienced
                  a sustained response with the combination. These
                  patients developed negative HCV-RNA tests and
                  normal aminotransferase levels upon completion of
                  treatment, with nine maintaining a negative HCV-RNA
                  test at the 24-week follow-up. Of the 10 patients
                  who had experienced no response with interferon,
                  five developed normal aminotransferase levels by
                  the end of therapy, and four had a negative HCV-RNA
                  test. At follow-up, three of these 10 patients
                  continued to have negative HCV-RNA tests and normal
                  aminotransferase levels. Reductions in leukocyte
                  counts and hemoglobin concentrations were the most
                  common adverse effects reported. However, none of
                  the patients discontinued therapy due to adverse
                  reactions. This study was limited by a small sample
                  size (n=20) and the lack of clear
                  inclusion/exclusion criteria. Additionally,
                  patients enrolled in this study had varying degrees
                  of disease severity, including a few with severe
                  liver cirrhosis.
                  
                  Combination therapy with
                  interferon and ribavirin was also evaluated in a
                  clinical trial enrolling 10 patients with chronic
                  hepatitis C (six with a non-sustained response to
                  previous interferon therapy and four with no
                  response).6 Patients were given
                  interferon alpha-2b (3 MU SQ TIW) and ribavirin
                  (1000-1200 mg/day PO) for 24 weeks and were
                  monitored for 24 weeks after discontinuation of
                  therapy. All four non-sustained responders had
                  normal aminotransferase levels at the end of
                  therapy and at follow-up. Among the non-responders,
                  three out of six had normal aminotransferase levels
                  at the end of therapy, but only one at follow-up.
                  All four non-sustained responders developed
                  negative HCV-RNA tests, with three remaining
                  negative at follow-up. In the non-responder group,
                  two patients became HCV-RNA negative and remained
                  negative at follow-up. All patients completed the
                  study. Common adverse drug reactions included mild
                  reductions in hemoglobin, and decreased white blood
                  cell and platelet counts. This study was limited by
                  a small sample size and the lack of clear exclusion
                  criteria. Additionally, it was unclear if all
                  patients enrolled in this study had the same degree
                  of disease severity.
                  
                  The use of
                  interferon/ribavirin combination therapy in
                  interferon-naive patients has also been evaluated.
                  One study compared the efficacy of interferon
                  alpha-2b/ribavirin combination therapy to that of
                  interferon with a placebo capsule. 7
                  This was a randomized, double-blind,
                  placebo-controlled study enrolling 100 patients
                  with chronic hepatitis C. Patients were randomly
                  assigned to treatment with interferon alpha-2b (3
                  MU SQ TIW) and ribavirin (1000-1200 mg/day PO) or
                  interferon (3 MU SQ TIW) and placebo. The duration
                  of treatment was 24 weeks, with an additional
                  24-week follow-up period. An additional follow-up
                  was performed one year after discontinuation of
                  therapy. Thirty-six percent (18/50) in the
                  interferon/ribavirin group had a sustained response
                  vs. 18% (9/50) in the interferon/placebo group. At
                  one-year follow up, 42% of the patients in the
                  interferon/ribavirin group maintained a sustained
                  response vs. 20% of those in the interferon/placebo
                  arm (p=0.03). Common adverse reactions experienced
                  included fatigue, nausea, headache, alopecia, and
                  anemia. A total of seven patients discontinued
                  treatment due to adverse drug effects. This study
                  included a relatively large sample size, and the
                  inclusion/exclusion criteria were clear. In
                  addition, complete patient demographics, including
                  the degree of disease severity, were
                  provided.
                  
                  The use of
                  ribavirin/interferon combination therapy has also
                  been studied in liver transplant recipients with
                  hepatitis C infection. 8 Mazzaferro et
                  al. studied the effects of interferon/ribavirin
                  combination therapy in 21 patients following liver
                  transplant. Combination interferon alpha-2b (3 MU
                  SQ TIW) and ribavirin (10 mg/kg/d PO) therapy was
                  started three weeks after liver transplant in all
                  HCV-RNA positive patients discharged from the ICU
                  on an oral diet. These patients continued on the
                  combination therapy for one year and were followed
                  every two weeks. After the first month and a half
                  of therapy, all patients had normal alanine
                  aminotran-sase serum concentrations. At the
                  one-year follow-up, 20 of the 21 patients were
                  alive, and 8 of these 20 were HCV-RNA negative.
                  Common adverse reactions reported were anemia and
                  asthenia, but none of the patients discontinued
                  treatment because of adverse affects. However, 43%
                  experienced adverse drug reactions (primarily
                  anemia) and required dosage reduction. This study
                  was poorly reported, and limited patient
                  demographics and baseline data were
                  presented.
                  
                  Adverse Effects:The most
                  common adverse effects seen during combi-nation
                  therapy with interferon alpha-2b and ribavirin
                  included flu-like symptoms, headache, fatigue,
                  fever, and myalgia. Other commonly reported side
                  effects were nausea, anorexia, insomnia, alopecia,
                  and irritability. Neutropenia, elevated uric acid
                  levels, and thyroid abnormalities were also
                  reported.2 Ribavirin induces a
                  dose-related hemolysis, and most patients
                  experience a decrease in hemoglobin levels of 1-2
                  g/dL.
                  
                  Drug
                  Interaction:Co-administration of
                  ribavirin with an antacid preparation containing
                  magnesium, aluminum, and simethicone resulted in a
                  14% decrease in mean ribavirin area under the
                  time-concentration curve. The clinical relevance of
                  this interaction is unknown.2
                  
                  Precautions and
                  Contraindications:Combination
                  interferon/ribavirin therapy is categor-ized by the
                  FDA as pregnancy category X. This combination must
                  be avoided in women who are or may become pregnant.
                  Therapy should not be started until pregnancy is
                  ruled out. Interferon/ribavirin combination therapy
                  is contraindicated in patients with autoimmune
                  hepatitis or those with a history of
                  hypersensitivity to interferon or ribavirin. In
                  addition, patients with a history of unstable
                  cardiac disease should not be started on this
                  combination therapy, since anemia associated with
                  this treatment can result in further deterioration
                  of cardiac function. Interferon/ribavirin therapy
                  must also be used with extreme caution in patients
                  with a history of preexisting psychiatric
                  disorders. Severe psychiatric adverse effects
                  including depression and suicidal behavior have
                  been reported with the use of this combination.
                  Because patients have complained of loss of visual
                  acuity while on this therapy, a visual exam is
                  recommended prior to initiation. Combination
                  interferon/ribavirin therapy should be used with
                  caution in patients with creatinine clearance
                  measurements less than 50
                  mL/min.2
                  
                  Dosage and
                  Administration:The recommended dosing
                  guidelines for ribavirin and interferon alpha-2b
                  are provided in Table 2. Since the long-term safety
                  and efficacy of this combination therapy has not
                  been evaluated, treatment should be limited to a
                  period of six months.
                  
                  Table 2.
                           Recommended Dosage
                           GuidelinesBody
                           Weight
                        Interferon
                           alpha-2b
                        Ribavirin< 75
                           Kg
                        3 MU SQ
                           TIW
                        2x200 mg caps AM
                           (PO)3x200 mg caps PM
                           (PO)> 75
                           Kg
                        3 MU SQ
                           TIW
                        3x200 mg caps AM
                           (PO)3x200 mg caps PM
                           (PO)For patients with a
                  history of stable cardiovascular disease, a
                  permanent dose reduction is required if hemoglobin
                  levels decrease by more that 2 g/dL during any
                  four-week period. The dose of ribavirin must be
                  decreased to 600 mg/day in patients with hemoglobin
                  levels less than 10 g/dL. If hemoglobin falls below
                  8.5 g/dL, therapy must be
                  discontinued.2
                  
                  
                  
                  Cost:
                  
                  Table 3. Cost
                           of Rebetron®Patient's
                           Weight
                        Monthly Cost
                           of Therapy> 75
                           Kg
                        $ 910*< 75
                           Kg
                        $ 815**Federal
                           Supply Schedule | Table 1. Mean
                           Pharmacokinetic Parameters for Interferon
                           alpha-2b and Ribavirin | Parameter                       | Interferon
                           alpha-2b | Ribavirin                         |                                       | Single
                           Dose | Multiple
                           Dose | Single
                           Dose | Multiple
                           Dose |   | 3
                           MU | 3 MU
                           TIW | 600
                           mg | 600 mg
                           BID | Tmax(h) | 7     | 5   | 1.7 | 3     | Cmax*  | 13.9    | 29.7 | 782 | 3680 | AUC** | 142                                                                                                          | 333                                                                                                               | 13400                                                                                        | 228000                                 | T1/2(h)                                        | 6.8       | 6.5                                | 43.6                                   | 298                                              | * U/mL for
                           interferon alpha-2b and ng/mL for
                           ribavirin | ** U.h/mL for
                           interferon alpha-2b and ng.h/mL for
                           ribavirin | Table 2.
                           Recommended Dosage
                           Guidelines | Body
                           Weight | Interferon
                           alpha-2b | Ribavirin                                        | < 75
                           Kg | 3 MU SQ
                           TIW | 2x200 mg caps AM
                           (PO) |                                                       |                                             | 3x200 mg caps PM
                           (PO)   | > 75
                           Kg | 3 MU SQ
                           TIW | 3x200 mg caps AM
                           (PO) |        |                                                     | 3x200 mg caps PM
                           (PO) | Table 3. Cost
                           of Rebetron® | Patient's
                           Weight | Monthly Cost
                           of Therapy | > 75
                           Kg | $ 910* | < 75
                           Kg | $ 815* | *Federal
                           Supply Schedule |  | Up to Top | Conclusion:
                  
                  The combination of
                  interferon alpha-2b and ribavirin appears to be
                  effective in patients who have failed to respond or
                  maintain a sustained response to interferon
                  monotherapy.
                  
                  Additional long-term
                  studies and studies in interferon-naive patients
                  are warranted.
                  
                  
                  
                  References:
                  
                  1.Dana F, Becherer
                  PR, Bacon BR. Hepatitis C virus. Postgrad
                  Med 1994; 95 (6):121-130.
                  
                  2.Schering-Plough
                  Corporation. Rebetron® Package Insert,
                  1998.
                  
                  3.Najm W. Viral
                  hepatitis: how to manage type C and D infections.
                  Geriatrics1997; 52 (5): 28-37.
                  
                  4.Wright TL.
                  Chronic hepatitis B and C. Postgrad Med
                  1992; 92 (4): 75-8
                  
                  5.Schvarcz R, Ando
                  Y, Sonnerborg A, Weiland O. Combination treatment
                  with interferon alpha-2b and ribavirin for chronic
                  hepatitis C in patients who have failed to achieve
                  sustained response to interferon alone: Swedish
                  experience. J Hepatol 1995; 23 (Suppl. 2):
                  17-21.
                  
                  6.Schvarez R, Yun
                  ZB, Sonnerborg A, Weiland O. Combined treatment
                  with interferon alpha-2b and ribavirin for chronic
                  hepatitis C in patients with a previous
                  non-response or non-sustained response to
                  interferon alone. J Med Virol 1995; 46:
                  43-47.
                  
                  7.Reichard O,
                  Norkrans G, Fryden A, Braconier J, Sonnerborg A,
                  Weiland O. Randomized, double-blind,
                  placebo-controlled trial of interferon alpha-2b
                  with and without ribavirin for chronic hepatitis C.
                  Lancet 1998; 351: 83-87.
                  
                  8.Mazzaferro V,
                  Regalia E, Pulvirenti A, Tagger A, Andreola S,
                  Pasquali M, et al. Prophylaxis against HCV
                  recurrence after liver transplantation: effects of
                  interferon and ribavirin combination.
                  Transplantation 1997; 29:
                  519-521.
                  
                  9.Bizollon T,
                  Ducerf C, Trepo C. New approaches to the treat-ment
                  of hepatitis C virus infection after liver
                  transplantation using ribavirin. J Hepatol
                  1995; 23 (Suppl. 2): 22-25.
                  
                  
                  
                  Editors'
                  Note
                  
                  We wish to thank
                     Drs. Daryl Lau and Jay Hoofnagle
                     for their comments and helpful suggestions
                     regarding the Rebetron® article.
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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | September/October 1998                                                                                                              
|In This IssueInfluenza
                  Vaccination:
                  1998-1999*Interferon
                  alpha-2b/Ribavirin (Rebetron®):
                  A Brief Review
                  
                  Drug
                  Information Service
                  Pharmacy Department
                  Warren G. Magnuson Clinical Center
                  National Institutes of Health
                  Bethesda, Maryland 20892-1196
                  Charles E. Daniels, Ph.D.
                  Chief, Pharmacy DepartmentEditor-in-Chief
                  Karim Anton Calis, Pharm.D., M.P.H.
                  Coordinator, Drug Information Service, and
                  Endocrinology Clinical Pharmacy Specialist[email protected]Associate
                  EditorMaryam R.
                  Mohassel, Pharm.D.
                  Specialized Resident in Drug Information Practice
                  and Pharmacotherapy[email protected]
                  
                  Archives                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Influenza Vaccination:
                  1998-1999
                  
                  Each year, infections due
                  to the influenza virus result in substantial
                  morbidity and mortality worldwide. Vaccination
                  offers appreciable protection against the influenza
                  virus for individuals and contributes to improved
                  overall public health.
                  
                  A new trivalent vaccine is
                  now available for the 1998-1999 influenza season.
                  The vaccine is recommended for patients with
                  chronic medical disorders, children with asthma,
                  residents of long-term care facilities, and the
                  elderly. Health-care workers and household contacts
                  of elderly and high-risk patients are also strongly
                  encouraged to receive the vaccine.
                  
                  Protection conferred by
                  the influenza vaccine typically begins two weeks
                  after vaccination and may last for six months or
                  longer. Serum antibodies in some elderly patients
                  can diminish more rapidly to non-protective levels.
                  Because large outbreaks in the United States
                  usually occur between December and early March, the
                  optimal time to receive the vaccination is between
                  October and November. However, administration of
                  the vaccine is appropriate anytime from September
                  to the end of the influenza season.
                  
                  The vaccine formulation is
                  changed annually because of the antigenic
                  variability of the influenza virus. Antigens in the
                  current vaccine are derived from
                  A/Sydney/05/97-like (H3N2), A/Beijing/262/95-like
                  (H1N1), and B/Beijing/184/93-like
                  viruses.
                  
                  Influenza vaccine is
                  produced from inactivated virus grown in chicken
                  eggs. Individuals who have experienced severe
                  hypersensitivity reactions to eggs or egg products
                  should not receive the vaccine. An intramuscular
                  dose of 0.5 mL of the split-virus formulation can
                  be administered (in the deltoid) to adults and
                  children at least three years of age. Recipients of
                  the vaccine may experience soreness at the site of
                  injection, fever, and malaise that may persist for
                  one or two days.
                  
                  Questions about influenza
                  or the vaccine should be directed to the Hospital
                  Epidemiology Service at 6-2209 or the NIH Drug
                  Information Service at 6-2407. For questions about
                  the vaccination schedule, contact the Occupational
                  Medical Service at 6-4411.
                  
                  Interferon
                  alpha-2b/Ribavirin (Rebetron®):
                  A Brief Review
                  
                  Chronic hepatitis C
                  infection is considered the single most common
                  cause of cirrhosis, hepatic carcinoma, and chronic
                  liver disease.Patients with this infection
                  typically present with elevations in serum
                  aminotransferase concentrations (specifically
                  alanine amino-transferase) and positive serum
                  HCV-RNA. Interferon alpha is the principal
                  treatment available to patients with chronic
                  hepatitis C. Interferon alpha-2b, given
                  subqutaneously (SQ) three times a week (TIW) for 12
                  months, can decrease serum aminotransferase
                  concentrations and render serum HCV-RNA
                  undetectable. Once treatment is discontinued,
                  however, the majority of patients relapse, and only
                  20% maintain a sustained response. Ribavirin, a
                  nucleoside analog administered orally, has been
                  used in combination with interferon alpha-2b to
                  improve the overall response rate. Previously,
                  ribavirin was available in the United States only
                  in an aerosol form for the treatment of respiratory
                  syncytial virus infections in infants and young
                  children.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
|Up to Top                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Description:Intron-A®
                  is Schering Corporation's brand name for interferon
                  alpha-2b, a purified sterile recombinant interferon
                  product. Intron-A® injection is a clear,
                  colorless solution which is available as a 3-MU
                  single-dose vial (3 MU/0.5 ML), an 18-MU multi-dose
                  vial (3 MU/0.5 ML), and an 18-MU multi-dose pen (3
                  MU/0.2 ML). Rebetol® is Schering Corporation's
                  brand name for ribavirin, a nucleoside analog with
                  antiviral activity. Rebetol® capsules consist
                  of a white powder in a white-opaque gelatin
                  capsule. Each capsule contains 200 mg of ribavirin.
                  The combination of interferon and ribavirin is
                  marketed as a package containing a two-week supply
                  of both medications.2
                  
                  Indication:The
                  combination therapy of oral ribavirin and
                  recombinant interferon alpha-2b injection is
                  indicated for the treatment of chronic hepatitis C
                  in patients with compensated liver disease who have
                  relapsed following alpha interferon therapy
                  alone.2
                  
                  
                  
                  Pharmacology:Ribavirin is a
                  nucleoside analog that inhibits the repli-cation of
                  many different RNA and DNA viruses, including some
                  related to HCV. 1, 2 Interferon alpha-2b
                  is a recombinant alpha interferon with both
                  antiviral and immuno-modulatory effects. It blocks
                  viral replication and inhibits viral activity by
                  reducing entry of viruses into cells, impairing
                  viral uncoating, and inhibiting viral mRNA and
                  protein synthesis.3 Approximately 60% of
                  patients with chronic hepatitis C have
                  normalization of serum aminotransferase
                  concentrations during treatment with interferon.
                  Nearly 40% of these patients show undetectable
                  serum HCV-RNA levels. However, the majority of
                  these patients relapse once interferon treatment is
                  discontinued.4
                  
                  Pharmacokinetics:Single- and
                  multiple-dose pharmacokinetic properties of
                  interferon alpha-2b and ribavirin are summarized in
                  Table 1.2
                  
                  Ribavirin is rapidly and
                  extensively absorbed following oral administration.
                  However, the absolute bioavailability is decreased
                  due to first pass metabolism. Both AUC and
                  Cmaxare increased by 70% when ribavirin
                  is administered with high-fat meals. Ribavirin is
                  metabolized via two pathways: a reversible
                  phosphorylation pathway in nucleated cells and a
                  degradative pathway involving deribosylation and
                  amide hydrolysis, yielding a triazole carboxylic
                  acid metabolite. Ribavirin and its triazole
                  carboxamide and triazole carbo-xylic acid
                  metabolites are excreted renally. Following oral
                  administration, approximately 61% of the ribavirin
                  dose is excreted in the urine, and 12% in the
                  feces. In vitro studies suggest little or no
                  cytochrome P-450 enzyme-mediated metabolism of
                  ribavirin. No pharmacokinetic interactions between
                  ribavirin and interferon alpha-2b have been noted.
                  2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
|Up to Top                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Table 1. Mean
                           Pharmacokinetic Parameters for Interferon
                           alpha-2b and RibavirinParameter
                        Interferon
                           alpha-2b
                        RibavirinSingle
                           Dose
                        Multiple
                           Dose
                        Single
                           Dose
                        Multiple
                           Dose3
                           MU
                        3 MU
                           TIW
                        600
                           mg
                        600 mg
                           BIDTmax(h)
                        7
                        5
                        1.7
                        3Cmax*
                        13.9
                        29.7
                        782
                        3680AUC**
                        142
                        333
                        13400
                        228000T1/2(h)
                        6.8
                        6.5
                        43.6
                        298* U/mL for
                           interferon alpha-2b and ng/mL for
                           ribavirin** U.h/mL for
                           interferon alpha-2b and ng.h/mL for
                           ribavirin
                  
                  Selected Clinical
                  Trials:Several
                  clinical trials have investigated the efficacy of
                  interferon/ribavirin combination therapy in the
                  management of chronic hepatitis C. Most of these
                  studies involved patients who have failed to
                  respond or maintain a sustained response to
                  interferon monotherapy. The efficacy of interferon
                  combination therapy has also been compared to that
                  of interferon therapy alone in a number of
                  randomized, double-blind, placebo-controlled
                  clinical trials which included interferon-naive
                  patients.
                  
                  In a Swedish clinical
                  trial, twenty patients with chronic hepatitis C (10
                  with a history of non-sustained response to
                  interferon, and 10 with no response at all) were
                  started on the interferon alpha-2b (3 MU SQ TIW)
                  and ribavirin (1000-1200 mg/day PO)
                  combination.5 All patients had positive
                  HCV-RNA tests and elevated aminotransferase levels
                  for at least six months prior to enrollment.The duration of treatment was 24 weeks, and
                  all patients were monitored for an additional 24
                  weeks after discontinuation of therapy. All 10
                  patients who had previously experienced a
                  non-sustained response with interferon, experienced
                  a sustained response with the combination. These
                  patients developed negative HCV-RNA tests and
                  normal aminotransferase levels upon completion of
                  treatment, with nine maintaining a negative HCV-RNA
                  test at the 24-week follow-up. Of the 10 patients
                  who had experienced no response with interferon,
                  five developed normal aminotransferase levels by
                  the end of therapy, and four had a negative HCV-RNA
                  test. At follow-up, three of these 10 patients
                  continued to have negative HCV-RNA tests and normal
                  aminotransferase levels. Reductions in leukocyte
                  counts and hemoglobin concentrations were the most
                  common adverse effects reported. However, none of
                  the patients discontinued therapy due to adverse
                  reactions. This study was limited by a small sample
                  size (n=20) and the lack of clear
                  inclusion/exclusion criteria. Additionally,
                  patients enrolled in this study had varying degrees
                  of disease severity, including a few with severe
                  liver cirrhosis.
                  
                  Combination therapy with
                  interferon and ribavirin was also evaluated in a
                  clinical trial enrolling 10 patients with chronic
                  hepatitis C (six with a non-sustained response to
                  previous interferon therapy and four with no
                  response).6 Patients were given
                  interferon alpha-2b (3 MU SQ TIW) and ribavirin
                  (1000-1200 mg/day PO) for 24 weeks and were
                  monitored for 24 weeks after discontinuation of
                  therapy. All four non-sustained responders had
                  normal aminotransferase levels at the end of
                  therapy and at follow-up. Among the non-responders,
                  three out of six had normal aminotransferase levels
                  at the end of therapy, but only one at follow-up.
                  All four non-sustained responders developed
                  negative HCV-RNA tests, with three remaining
                  negative at follow-up. In the non-responder group,
                  two patients became HCV-RNA negative and remained
                  negative at follow-up. All patients completed the
                  study. Common adverse drug reactions included mild
                  reductions in hemoglobin, and decreased white blood
                  cell and platelet counts. This study was limited by
                  a small sample size and the lack of clear exclusion
                  criteria. Additionally, it was unclear if all
                  patients enrolled in this study had the same degree
                  of disease severity.
                  
                  The use of
                  interferon/ribavirin combination therapy in
                  interferon-naive patients has also been evaluated.
                  One study compared the efficacy of interferon
                  alpha-2b/ribavirin combination therapy to that of
                  interferon with a placebo capsule. 7
                  This was a randomized, double-blind,
                  placebo-controlled study enrolling 100 patients
                  with chronic hepatitis C. Patients were randomly
                  assigned to treatment with interferon alpha-2b (3
                  MU SQ TIW) and ribavirin (1000-1200 mg/day PO) or
                  interferon (3 MU SQ TIW) and placebo. The duration
                  of treatment was 24 weeks, with an additional
                  24-week follow-up period. An additional follow-up
                  was performed one year after discontinuation of
                  therapy. Thirty-six percent (18/50) in the
                  interferon/ribavirin group had a sustained response
                  vs. 18% (9/50) in the interferon/placebo group. At
                  one-year follow up, 42% of the patients in the
                  interferon/ribavirin group maintained a sustained
                  response vs. 20% of those in the interferon/placebo
                  arm (p=0.03). Common adverse reactions experienced
                  included fatigue, nausea, headache, alopecia, and
                  anemia. A total of seven patients discontinued
                  treatment due to adverse drug effects. This study
                  included a relatively large sample size, and the
                  inclusion/exclusion criteria were clear. In
                  addition, complete patient demographics, including
                  the degree of disease severity, were
                  provided.
                  
                  The use of
                  ribavirin/interferon combination therapy has also
                  been studied in liver transplant recipients with
                  hepatitis C infection. 8 Mazzaferro et
                  al. studied the effects of interferon/ribavirin
                  combination therapy in 21 patients following liver
                  transplant. Combination interferon alpha-2b (3 MU
                  SQ TIW) and ribavirin (10 mg/kg/d PO) therapy was
                  started three weeks after liver transplant in all
                  HCV-RNA positive patients discharged from the ICU
                  on an oral diet. These patients continued on the
                  combination therapy for one year and were followed
                  every two weeks. After the first month and a half
                  of therapy, all patients had normal alanine
                  aminotran-sase serum concentrations. At the
                  one-year follow-up, 20 of the 21 patients were
                  alive, and 8 of these 20 were HCV-RNA negative.
                  Common adverse reactions reported were anemia and
                  asthenia, but none of the patients discontinued
                  treatment because of adverse affects. However, 43%
                  experienced adverse drug reactions (primarily
                  anemia) and required dosage reduction. This study
                  was poorly reported, and limited patient
                  demographics and baseline data were
                  presented.
                  
                  Adverse Effects:The most
                  common adverse effects seen during combi-nation
                  therapy with interferon alpha-2b and ribavirin
                  included flu-like symptoms, headache, fatigue,
                  fever, and myalgia. Other commonly reported side
                  effects were nausea, anorexia, insomnia, alopecia,
                  and irritability. Neutropenia, elevated uric acid
                  levels, and thyroid abnormalities were also
                  reported.2 Ribavirin induces a
                  dose-related hemolysis, and most patients
                  experience a decrease in hemoglobin levels of 1-2
                  g/dL.
                  
                  Drug
                  Interaction:Co-administration of
                  ribavirin with an antacid preparation containing
                  magnesium, aluminum, and simethicone resulted in a
                  14% decrease in mean ribavirin area under the
                  time-concentration curve. The clinical relevance of
                  this interaction is unknown.2
                  
                  Precautions and
                  Contraindications:Combination
                  interferon/ribavirin therapy is categor-ized by the
                  FDA as pregnancy category X. This combination must
                  be avoided in women who are or may become pregnant.
                  Therapy should not be started until pregnancy is
                  ruled out. Interferon/ribavirin combination therapy
                  is contraindicated in patients with autoimmune
                  hepatitis or those with a history of
                  hypersensitivity to interferon or ribavirin. In
                  addition, patients with a history of unstable
                  cardiac disease should not be started on this
                  combination therapy, since anemia associated with
                  this treatment can result in further deterioration
                  of cardiac function. Interferon/ribavirin therapy
                  must also be used with extreme caution in patients
                  with a history of preexisting psychiatric
                  disorders. Severe psychiatric adverse effects
                  including depression and suicidal behavior have
                  been reported with the use of this combination.
                  Because patients have complained of loss of visual
                  acuity while on this therapy, a visual exam is
                  recommended prior to initiation. Combination
                  interferon/ribavirin therapy should be used with
                  caution in patients with creatinine clearance
                  measurements less than 50
                  mL/min.2
                  
                  Dosage and
                  Administration:The recommended dosing
                  guidelines for ribavirin and interferon alpha-2b
                  are provided in Table 2. Since the long-term safety
                  and efficacy of this combination therapy has not
                  been evaluated, treatment should be limited to a
                  period of six months.
                  
                  Table 2.
                           Recommended Dosage
                           GuidelinesBody
                           Weight
                        Interferon
                           alpha-2b
                        Ribavirin< 75
                           Kg
                        3 MU SQ
                           TIW
                        2x200 mg caps AM
                           (PO)3x200 mg caps PM
                           (PO)> 75
                           Kg
                        3 MU SQ
                           TIW
                        3x200 mg caps AM
                           (PO)3x200 mg caps PM
                           (PO)For patients with a
                  history of stable cardiovascular disease, a
                  permanent dose reduction is required if hemoglobin
                  levels decrease by more that 2 g/dL during any
                  four-week period. The dose of ribavirin must be
                  decreased to 600 mg/day in patients with hemoglobin
                  levels less than 10 g/dL. If hemoglobin falls below
                  8.5 g/dL, therapy must be
                  discontinued.2
                  
                  
                  
                  Cost:
                  
                  Table 3. Cost
                           of Rebetron®Patient's
                           Weight
                        Monthly Cost
                           of Therapy> 75
                           Kg
                        $ 910*< 75
                           Kg
                        $ 815**Federal
                           Supply Schedule | Table 1. Mean
                           Pharmacokinetic Parameters for Interferon
                           alpha-2b and Ribavirin | Parameter                              | Interferon
                           alpha-2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Ribavirin                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |  | Single
                           Dose | Multiple
                           Dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Single
                           Dose | Multiple
                           Dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                      | 3
                           MU | 3 MU
                           TIW            | 600
                           mg | 600 mg
                           BID | Tmax(h)                                | 7                                        | 5                                      | 1.7                                      | 3 | Cmax*                           | 13.9                                | 29.7                              | 782                                   | 3680    | AUC** | 142 | 333 | 13400 | 228000 | T1/2(h) | 6.8  | 6.5 | 43.6 | 298   | * U/mL for
                           interferon alpha-2b and ng/mL for
                           ribavirin | ** U.h/mL for
                           interferon alpha-2b and ng.h/mL for
                           ribavirin | Table 2.
                           Recommended Dosage
                           Guidelines | Body
                           Weight | Interferon
                           alpha-2b | Ribavirin | < 75
                           Kg | 3 MU SQ
                           TIW | 2x200 mg caps AM
                           (PO) |                                                                                                              |                                                                                                                   | 3x200 mg caps PM
                           (PO)                                             | > 75
                           Kg     | 3 MU SQ
                           TIW         | 3x200 mg caps AM
                           (PO) |                                    |                                        | 3x200 mg caps PM
                           (PO) | Table 3. Cost
                           of Rebetron® | Patient's
                           Weight | Monthly Cost
                           of Therapy | > 75
                           Kg | $ 910*                                 | < 75
                           Kg               | $ 815* | *Federal
                           Supply Schedule |                                                 
|Table 1. Mean
                           Pharmacokinetic Parameters for Interferon
                           alpha-2b and Ribavirin                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
|Parameter                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Interferon
                           alpha-2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Ribavirin                                                                                                                           
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Single
                           Dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Multiple
                           Dose                                                                                             | Single
                           Dose | Multiple
                           Dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 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                                                                                                                                                                                                                                                                                                                                                        | 6.8                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            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|* U/mL for
                           interferon alpha-2b and ng/mL for
                           ribavirin                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
|** U.h/mL for
                           interferon alpha-2b and ng.h/mL for
                           ribavirin                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
|Table 2.
                           Recommended Dosage
                           Guidelines                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
|Body
                           Weight                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Interferon
                           alpha-2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Ribavirin                                                                                                                           
|< 75
                           Kg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | 3 MU SQ
                           TIW                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Monthly Cost
                           of Therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
|> 75
                           Kg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
|< 75
                           Kg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
|*Federal
                           Supply Schedule                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
|Up to Top                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Conclusion:
                  
                  The combination of
                  interferon alpha-2b and ribavirin appears to be
                  effective in patients who have failed to respond or
                  maintain a sustained response to interferon
                  monotherapy.
                  
                  Additional long-term
                  studies and studies in interferon-naive patients
                  are warranted.
                  
                  
                  
                  References:
                  
                  1.Dana F, Becherer
                  PR, Bacon BR. Hepatitis C virus. Postgrad
                  Med 1994; 95 (6):121-130.
                  
                  2.Schering-Plough
                  Corporation. Rebetron® Package Insert,
                  1998.
                  
                  3.Najm W. Viral
                  hepatitis: how to manage type C and D infections.
                  Geriatrics1997; 52 (5): 28-37.
                  
                  4.Wright TL.
                  Chronic hepatitis B and C. Postgrad Med
                  1992; 92 (4): 75-8
                  
                  5.Schvarcz R, Ando
                  Y, Sonnerborg A, Weiland O. Combination treatment
                  with interferon alpha-2b and ribavirin for chronic
                  hepatitis C in patients who have failed to achieve
                  sustained response to interferon alone: Swedish
                  experience. J Hepatol 1995; 23 (Suppl. 2):
                  17-21.
                  
                  6.Schvarez R, Yun
                  ZB, Sonnerborg A, Weiland O. Combined treatment
                  with interferon alpha-2b and ribavirin for chronic
                  hepatitis C in patients with a previous
                  non-response or non-sustained response to
                  interferon alone. J Med Virol 1995; 46:
                  43-47.
                  
                  7.Reichard O,
                  Norkrans G, Fryden A, Braconier J, Sonnerborg A,
                  Weiland O. Randomized, double-blind,
                  placebo-controlled trial of interferon alpha-2b
                  with and without ribavirin for chronic hepatitis C.
                  Lancet 1998; 351: 83-87.
                  
                  8.Mazzaferro V,
                  Regalia E, Pulvirenti A, Tagger A, Andreola S,
                  Pasquali M, et al. Prophylaxis against HCV
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                  Editors'
                  Note
                  
                  We wish to thank
                     Drs. Daryl Lau and Jay Hoofnagle
                     for their comments and helpful suggestions
                     regarding the Rebetron® article.