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Ribavirin Capsules, Tablets, Oral Solution

Ribavirin Inhalation Solution

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNINGS: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

• Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. (See WARNINGS).

• The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. (See WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

• Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Information for Patients and Pregnancy Category X).

USE OF AEROSOLIZED RIBAVIRIN IN PATIENTS REQUIRING MECHANICAL VENTILATOR ASSISTANCE SHOULD BE UNDERTAKEN VENTILATOR BEING USED AND THIS MODE OF ADMINISTRATION OF THE DRUG. STRICT ATTENTION MUST BE PAID PRECIPITATE, WHICH CAN RESULT IN MECHANICAL VENTILATOR DYSFUNCTION AND ASSOCIATED INCREASED PULMONARY SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH INITIATION OF AEROSOLIZED DURING TREATMENT. IF INITIATION OF AEROSOLIZED RIBAVIRIN TREATMENT APPEARS TO PRODUCE SUDDEN DETERIORATION ONLY WITH EXTREME CAUTION, CONTINUOUS MONITORING AND CONSIDERATION OF CONCOMITANT ADMINISTRATION RIBAVIRIN IS NOT INDICATED FOR USE IN ADULTS. PHYSICIANS AND PATIENTS SHOULD BE AWARE THAT RIBAVIRIN ALL ANIMAL SPECIES IN WHICH ADEQUATE STUDIES HAVE BEEN CONDUCTED (RODENTS AND RABBITS); (SEE CONTRAINDICATIONS).



1. DESCRIPTION

Ribavirin is a nucleoside analog with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C8H12N4O5 and the molecular weight is 244.21.

Ribavirin capsules (by SANDOZ) consist of white powder in a white, opaque, gelatin capsule. Each capsule, for oral administration, contains 200 mg ribavirin. In addition, each capsule contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol and povidone. The capsule shell consists of gelatin and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of FD&C Blue #2 aluminum lake, propylene glycol, shellac and titanium dioxide.

Ribavirin tablets (by TEVA) is available as a light-pink to pink, round standard normal convex, coated tablet for oral administration. Each tablet contains 200 mg of ribavirin and the following inactive ingredients: calcium phosphate dibasic, croscarmellose sodium, iron oxide black, iron oxide red, iron oxide yellow, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, talc, and titanium dioxide.

Ribavirin Oral Solution is a clear, colorless to pale or light yellow bubble gum-flavored liquid. Each milliliter of the solution contains 40 mg of ribavirin and the inactive ingredients sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.

Ribavirin for inhalation solution is a sterile, lyophilized powder to be reconstituted for aerosol administration. Each 100 mL glass vial contains 6 grams of ribavirin, and when reconstituted to the recommended volume of 300 mL with sterile water for injection or sterile water for inhalation (no preservatives added), will contain 20 mg of ribavirin per mL, pH approximately 5.5. Aerosolization is to be carried out in a Small Particle Aerosol Generator (SPAG-2) nebulizer only.

2. INDICATIONS AND USAGE

2.1 Ribavirin capsules and oral solution are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease.

2.2 Ribavirin tablets in combination with peginterferon alfa-2a are indicated for the treatment of patients 5 years of age and older with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha.

The following points should be considered when initiating ribavirin combination therapy with peginterferon alfa-2a:

• This indication is based on clinical trials of combination therapy in patients with CHC and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm3.

• This indication is based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks, based on HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.

• Safety and efficacy data are not available for treatment longer than 48 weeks.

• The safety and efficacy of ribavirin tablets and peginterferon alfa-2a therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy.

• The safety and efficacy of ribavirin therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Ribavirin should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

2.3 Ribavirin inlation solution is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy.

Only severe RSV lower respiratory tract infection should be treated with ribavirin. The vast majority of infants and children with RSV infection have disease that is mild, self-limited, and does not require hospitalization or antiviral treatment. Many children with mild lower respiratory tract involvement will require shorter hospitalization than would be required for a full course of ribavirin aerosol (3 to 7 days) and should not be treated with the drug. Thus the decision to treat with ribavirin should be based on the severity of the RSV infection. The presence of an underlying condition such as prematurity, immunosuppression or cardiopulmonary disease may increase the severity of clinical manifestations and complications of RSV infection.

Use of aerosolized ribavirin in patients requiring mechanical ventilator assistance should be undertaken only by physicians and support staff familiar with this mode of administration and the specific ventilator being used (seeWARNINGS, and DOSAGE AND ADMINISTRATION).

Diagnosis

RSV infection should be documented by a rapid diagnostic method such as demonstration of viral antigen in respiratory tract secretions by immunofluorescence or ELISA before or during the first 24 hours of treatment. Treatment may be initiated while awaiting rapid diagnostic test results. However, treatment should not be continued without documentation of RSV infection. Nonculture antigen detection techniques may have false positive or false negative results. Assessment of the clinical situation, the time of year and other parameters may warrant reevaluation of the laboratory diagnosis.

3. DOSAGE AND ADMINISTRATION

3.1 Ribavirin Capsules

Under no circumstances should ribavirin capsules be opened, crushed, or broken. Ribavirin capsules should be taken with food. Ribavirin capsules should not be used in patients with creatinine clearance less than 50 mL/min.

3.1.1 Ribavirin/INTRON A Combination Therapy

Adults

The recommended dose of PegIntron is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg ribavirin capsules orally based on patient body weight (see Table 1). The volume of PegIntron to be injected depends on the strength of PegIntron and patient’s body weight (see Table 1).

Duration of Treatment – Interferon Alpha-naïve Patients

The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks.

Duration of Treatment – Re-treatment with PegIntron/Ribavirin Capsules of Prior Treatment Failures

The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Table 1. Recommended Ribavirin Capsules/PegIntron Combination Therapy Dosing (Adults)

* When reconstituted as directed.

† For patients weighing greater than 105 kg (greater than 231 pounds), the PegIntron dose of 1.5 mcg/kg/week should be calculated based on the individual patient weight. Two vials of PegIntron may be necessary to provide the dose.

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Pediatric Patients

Dosing for pediatric patients is determined by body surface area for PegIntron and by body weight for ribavirin capsules. The recommended dose of PegIntron is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of ribavirin capsules orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving PegIntron/ribavirin capsules should remain on the pediatric dosing regimen. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

Table 2: Recommended Ribavirin Capsules* Dosing in Combination Therapy (Pediatrics)

3.1.2 Ribavirin Capsules/INTRON A Combination Therapy

Adults

Duration of Treatment – Interferon Alpha-naïve Patients

The recommended dose of INTRON A is 3 million IU three times weekly subcutaneously. The recommended dose of ribavirin capsules depends on the patient’s body weight (refer to Table 3). The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage, Adverse Reactions]. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

Duration of Treatment – Re-treatment with INTRON A/Ribavirin Capsules in Relapse Patients

In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

Table 3: Recommended Dosing

Pediatrics

The recommended dose of ribavirin capsules is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for pediatric dosing of ribavirin capsules in combination with INTRON A. INTRON A for Injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously. Refer to adult dosing table for greater than 61 kg body weight.

The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks.

3.1.3 Laboratory Tests

The following laboratory tests are recommended for all patients treated with ribavirin capsules, prior to beginning treatment and then periodically thereafter.

• Standard hematologic tests -including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions], complete and differential white blood cell counts, and platelet count.

• Blood chemistries -liver function tests and TSH.

• Pregnancy -including monthly monitoring for women of childbearing potential.

• ECG [see Warnings and Precautions].

3.1.4 Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin capsules/INTRON A therapy or ribavirin capsules/PegIntron therapy, modified, or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of PegIntron in adult patients on ribavirin capsules/PegIntron combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Dose reduction of PegIntron in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 4.

In the adult combination therapy study 2 dose reductions occurred in 42% of subjects receiving PegIntron 1.5 mcg/kg plus ribavirin capsules 800 mg daily including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with ribavirin capsules, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events [see Adverse Reactions].

Table 4: Two-Step Dose Reduction of PegIntron in Combination Therapy in Adults

* Must use vial. Minimum delivery for REDIPEN 0.3 mL.

† When reconstituted as directed.

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Dose reduction in pediatric patients is accomplished by modifying the recommended PegIntron dose in a two-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Table 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving PegIntron 60 mcg/m2 weekly plus ribavirin capsules 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended ribavirin capsules dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 5).

Ribavirin capsules should not be used in patients with creatinine clearance less than 50 mL/min. Subjects with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions, Use in Specific Populations].

Ribavirin capsules should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions].

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by greater than or equal to 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains less than 12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her ribavirin capsules dose modified or discontinued per Table 5 [see Warnings and Precautions].

Table 5: Guidelines for Dose Modification and Discontinuation of PegIntron, INTRON A or PegIntron/Ribavirin Capsules Based on Laboratory Parameters in Adults and Pediatrics

* For adult patients with a history of stable cardiac disease receiving PegIntron or INTRON A in combination with ribavirin, the PegIntron or INTRON A dose should be reduced by half and the ribavirin capsules dose by 200 mg/day if a greater than 2 g/dL decrease in hemoglobin is observed during any 4-week period. Both PegIntron and ribavirin capsules or INTRON A and ribavirin capsules should be permanently discontinued if patients have hemoglobin levels less than 12 g/dL after this ribavirin capsules dose reduction. Pediatric patients who have preexisting cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing.

† 1st dose reduction of ribavirin capsules is by 200 mg/day, except in patients receiving the 1400 mg dose it is by 400 mg/day; 2nd dose reduction of ribavirin capsules (if needed) is by an additional 200 mg/day.

‡ For patients on ribavirin capsules/PegIntron combination therapy: 1st dose reduction of PegIntron is to 1 mcg/kg/week, 2nd dose reduction (if needed) of PegIntron is to 0.5 mcg/kg/week. For patients on ribavirin capsules/INTRON A combination therapy, reduce INTRON A dose by 50%.

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Refer to the INTRON A Package Insert or PegIntron Powder for Injection Package Insert for additional information about how to reduce an INTRON A or PegIntron dose.

3.1.5 Discontinuation of Dosing

Adults

It is recommended that HCV genotype 1 interferon-alfa-naïve patients receiving PegIntron in combination with ribavirin, be discontinued from therapy if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable (greater than 10-20 IU/mL) after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Pediatrics (3-17 years of age)

It is recommended that patients receiving PegIntron/ribavirin capsules combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped less than 2 log10 compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA (greater than 10-20 IU/mL) at treatment Week 24.

3.2 Ribavirin Tablets

Ribavirin tablets should be taken with food. Ribavirin tablets should be given in combination with peginterferon alfa-2a; it is important to note that ribavirin tablets should never be given as monotherapy. See Peginterferon alfa-2a Package Insert for all instructions regarding peginterferon alfa-2a dosing and administration.

3.2.1 Chronic Hepatitis C Monoinfection

Adult Patients

The recommended dose of ribavirin tablets is provided in Table 6. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.

The daily dose of ribavirin is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 6).

Table 6. Peginterferon alfa-2a (PEGASYS®) and Ribavirin (COPEGUS®) Tablets Dosing Recommendations

Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks.

Data on genotypes 5 and 6 are insufficient for dosing recommendations.

* See Peginterferon alfa-2a Package Insert for further details on peginterferon alfa-2a dosing and administration, including dose modification in patients with renal impairment.

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Pediatric Patients

Peginterferon alfa-2a is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

Ribavirin tablets should be given in combination with peginterferon alfa-2a. Ribavirin is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for ribavirin are provided in Table 7. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.

Table 7. Ribavirin Tablets Dosing Recommendations for Pediatric Patients

* approximately 15 mg/kg/day

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3.2.2 Chronic Hepatitis C with HIV Coinfection

Adult Patients

The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is peginterferon alfa-2a 180 mcg subcutaneous once weekly and ribavirin tablets 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

3.2.3 Dose Modifications

Adult and Pediatric Patients

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin tablets/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, ribavirin tablets/peginterferon alfa-2a therapy should be discontinued. Table 8 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status.

Ribavirin tablets should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions].

Table 8. Ribavirin Tablet Dose Modification Guidelines in Adults and Pediatrics

The guidelines for ribavirin tablet dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once ribavirin tablet has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin tablets be increased to the original assigned dose (1000 mg to 1200 mg).

Pediatric Patients

Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in ribavirin tablet dose to the original dose may be attempted depending upon the physician’s judgment. If ribavirin has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin at one-half the full dose.

3.2.4 Renal Impairment

The total daily dose of ribavirin should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of peginterferon alfa-2a should be reduced for creatinine clearance less than 30 mL/min as follows in Table 9 [see Use in Specific Populations, Pharmacokinetics, and Peginterferon alfa-2a Package Insert].

Table 9. Dosage Modification for Renal Impairment

The dose of ribavirin should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, ribavirin should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting ribavirin, ribavirin tablets/peginterferon alfa-2a therapy should be discontinued.

No data are available for pediatric subjects with renal impairment.

3.2.5 Discontinuation of Dosing

Discontinuation of peginterferon alfa-2a/ribavirin tablets therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

Peginterferon alfa-2a/ribavirin tablets therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions].

3.3 Ribavirin Inhalation Solution

BEFORE USE, READ THOROUGHLY THE VALEANT SMALL PARTICLE AEROSOL GENERATOR SPAG-2 OPERATOR’S MANUAL FOR SMALL PARTICLE AEROSOL GENERATOR OPERATING INSTRUCTIONS. AEROSOLIZED RIBAVIRIN SHOULD NOT BE ADMINISTERED WITH ANY OTHER AEROSOL GENERATING DEVICE.

The recommended treatment regimen is 20 mg/mL ribavirin as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL the average aerosol concentration for a 12 hour delivery period would be 190 micrograms/liter of air. Aerosolized ribavirin should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.

Non-mechanically ventilated infants

Ribavirin should be delivered to an infant oxygen hood from the SPAG-2 aerosol generator. Administration by face mask or oxygen tent may be necessary if a hood cannot be employed (see SPAG-2 manual). However, the volume and condensation area are larger in a tent and this may alter delivery dynamics of the drug.

Mechanically Ventilated Infants

The recommended dose and administration schedule for infants who require mechanical ventilation is the same as for those who do not. Either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2. In either case, patients should have their endotracheal tubes suctioned every 1-2 hours, and their pulmonary pressures monitored frequently (every 2-4 hours). For both pressure and volume ventilators, heated wire connective tubing and bacteria filters in series in the expiratory limb of the system (which must be changed frequently, i.e., every 4 hours) must be used to minimize the risk of ribavirin precipitation in the system and the subsequent risk of ventilator dysfunction. Water column pressure release valves should be used in the ventilator circuit for pressure cycled ventilators, and may be utilized with volume cycled ventilators (SEE SPAG-2 MANUAL FOR DETAILED INSTRUCTIONS).

Method of Preparation

Ribavirin is supplied as 6 grams of lyophilized powder per 100 mL vial for aerosol administration only. By sterile technique, reconstitute drug with a minimum of 75 mL of sterile USP water for injection or inhalation in the original 100 mL glass vial. Shake well. Transfer to the clean, sterilized 500 mL SPAG-2 reservoir and further dilute to a final volume of 300 mL with Sterile Water for Injection, USP, or Inhalation. The final concentration should be 20 mg/mL. Important: This water should NOT have had any antimicrobial agent or other substance added. The solution should be inspected visually for particulate matter and discoloration prior to administration. Solutions that have been placed in the SPAG-2 unit should be discarded at least every 24 hours and when the liquid level is low before adding newly reconstituted solution.

4. CONTRAINDICATIONS

Ribavirin is contraindicated in:

• Women who are pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. Ribavirin is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions, Use in Specific Populations].

• Men whose female partners are pregnant.

• Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).

• In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug Interactions].

Ribavirin and peginterferon alfa-2a combination therapy is contraindicated in patients with:

• Autoimmune hepatitis.

• Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment [see Warnings and Precautions].

• Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see Warnings and Precautions].

• patients with creatinine clearance less than 50 mL/min. [see Use in Specific Populations].

• Coadministration of ribavirin capsules and didanosine is contraindicated as because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin [see Drug Interactions].

5. MECHANISM OF ACTION

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category X

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were 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 dosed orally at 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).

Treatment and Posttreatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses 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). However, 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.

Women of childbearing potential should not receive ribavirin unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months post-therapy based on a multiple-dose half-life (t½) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with ribavirin and for the 6-month post-therapy period (e.g., 15 half-lives for ribavirin clearance from the body).

Ribavirin Pregnancy Registry

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.

6.2 Nursing Mothers

It is not known whether the ribavirin product is excreted in human milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue ribavirin capsules.

6.3 Pediatric Use

Safety and effectiveness of ribavirin capsules in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with ribavirin capsules/INTRON A, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the safety findings observed.

Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see Warnings and Precautions]. As in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see Warnings and Precautions].

6.4 Geriatric Use

Clinical studies of ribavirin/INTRON A therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

Ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments should be made accordingly. Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See WARNINGS).

In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and/or cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (See WARNINGS).

6.5 Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

6.6 Renal Impairment

Renal function should be evaluated in all patients prior to initiation of ribavirin by estimating the patient’s creatinine clearance.

A clinical trial evaluated treatment with ribavirin and peginterferon alfa-2a in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, ribavirin was administered at a dose of 200 mg daily with no apparent difference in the adverse event profile in comparison to subjects with normal renal function. Dose reductions and temporary interruptions of ribavirin (due to ribavirin-related adverse reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects during treatment; and only one-third of these subjects received ribavirin for 48 weeks. Ribavirin plasma exposures were approximately 20% lower in subjects with ESRD on HD compared to subjects with normal renal function receiving the standard 1000/1200 mg ribavirin daily dose.

Subjects with moderate (n=17) or severe (n=14) renal impairment did not tolerate 600 mg or 400 mg daily doses of ribavirin, respectively, due to ribavirin-related adverse reactions, mainly anemia, and exhibited 20 to 30% higher ribavirin plasma exposures (despite frequent dose modifications) compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of ribavirin. Discontinuation rates were higher in subjects with severe renal impairment compared to that observed in subjects with moderate renal impairment or normal renal function. Pharmacokinetic modeling and simulation indicates that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma ribavirin exposure similar to patients with normal renal function receiving the approved regimen of ribavirin. These doses have not been studied in patients [see Dosage and Administration, Use in Specific Populations].

Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of ribavirin; and patients with creatinine clearance less than 30 mL/min should receive a reduced dose of peginterferon alfa-2a. The clinical and hematologic status of patients with creatinine clearance less than or equal to 50 mL/min receiving ribavirin should be carefully monitored. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn [see Dosage and Administration].

6.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.

6.8 Gender

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects. Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

6.9 Organ Transplant Recipients

The safety and efficacy of peginterferon alfa-2a and ribavirin treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on peginterferon alfa-2a, alone or in combination with ribavirin [see Adverse Reactions].

6.10 HIV or HBV Co-infection

The safety and efficacy of PegIntron/ribavirin capsules and INTRON A/ribavirin capsules for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

7. WARNINGS AND PRECAUTIONS

Significant adverse reactions associated with ribavirin/peginterferon alfa-2a combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.

The Peginterferon alfa-2a Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.

7.1 Pregnancy

Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin.

Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during ribavirin therapy and for 6 months after therapy has stopped [see Boxed Warning, Contraindications, Use in Specific Populations].

7.2 Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding) [see Dosage and Administration].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin [see Boxed Warning and Dosage and Administration].

7.3 Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with peginterferon alfa-2a/ribavirin should be discontinued immediately in patients with hepatic decompensation [see Contraindications].

7.4 Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions].

7.5 Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, patients should be closely monitored and, if appropriate, combination ribavirin/peginterferon alfa-2a treatment should be discontinued.

7.6 Bone Marrow Suppression

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Peginterferon alfa-2a, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions].

7.7 Pancreatitis

Ribavirin and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

7.8 Impact on Growth in Pediatric Patients

Pediatric subjects treated with peginterferon alfa-2a plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

7.9 Ophthalmologic Disorders

Ribavirin is used in combination therapy with alpha interferons. Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by treatment with alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferon treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

7.10 Dental and Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ribavirin capsules and interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations If vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards.

7.11 Concomitant Administration of Azathioprine

Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PegIntron, ribavirin capsules, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be reintroduced with concomitant azathioprine [see Drug Interactions].

7.12 Impact on Growth - Pediatric Use

Data on the effects of PegIntron plus ribavirin capsules on growth come from an open-label study in subjects 3 through 17 years of age, and weight and height changes are compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron plus ribavirin capsules lags behind that predicted by normative population data for the entire length of treatment. After about 6 months posttreatment (Follow-Up Week 24), subjects had weight gain rebounds and regained their weight to 53rd percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57th percentile). After about 6 months posttreatment, height gain stabilized and subjects treated with PegIntron plus ribavirin capsules had an average height percentile of 44th percentile, which was less than the average of the normative population and less than their average baseline height (51st percentile). Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment. Of the subjects experiencing severely inhibited growth, 20% had continued inhibited growth velocity (less than 3rd percentile) after 6 months of follow-up.

Among the boys studied, the age groups of 3-11 years old and 12-17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months posttreatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3-11 years old and treated for 48 weeks had the largest average drop in height and weight percentiles (13 percentiles and 7 percentiles, respectively), whereas girls 12-17 years old continued along their average baseline height and weight percentiles after 6 months posttreatment.

7.13 Usage Safeguards

Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, ribavirin capsules or oral solution must not be used alone. The safety and efficacy of ribavirin capsules and oral solution have only been established when used together with INTRON A or PegIntron (not other interferons) as a combination therapy.

The safety and efficacy of ribavirin capsules/INTRON A and PegIntron therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. Ribavirin capsules should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

There are significant adverse reactions caused by ribavirin capsules/INTRON A or PegIntron therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. The INTRON A and PegIntron package inserts should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

7.14 Laboratory Tests

Before beginning peginterferon alfa-2a/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

• Platelet count greater than or equal to 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)

• Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm3

• TSH and T4 within normal limits or adequately controlled thyroid function

• CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5,000 cells/mm3 in patients coinfected with HIV

• Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected patients

• Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV

Information for Patients

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking ribavirin. Ribavirin should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS and WARNINGS).

If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the teratogenic risk of ribavirin therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians should report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.

Patients receiving ribavirin capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient MEDICATION GUIDE for ribavirin capsules. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

The most common adverse experience occurring with ribavirin capsules is anemia, which may be severe. (See ADVERSE REACTIONS). Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter. (See Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.

Ribavirin Inhalation Solution: Information for Health Care Personnel

Health care workers directly providing care to patients receiving aerosolized ribavirin should be aware that ribavirin has been shown to be teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits). Although no reports of teratogenesis in offspring of mothers who were exposed to aerosolized ribavirin during pregnancy have been confirmed, no controlled studies have been conducted in pregnant women. Studies of environmental exposure in treatment settings have shown that the drug can disperse into the immediate bedside area during routine patient care activities with highest ambient levels closest to the patient and extremely low levels outside of the immediate bedside area. Adverse reactions resulting from actual occupational exposure in adults are described below (see Adverse Events in Health Care Workers). Some studies have documented ambient drug concentrations at the bedside that could potentially lead to systemic exposures above those considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the most sensitive animal species).

A 1992 study conducted by the National Institute of Occupational Safety and Health (NIOSH) demonstrated measurable urine levels of ribavirin in health care workers exposed to aerosol in the course of direct patient care. Levels were lowest in workers caring for infants receiving aerosolized ribavirin with mechanical ventilation and highest in those caring for patients being administered the drug via an oxygen tent or hood. This study employed a more sensitive assay to evaluate ribavirin levels in urine than was available for several previous studies of environmental exposure that failed to detect measurable ribavirin levels in exposed workers. Creatinine adjusted urine levels in the NIOSH study ranged from less than 0.001 to 0.140 μM of ribavirin per gram of creatinine in exposed workers. However, the relationship between urinary ribavirin levels in exposed workers, plasma levels in animal studies, and the specific risk of teratogenesis in exposed pregnant women is unknown.

It is good practice to avoid unnecessary occupational exposure to chemicals wherever possible. Hospitals are encouraged to conduct training programs to minimize potential occupational exposure to ribavirin. Health care workers who are pregnant should consider avoiding direct care of patients receiving aerosolized ribavirin. If close patient contact cannot be avoided, precautions to limit exposure should be taken. These include administration of ribavirin in negative pressure rooms; adequate room ventilation (at least six air exchanges per hour); the use of ribavirin aerosol scavenging devices; turning off the SPAG-2 device for 5 to 10 minutes prior to prolonged patient contact; and wearing appropriately fitted respirator masks. Surgical masks do not provide adequate filtration of ribavirin particles. Further information is available from NIOSH’s Hazard Evaluation and Technical Assistance Branch and additional recommendations have been published in an Aerosol Consensus Statement by the American Respiratory Care Foundation and the American Association for Respiratory Care.

8. ADVERSE REACTIONS

8.1 Ribavirin Capsules/Tablets/Oral Solution

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. (See WARNINGS). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients (See WARNINGS).

Ribavirin/INTRON A Combination Therapy

In clinical trials, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-emergent adverse events that occurred in the US studies with ≥5% incidence are provided in Table 10 by treatment group. In general, the selected treatment-emergent adverse events were reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.

Table 10. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Adult Patients

*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.

In addition, the following spontaneous adverse events have been reported during the marketing surveillance of ribavirin/INTRON A therapy: hearing disorder and vertigo.

Laboratory Values

Ribavirin/INTRON A Combination Therapy

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below.

Hemoglobin

Hemoglobin decreases among patients receiving ribavirin therapy began at Week 1, with stabilization by Week 4. In previously untreated patients treated for 48 weeks, the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse patients, the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the international study. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most patients.

Bilirubin and Uric Acid

Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in patients with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 11. Selected Hematologic Values During Treatment with Ribavirin Capsules plus INTRON A: Previously Untreated and Relapse Adult Patients

Postmarketing Experiences

The following adverse reactions have been identified during the post approval use of ribavirin capsules in combination with INTRON A: hearing disorder, vertigo, aplastic anemia and pure red cell aplasia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

8.2 Ribavirin Inhalation Solution

Deaths

Deaths during or shortly after treatment with aerosolized ribavirin have been reported in 20 cases of patients treated with ribavirin (12 of these patients were being treated for RSV infections). Several cases have been characterized as “possibly related” to ribavirin by the treating physician; these were in infants who experienced worsening respiratory status related to bronchospasm while being treated with the drug. Several other cases have been attributed to mechanical ventilator malfunction in which ribavirin precipitation within the ventilator apparatus led to excessively high pulmonary pressures and diminished oxygenation. In these cases the monitoring procedures described in the current package insert were not employed (seeDescription of Studies,WARNINGS, and DOSAGE AND ADMINISTRATION).

Pulmonary and Cardiovascular

Pulmonary function significantly deteriorated during aerosolized ribavirin treatment in six of six adults with chronic obstructive lung disease and in four of six asthmatic adults. Dyspnea and chest soreness were also reported in the latter group. Minor abnormalities in pulmonary function were also seen in healthy adult volunteers.

In the original study population of approximately 200 infants who received aerosolized ribavirin, several serious adverse events occurred in severely ill infants with life-threatening underlying diseases, many of whom required assisted ventilation. The role of ribavirin in these events is indeterminate. Since the drug’s approval in 1986, additional reports of similar serious, though non-fatal, events have been filed infrequently. Events associated with aerosolized ribavirin use have included the following:

Pulmonary: Worsening of respiratory status, bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis and ventilator dependence.

Cardiovascular: Cardiac arrest, hypotension, bradycardia and digitalis toxicity. Bigeminy, bradycardia and tachycardia have been described in patients with underlying congenital heart disease.

Some subjects requiring assisted ventilation experienced serious difficulties, due to inadequate ventilation and gas exchange.

Precipitation of drug within the ventilatory apparatus, including the endotracheal tube, has resulted in increased positive end expiratory pressure and increased positive inspiratory pressure. Accumulation of fluid in tubing (“rain out”) has also been noted.

Measures to avoid these complications should be followed carefully (see DOSAGE AND ADMINISTRATION).

Hematologic

Although anemia was not reported with use of aerosolized ribavirin in controlled clinical trials, most infants treated with the aerosol have not been evaluated 1 to 2 weeks post-treatment when anemia is likely to occur. Anemia has been shown to occur frequently with experimental oral and intravenous ribavirin in humans. Also, cases of anemia (type unspecified), reticulocytosis and hemolytic anemia associated with aerosolized ribavirin use have been reported through post-marketing reporting systems. All have been reversible with discontinuation of the drug.

Other

Rash and conjunctivitis have been associated with the use of aerosolized ribavirin. These usually resolve within hours of discontinuing therapy. Seizures and asthenia associated with experimental intravenous ribavirin therapy have also been reported.

Adverse Events in Health Care Workers

Studies of environmental exposure to aerosolized ribavirin in health care workers administering care to patients receiving the drug have not detected adverse signs or symptoms related to exposure. However, 152 health care workers have reported experiencing adverse events through post-marketing surveillance. Nearly all were in individuals providing direct care to infants receiving aerosolized ribavirin. Of 358 events from these 152 individual health care worker reports, the most common signs and symptoms were headache (51% of reports), conjunctivitis (32%), and rhinitis, nausea, rash, dizziness, pharyngitis, or lacrimation (10-20% each). Several cases of bronchospasm and/or chest pain were also reported, usually in individuals with known underlying reactive airway disease. Several case reports of damage to contact lenses after prolonged close exposure to aerosolized ribavirin have also been reported. Most signs and symptoms reported as having occurred in exposed health care workers resolved within minutes to hours of discontinuing close exposure to aerosolized ribavirin (also see Information for Health Care Personnel).

The symptoms of RSV in adults can include headache, conjunctivitis, sore throat and/or cough, fever, hoarseness, nasal congestion and wheezing, although RSV infections in adults are typically mild and transient. Such infections represent a potential hazard to uninfected hospital patients. It is unknown whether certain symptoms cited in reports from health care workers were due to exposure to the drug or infection with RSV. Hospitals should implement appropriate infection control procedures.

8.3 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a/ribavirin combination therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System disorders: Pure red cell aplasia

Ear and Labyrinth disorders: Hearing impairment, hearing loss

Eye disorders: Serous retinal detachment

Immune disorders: Liver and renal graft rejection

Metabolism and Nutrition disorders: Dehydration

Skin and Subcutaneous Tissue disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

9. OVERDOSAGE

There is limited experience with overdosage. Acute ingestion of up to 20 grams of ribavirin capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse events related to the therapeutic use of INTRON A and ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

There is no specific antidote for INTRON A or ribavirin, and hemodialysis and peritoneal dialysis are not effective treatment of overdose of either agent.

No overdosage with ribavirin by aerosol administration has been reported in humans. The LD50 in mice is 2 g orally and is associated with hypoactivity and gastrointestinal symptoms (estimated human equivalent dose of 0.17 g/kg, based on body surface area conversion). The mean plasma half-life after administration of aerosolized ribavirin for pediatric patients is 9.5 hours. Ribavirin is concentrated and persists in red blood cells for the life of the erythrocyte (see Pharmacokinetics).

10. DRUG INTERACTIONS

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.

10.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients.

In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions].

Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, ribavirin or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see Warnings and Precautions and Dosage and Administration].

Didanosine

Co-administration of ribavirin and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications].

Zidovudine

In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.

10.2 Drugs Metabolized by Cytochrome P450

In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

10.3 Azathioprine

The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions].

11. PHARMACOKINETICS

11.1 Ribavirin Capsules/Tablets/Oral Solution

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 12. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUCtf (AUC from time zero to last measurable concentration) following single doses of 200 to 1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400 to 600 mg.

Upon multiple oral dosing, based on AUC12 hr, a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

In this section of the label, numbers in parenthesis indicate % coefficient of variation.

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when ribavirin capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies with ribavirin/INTRON® A (interferon alfa-2b, recombinant) were conducted without instructions with respect to food consumption. During clinical studies with ribavirin/INTRON A, all subjects were instructed to take ribavirin capsules with food. (See DOSAGE AND ADMINISTRATION).

Effect of Antacid on Absorption of Ribavirin

Coadministration of ribavirin capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta®) resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

Table 12. Mean (% CV) Pharmacokinetic Parameters for Ribavirin Capsules when Administered Individually to Adults

*N=11

†ng/mL

‡ng•hr/mL

§data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N=5

¶N=6

_____________________________________________________________

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzymemediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A injection and ribavirin capsules in a multiple-dose pharmacokinetic study.

11.2 Ribavirin Inhalation Solution

Assay for ribavirin in human materials is by a radioimmunoassay which detects ribavirin and at least one metabolite.

Ribavirin, when administered by aerosol, is absorbed systemically. Four pediatric patients inhaling ribavirin aerosol administered by face mask for 2.5 hours each day for 3 days had plasma concentrations ranging from 0.44 to 1.55 μM, with a mean concentration of 0.76 μM. The plasma half-life was reported to be 9.5 hours. Three pediatric patients inhaling aerosolized ribavirin administered by face mask or mist tent for 20 hours each day for 5 days had plasma concentrations ranging from 1.5 to 14.3 μM, with a mean concentration of 6.8 μM.

The bioavailability of aerosolized ribavirin is unknown and may depend on the mode of aerosol delivery. After aerosol treatment, peak plasma concentrations of ribavirin are 85% to 98% less than the concentration that reduced RSV plaque formation in tissue culture. After aerosol treatment, respiratory tract secretions are likely to contain ribavirin in concentrations many fold higher than those required to reduce plaque formation. However, RSV is an intracellular virus and it is unknown whether plasma concentrations or respiratory secretion concentrations of the drug better reflect intracellular concentrations in the respiratory tract.

In man, rats, and rhesus monkeys, accumulation of ribavirin and/or metabolites in the red blood cells has been noted, plateauing in red cells in man in about 4 days and gradually declining with an apparent half-life of 40 days (the half-life of erythrocytes). The extent of accumulation of ribavirin following inhalation therapy is not well defined.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names:

COPEGUS (Tablets), by ROCHE.

REBETOL (Capsules), by SCHERING PLOUGH RES.

REBETOL (Oral Solution), by SCHERING PLOUGH RES.

VIRAZOLE (Powder for Inhalation Solution), by VALEANT PHARM INTL.

b) Generic drugs:

Capsules: RIBAVIRIN (by various manufacturers), RIBASPHERE (by THREE RIVERS PHARMS).

Tablets: RIBAVIRIN (by various manufacturers).

Oral Solution: No generic.

Powder for Inhalation Solution: No generic.

2) How Supplied:

Ribavirin capsules (by SANDOZ), 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608
on body, and are supplied as follows:

NDC 0781-2043-42 in bottles of 42 capsules
NDC 0781-2043-16 in bottles of 56 capsules
NDC 0781-2043-67 in bottles of 70 capsules
NDC 0781-2043-04 in bottles of 84 capsules
NDC 0781-2043-01 in bottles of 100 capsules
NDC 0781-2043-28 in bottles of 168 capsules
NDC 0781-2043-10 in bottles of 1000 capsules
NDC 0781-2043-13 in unit dose package of 100 capsules

Ribavirin tablets (by TEVA), 200 mg for oral administration are available as follows:

Each tablet contains 200 mg of ribavirin and is light-pink to pink, round standard normal convex, coated tablet, debossed with “93” on one side and “7232” on the other side in bottles of 168.

REBETOL Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble gum-flavored liquid and it is packaged in 4-oz amber glass bottles (100 mL/bottle) with child-resistant closures (NDC 0085-1318-01).

VIRAZOLE (Ribavirin for Inhalation Solution, USP) is supplied in four packs containing 100 mL glass vials with 6 grams of Sterile, lyophilized drug (NDC 0187-0007-14) which is to be reconstituted with 300 mL Sterile Water for Injection or Sterile Water for Inhalation (no preservatives added) and administered only by a small particle aerosol generator (SPAG-2).

3) Storage:

Store capsules and tablets at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

REBETOL Oral Solution should be stored between 2° to 8°C (36° to 46°F) or at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Vials containing the lyophilized drug powder should be stored in a dry place at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Reconstituted solutions may be stored, under sterile conditions, at room temperature (20-30°C, 68-86°F) for 24 hours. Solutions which have been placed in the SPAG-2 unit should be discarded at least every 24 hours.

Rx only

Rev 02/13