Ribavirin and Interferon Alfa-2b, Recombinant (Systemic )


VA CLASSIFICATION
Primary: AM810

Commonly used brand name(s): Intron A; Rebetol; Rebetron (in combination with Intron A); Rebetron (in combination with Rebetol).


Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms sections(s).

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral—

Indications

Accepted

Hepatitis C, chronic, active (treatment)—Ribavirin and recombinant interferon alfa-2b combination is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy {01}{02}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Interferon alfa–2b, recombinant: Synthetic. A protein chain of 165 amino acids produced by a recombinant DNA process involving genetically engineered Escherichia coli. Purification procedure includes affinity chromatography using a murine monoclonal antibody. Contains only a single alpha interferon subtype {01}.

Chemical group—
    Ribavirin: Synthetic nucleoside (guanosine) analog {01}{03}.
    Interferon, alfa–2b, recombinant: Related to naturally occurring alpha interferons {01}.
    Interferons are produced by immune cells in response to viral infections or various synthetic and biologic inducers{03}.
Molecular weight—
    Ribavirin: 244.21{01}
    Interferon, alfa-2b, recombinant: 19,271 daltons{01}

Mechanism of action/Effect:

The mechanism of inhibition of hepatitis C virus RNA by ribavirin and recombinant interferon alfa-2b combination therapy has not been established{01}. Ribavirin may exert immunomodulatory effects rather than antiviral effects in the treatment of chronic hepatitis C{03}. Interferon may have a variety of actions, including, antiviral and immunomodulatory actions, in the treatment of chronic hepatitis C. Antiviral effects include inhibiting viral replication. Proposed mechanisms of the effects on the immune cells include: increasing immune cell proliferation (amplifying the expression of human leukocyte antigen class I antigens on cell surfaces), maturation (cytotoxic T cells), and activity (natural killer cell) {03}.


Duration of effect

Duration of effect beyond 24 weeks for patients who have relapsed and 48 weeks in patients who have previously been untreated is not established {01}.


Absorption:

Ribavirin—Rapidly and extensively absorbed following oral administration; average absolute bioavailability is 64% {01}.


Distribution:

Ribavirin—Extensively distributed into red blood cells {01}.

Protein binding:

Ribavirin—No significant plasma protein binding {01}

Biotransformation:

Ribavirin—Hepatic. Ribavirin undergoes metabolism by 2 mechanisms: 1) reversible phosphorylation in nucleated cells; and 2) degradation (deribosylation and amide hydrolysis) to triazole carboxamide and triazole carboxylic acid. The metabolites are excreted renally. In vitro data demonstrated minimal to no cytochrome P450 enzyme-mediated metabolism {01}.


Interferon, alfa-2b—Renal, complete. Interferon alfa-2b undergoes rapid proteolytic degradation during tubular reabsorption, with only negligible systemic reappearance of intact compound {04}{05}.


Half-life:

Ribavirin—

Oral:

• Single dose–43.6 hours


• Multiple dose–298 hours{01}


Interferon, alfa-2b—

Subcutaneous:

• Single dose–6.8 hours


• Multiple dose–6.5 hours{01}


Time to peak concentration:

Ribavirin—

Oral:

• Single dose–1.7 hours


• Multiple dose–3 hours{01}


Interferon, alfa-2b—

Subcutaneous:

• Single dose–7 hours


• Multiple dose–5 hours{01}


Peak serum concentration:
Ribavirin



• Single dose— Oral 600 milligram (mg) produces a mean concentration of 782 nanograms/milliliter (ng/mL) {01}.


• Multiple dose—Oral 600 mg twice daily produces a mean concentration of 3680 ng/mL {01}.
Interferon, alfa-2b



• Single dose— Subcutaneous 3 million international units (MIU) produces a mean concentration of 13.9 international unit/milliliter (IU/mL) {01}.


• Multiple dose—Subcutaneous 3 MIU three times a week produces a mean concentration of 29.7 IU/mL {01}

Elimination:


Ribavirin——
        Renal—Ribavirin and its metabolites are excreted renally. Approximately 61% of the radioactivity was eliminated in the urine after oral administration of 600 mg of 14C-ribavirin, in 336 hours; 17% of an administered dose is excreted unchanged in the urine.
        Fecal—Approximately 12% of the radioactivity was eliminated in the feces after oral administration of 600 mg of 14C-ribavirin, in 336 hours.



Interferon, alfa–2b——
        Renal—Recombinant interferon alfa-2b administered subcutaneously undergoes rapid proteolytic degradation during tubular reabsorption, with only negligible systemic reappearance of intact compound {04}{05}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to any alpha interferon may also be sensitive to any other alpha interferon {01}.

Patients sensitive to ribavirin may be sensitive to ribavirin and recombinant interferon alfa-2b combination therapy.{01}

Carcinogenicity


Ribavirin:

Studies have not been done in either animals or humans. However, multiple in vitro and animal in vivo genotoxicity assays demonstrate a potential to be carcinogenic {01}.



Interferon alfa-2b:

Studies have not been done in either animals or humans {01}


Mutagenicity


Ribavirin:

Ribavirin showed increased incidences of mutation and cell transformation in multiple genotoxicity assays. It was shown to be active in the Balb/3T3 In vitro cell transformation assay. Ribavirin was shown to be mutagenic in the mouse lymphoma assay and at doses of 20 to 200 milligrams/kilogram (estimated human equivalent of 1.67 to 16.7 mg per kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24- hour dose of ribavirin) in a mouse lymphoma assay. However, a dominant lethal assaying rats has not shown that ribavirin is mutagenic {01}.



Interferon alfa-2b:

Studies have shown recombinant interferon alfa-2b is not mutagenic {01}.


Pregnancy/Reproduction
Fertility—
Reproductive toxicology studies demonstrate reproduction adverse effects for ribavirin and interferon alfa-2b when administered alone. Although data are lacking for both agents together, it should be assumed that the combination of these agents produces similar effects to either agent administered alone. {01}

Fertile women and partners of fertile women should not receive combination therapy consisting of ribavirin and recombinant interferon alfa-2b unless the patient and partner are using effective contraception (two reliable forms). Based on the half-life of a multiple dose of ribavirin (12 days), effective contraception must be used for 6 months post-treatment.

Ribavirin and recombinant interferon alfa-2b combination therapy should be used with caution in fertile men because studies in mice using this therapy resulted in abnormalities in sperm. Discontinuation of treatment resulted in total recovery from ribavirin-induced testicular toxicity within one or two spermatogenesis cycles.

Pregnancy—

Ribavirin

Ribavirin is not recommended during pregnancy. Risk-benefit must be carefully considered. {01}.

Studies in animals have shown that ribavirin causes significant embryocidal and/or teratogenic effects in animals. The effects occurred at doses as low as one twentieth of the recommended human dose. Studies demonstrate malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract. The incidence and severity of teratogenicity are dose-related. The survival of the fetuses and offspring was reduced. Studies in rats and rabbits demonstrated no effect in dose levels well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri-postnatal toxicity study in rats given oral doses of up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin)

Ribavirin accumulates in intracellular components from where it is cleared very slowly. It is unknown if teratogenic effects occur upon fertilization of the ova by a sperm containing ribavirin. Rat studies demonstrate that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent dose of 7.14 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times the maximum recommended human dose of ribavirin) {01}. Because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.



Interferon alfa-2b, recombinant

Adequate and well-controlled studies in humans have not been done. Studies in Macaca mulatta (rhesus) monkeys at doses of 15 to 30 million international (IU/kg) units/kilogram (estimated human equivalent of 5 and 10 million IU/kg) demonstrated an abortifacient effect. {01}


FDA Pregnancy Category X

Combination ribavirin and interferon alfa-2b must not be used by women who are pregnant or by men whose female partners are pregnant. Pregnancy must be avoided in female patients and in female partners of male patients taking combination therapy. Immediately prior to initiation of therapy a pregnancy test must be performed to confirm the female patient is not pregnant. Two forms of contraception must be used during treatment and during the 6 months after treatment in women of childbearing potential and men {01}.

Postpartum —
A peri/postnatal toxicity study in rats demonstrated no toxicity or effects on offspring when doses up to 1 milligram/kilogram/day (estimated human equivalent dose of 0.17 milligrams/kilograms based on body surface area or approximately 0.01 times the maximum recommended human 24 hour dose of ribavirin {01}

Breast-feeding

It is not known whether ribavirin and recombinant interferon alfa-2b are excreted in human breast milk. However, interferon is excreted into the milk of mice. Because of the potential for serious adverse effect, risk-benefit should be considered when administering to nursing women.

Pediatrics

Appropriate studies on the relationship of age to the effects of ribavirin and recombinant interferon alfa-2b combination have not been performed in pediatric patients younger than 18 years of age. Safety and efficacy have not been established {01}.


Geriatrics


No information is available on the relationship of age to the effects of ribavirin and recombinant interferon alfa-2b combination in geriatric patients {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Myelosuppressive agents    (Caution should be exercised when using interferon with other potentially myelosuppressive agents, including zidovudine, because additive bone marrow depression may occur{04}.)


Zidovudine    (In vitro studies have shown that, when combined, ribavirin is antagonistic to zidovudine's antiviral effect. Ribavirin and zidovudine should not be used concurrently{06}. )


Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Bilirubin, serum
Uric acid, serum    (moderate increases associated with hemolytic anemia; occurs most often in patients with Gilbert's syndrome; normalization of levels within 4 weeks of discontinuation.)


Hemoglobin
White blood cells
Platelets    (may be decreased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


This medication should not be used when the following medical problems exist (reasons given where appropriate; » = major clinical significance) :
» Hepatitis, autoimmune {01}
» Hypersensitivity to either ribavirin or alpha interferons{01}.    (Acute serious hypersensitivity reactions have been observed, if this develops therapy should be discontinued immediately and appropriate medical therapy started.)

{07}
Risk-benefit should be considered when the following medical problems exist (reasons given where appropriate; » = major clinical significance)
Autoimmune disease or
Psoriasis    (exacerbation of autoimmune disease and psoriasis has been reported in patients on alpha interferons {01})


» Anemia, severe or
» Cardiac disease    (Hemolytic anemia has been reported with a frequency of 10%. Anemia requires a dose reduction or discontinuation of both ribavirin and recombinant interferon alfa-2b. Anemia from ribavirin therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease {01})


Diabetes mellitus or
Hypertension     (Patients with diabetes or hypertension taking alpha interferons have experienced ophthalmic disorders [retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction in rare instances]. Patients on recombinant interferon alfa-2b have experienced diabetes mellitus and hyperglycemia {01})


» Hemoglobinopathies    (Hemoglobinopathies, including thalassemia and sickle-cell anemia, may worsen if the patient develops anemia from ribavirin therapy{01} )


Hepatitis C, chronic    (Monotherapy with ribavirin should not be used because of a lack of effect {01}.)


Pancreatitis    (Fatal and non-fatal pancreatitis has been observed in patients being treated with combination therapy. Therapy should be suspended in patients with signs and symptoms of pancreatitis and therapy should be discontinued in patients with confirmed pancreatitis.)

{07}
» Psychiatric illness    (Severe psychiatric events including depression , psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicide), and rare instances of homicidal ideation have occurred during combination therapy with ribavirin and interferon alfa-2b in both patients with and without a previous psychiatric illness. A patient who experiences moderate depression [persistent low mood, loss of interest, poor self-image, and/or hopelessness] should have the recombinant interferon alfa-2b dose temporarily discontinued or consider medical therapy. Ribavirin and recombinant interferon alfa-2b should be discontinued in patients who experience severe depression or suicidal ideation/attempt; close monitoring with medical management also recommended{01})

{07}
Pulmonary function impairment    (Pulmonary symptoms including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, including fatality, have been reported during therapy with ribavirin and recombinant interferon alfa-2b. Therapy may need to be discontinued if there is evidence of pulmonary infiltrates or pulmonary function impairment {01})


Renal impairment    (Caution is recommended in patients with a creatinine clearance of less than 50 milliliters/minute{01})


Transplantation, liver or other organ or
Hepatitis C, decompensated or
Hepatitis C, unresponsive to interferon therapy or
Hepatitis B, coinfection or
Human immunodeficiency virus, coinfection    (Safety and efficacy of ribavirin and interferon alfa-2b have not been established in these conditions{01})


Thyroid abnormalities    (Ribavirin and recombinant interferon alfa-2b should be discontinued in patients who develop thyroid abnormalities during treatment whose thyroid function cannot be controlled by medication {01})


Viral infections caused by human immunodeficiency virus, adenovirus, early respiratory syncytial virus, parainfluenza, or influenza    (Safety and efficacy of ribavirin monotherapy for the treatment of these viral infections have not been established; ribavirin monotherapy should not be used for these indications {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hematologic tests, standard—including hemoglobin    (should be monitored at baseline and week 2 and week 4 of therapy, and as clinically appropriate .)


Blood cell counts—complete and differential    (should be monitored at baseline and week 2 and week 4 of therapy, and as clinically appropriate)


{01}
Blood chemistries, including serum bilirubin concentration and serum uric acid determination
Liver function test
Thyroid function test
Psychiatric changes    ( Patients with and without a history of pre-existing psychiatric disorders should be carefully monitored for evidence of depression and other psychiatric symptoms.)

{07}
Pregnancy test    (prior to starting therapy and monthly monitoring for women of childbearing potential {01})


Electrocardiograms (ECG)    (baseline and during therapy in patients with pre-existing cardiac abnormalities and/or are in advanced stages of cancer {04})


Visual eye examination    (baseline visual eye examination is recommended in diabetic or hypertensive patients. Ophthalmic disorders [retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction in rare instances] have been reported with alpha interferons {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for immediate medical attention
Incidence more frequent
    
Chest pain {01}
depression {01}(mood changes), dyspnea {01}(trouble breathing), hemolytic anemia {01}(unusual tiredness or weakness)—hemoglobin level decreases occur at week 1 of therapy and stabilize by week 4
thyroid function abnormalities (usually asymptomatic ){01}—Approximately, 1% to 6% of patients without pre-existing thyroid abnormalities developed abnormalities requiring clinical intervention {01}.

Incidence rare
    
Suicidal behavior (thoughts of suicide)—ideation, attempts, and suicides have occurred with combination ribavirin and recombinant interferon alfa-2b and monotherapy alpha interferon in patients with and without a previous psychiatric illness {01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
alopecia {01}( thinning of the hair, temporary), anorexia {01}(loss of appetite), arthralgia {01}(joint pain), dizziness {01}
dyspepsia {01}(upset stomach), emotional lability {01}(large swing in moods), fatigue {01}
fever {01}
headache {01}
impaired concentration
impaired taste
influenza-like symptoms such as asthenia {01}(unusual tiredness or weakness), Injection site inflammation {01}(redness and warm feeling at the site of injection ), insomnia {01}(trouble sleeping), irritability {01}
myalgia or musculoskeletal pain {01}(muscle aches and pain), nausea or vomiting {01}
nervousness {01}
rash or pruritus {01}(red itchy skin ), rigors {01}(shaking ), sinusitis {01}{01}(headache ; stuffy nose){01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing)

Clinical effects of overdose
Adverse events were absent in a patient with the maximum reported overdose of 39 million units of recombinant interferon alfa-2b plus 10 grams of ribavirin {01}{02}.

Treatment of overdose
Supportive care including monitoring vital signs and observation of clinical status is recommended in overdose situations. There is no specific antidote for an overdose with ribavirin. Activated charcoal may be used to aid in removal of ribavirin, although no data exist to support this practice {02}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ribavirin and Interferon Alfa-2b, Recombinant (Systemic) .
Consider advising the patient on the following (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to ribavirin or alpha interferons

Pregnancy—Ribavirin is contraindicated during pregnancy





Breast-feeding—Consider risk-benefit before initiating combination ribavirin and recombinant interferon alfa-2b or continuing to breast-feed while on combination therapy



Use in adolescents—
Safety and efficacy have not been established in pediatric patients younger than 18 years of age

Medical problems especially, severe anemia, autoimmune hepatitis, cardiac disease, hemoglobinopathies, pancreatitis, and psychiatric illness

Proper use of this medication
» Using as directed by physician and reading patient package insert carefully with regard to:   —Preparation of the injection
   —Use of disposable syringes
   —Proper administration technique
   —Stability of the injection


Administration at bedtime to minimize inconvenience of fatigue

Patients should be well hydrated, especially during the initial stages of treatment

» Proper dosing
Skipping missed dose and going back to regular schedule; not doubling doses; checking with physician.

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician.

» Counseling women of childbearing potential on the importance of using two reliable forms of effective contraception

» Caution in taking alcohol or other central nervous system depressants during therapy

» Caution when driving or doing anything else requiring alertness because of possible fatigue and dizziness

» Importance of contacting physician if depression or suicidal tendencies occur

» Frequency of fever, headache, and flu-like symptoms; possible need for analgesics/antipyretics before and after a dose is given

Caution if bone marrow depression occurs
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising injury could occur

Follow-up
Emphasize the importance of follow-up with physician for the required laboratory tests


Side/adverse effects
» Signs of potential serious side adverse effects such as chest pain, depression, dyspnea, anemia, thyroid function abnormalities, and suicidal behavior and severe psychiatric adverse effects


General Dosing Information
Ribavirin capsules are administered orally and recombinant interferon alfa-2b injection is administered subcutaneously. Dosing of ribavirin is based on the patient's body weight. The duration of treatment is patient-specific based on baseline disease characteristics, response to therapy, and tolerability of the regimen. After 24 weeks of treatment, virologic response should be assessed. Discontinuation of treatment should be considered in any patient who has not achieved a HCV-RNA below the limit of detection of the assay by 24 weeks. Safety and efficacy data beyond 48 weeks in previously untreated patients and 24 weeks in relapse patients are unavailable {01}.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication {01}.

A negative pregnancy test must be obtained prior to initiating combination therapy with ribavirin and recombinant interferon alfa-2b {01}.

A puncture-resistant container for the disposal of used syringes and needles should be given to patients who will be administering recombinant interferon alfa-2b at home {01}.


Oral and Parenteral Dosage Forms

RIBAVIRIN and INTERFERON ALFA-2B, RECOMBINANT, CAPSULES and INJECTION

Usual Adult Dose
Hepatitis C, chronic (treatment)
Table 1 shows recommended dosing for both oral ribavirin and subcutaneous interferon alfa-2b, recombinant. The recommended duration of treatment for patients previously untreated with interferon is twenty-four to forty-eight weeks. For patients who relapse following interferon therapy, the recommended duration is twenty-four weeks.

Table 1. Recommended dosing {01}



Body weight*  Ribavirin capsules ORAL  interferon alfa-2b, recombinant injection SUBCUTANEOUSLY†† 
£ 75 kg  400 mg every morning 600 mg every evening  3 million IU 3 times a week  
> 75 kg  600 mg every morning 600 mg every evening  3 million IU 3 times a week  
*  kg=kilograms
 mg=milligrams
†† IU=International Units
.

Note: Ribavirin may be administered without regard to food {01}.

Table 2
shows the guidelines for dose modifications for both ribavirin and interferon based on hematological (hemoglobin, white blood cell count, neutrophil count and platelet count) abnormalities.

Table 2. Guidelines for Dose Modifications {01}



  Dose Reduction* Ribavirin 600 mg** daily interferon alfa-2b, recombinant 1.5 million IU*** three times weekly  Permanent Discontinuation of Treatment ribavirin and interferon alfa-2b, recombinant 
Hemoglobin  <10g/dL (ribavirin) Cardiac History patients only: ³2g/dL decrease during any 4–week period during treatment (ribavirin and interferon alfa-2b), recombinant   <8.5g/dL Cardiac History patients only: <12g/dL after 4 weeks of dose reduction  
White blood cell count ††  <1.5×109/L (interferon alfa-2b, recombinant)  <1.0×109/L 
Neutrophil count††  <0.75×109/L (interferon alfa-2b, recombinant)  <0.5×109/L 
Platelet††  <50×109/L (interferon alfa-2b, recombinant)  <25×109/L 
* Study medication to be dose reduced is shown in parenthesis.

**  mg=milligrams


**  IU=International Units


  g/dL=grams/deciliter


††  L=liters


Usual pediatric dose
Safety and effectiveness in patients younger than 18 years of age have not been established.

Strength(s) usually available
U.S.—



Ribavirin


200 milligrams (Rx) [Rebetol (Croscarmellose sodium) (lactose monohydrate ) (magnesium stearate) ( microcrystalline cellulose)]{01} [Rebetron (in combination with Intron A){01}]



Interferon alfa-2b, recombinant


3 million International Units (IU) per 0.5 mL (Rx) [Intron A (Albumin (human) free) ( m-cresol) (polysorbate 80)]{01} [Rebetron (in combination with Rebetol){01}]


18 million IU multidose vial (22.8 million IU per 3.8 milliliters (mL [3 million IU per 0.5 mL]) (Rx) [Intron A (Albumin (human) free) (m-cresol) ( polysorbate 80)]{01} [Rebetron (in combination with Rebetol){01}]


18 million IU multidose pen (22.5 million IU per 1.5 mL [3 million IU per 0.2 mL]) (Rx) [Intron A (Albumin (human) free) (m-cresol) (polysorbate 80)]{01} [Rebetron (in combination with Rebetol){01}]

Canada—



Ribavirin


200 milligrams (Rx) [Rebetol (Croscarmellose sodium) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose)]{02} [Rebetron (in combination with Intron A){02}]



Interferon alfa-2b


3 million International Units (IU) per 0.5 mL (Rx) [Intron A (Albumin (human) free) ( m-cresol) (polysorbate 80)]{02} [Rebetron (in combination with Rebetol){02}]

Packaging and storage:
Store capsules plus interferon alfa-2b combination between 2 and 8° C (36 and 46° F){01}{02}.

Ribavirin— When separated, ribavirin capsules should be stored in the refrigerator between 2 and 8° C (36 and 46° F) {01}{02} or at 25° C (77° F) {01}; excursions are permitted between 15 and 30° C (59 and 86° F) {01}{01}.

Interferon alfa-2b—

• When separated, the vials and the multidose pens should be stored in the refrigerator between 2 and 8° C (36 and 46° F){01}.


Stability:
Interferon alfa-2b recombinant injection in vials is stable at 35 °C (95 °F) for up to 7 days and at 30 °C (86 °F) for up to 14 days. Interferon alfa-2b recombinant injection in a multidose pen is stable at 30 °C (86 °F) for up to 2 days{01}{01}.



Developed: 10/1/1999
Revised: 05/16/2001



References
  1. Product Information: Rebetron(TM), ribavirin capsules and interferon alfa-2b, recombinant injection. Schering Corp., Kenilworth, NJ, USA, 12/98.
  1. Product Information: Rebetron, ribavirin capsules plus interferon alfa-2b solution for injection. Schering Canada Inc., Pointe-Claire, Quebec, Canada, 4/99.
  1. Lam NP: Hepatitis C: Natural history, diagnosis, and management. Am J Health-Syst Pharm 1999; 56:961–973.
  1. Product Information: Intron (R) A, interferon alfa-2b, recombinant injection. Schering Corp., Kenilworth, NJ, USA, 3/98.
  1. Wills RJ, Dennis S, Spiegel HE et al: Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection. Clin Pharmacol Ther 1984; 35:722-727.
  1. Product Information: Retrovir(R), zidovudine. GlaxoWellcome, Research Triangle Park, NC, USA, 9/96.
  1. Product Information: Rebetron(TM), ribavirin capsules and interferon alfa-2b, recombinant injection. Schering Corp., Kenilworth, NJ (PI revised 12/2000) PI reviewed 5/2001.
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