Ribavirin

Pronunciation

Pronunciation: RYE-ba-VYE-rin
Class: Antiviral agent

Trade Names

Copegus
- Tablets, oral 200 mg

Rebetol
- Capsules, oral 200 mg
- Solution, oral 40 mg/mL

Ribasphere
- Tablets, oral 200 mg
- Tablets, oral 400 mg
- Tablets, oral 600 mg
- Capsules, oral 200 mg

Virazole
- Lyophilized powder for solution, inhalation 6 g

Pharmacology

Has antiviral inhibitory activity against respiratory syncytial virus (RSV), influenza A and B, and herpes simplex virus. Exact mechanism is unknown.

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Pharmacokinetics

Absorption

Inhalation

Absorbed systemically. Bioavailability depends on the mode of aerosol delivery.

Capsules/Oral solution

Rapidly and extensively absorbed. Absolute bioavailability averaged 64%. Following dosing with 600 mg twice daily, steady state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2,200 ng/mL.

Tablets

T max following multiple doses is 2 h and C max is 2,748 ng/mL. AUC is 25,361 ng•h/mL.

Distribution

Ribavirin does not bind to plasma proteins.

Inhalation

Highest concentrations were found in the respiratory tract and erythrocytes.

Metabolism

Metabolized to deribosylated ribavirin in the liver.

Elimination

Inhalation

The half-life is 40 days (half-life of erythrocytes). Plasma half-life is 9.5 h.

Capsules/Oral solution

After oral administration, approximately 61% and 12% was eliminated in the urine and feces, respectively, in 336 h. Unchanged ribavirin accounted for 17% of the administered dose. Upon discontinuation of dosing, the mean half-life was 298 h.

Tablets

After a single oral dose, the terminal half-life is 120 to 170 h and apparent Cl is 26 L/h.

Special Populations

Renal Function Impairment
Capsules/Oral solution

The mean AUC tf value was 3-fold greater in subjects with CrCl values between 10 and 30 mL/min compared with control subjects (CrCl more than 90 mL/min). In subjects with CrCl values between 30 and 60 mL/min, AUC tf was 2-fold greater compared with control subjects. Ribavirin is not effectively removed by hemodialysis. Do not use oral ribavirin to treat patients with CrCl less than 50 mL/min.

Copegus

Cl was reduced in patients with CrCl less than 50 mL/min compared with patients with healthy renal function. Plasma exposure was decreased 20% in patients with ESRD on chronic hemodialysis. Dosage adjustment is recommended.

Hepatic Function Impairment

C max increases with increasing severity of hepatic impairment.

Elderly

Pharmacokinetic evaluations have not been performed.

Children

Pharmacokinetic parameters are similar between adults and children.

Gender

Pharmacokinetics are similar in men and women.

Race

No differences in pharmacokinetics have been demonstrated.

Indications and Usage

Capsules/Oral solution

In combination with interferon alfa-2b for the treatment of chronic hepatitis C in patients 3 y and older with compensated liver disease.

Inhalation

Treatment of hospitalized infants and young children with severe lower respiratory tract infections caused by RSV.

Tablets

In combination with peginterferon alfa-2a for the treatment of adults with chronic hepatitis C virus (HCV) infection who have compensated liver disease and have not been previously treated with interferon alpha; may be used in patients coinfected with HIV.

Unlabeled Uses

Treatment of viral hemorrhagic fevers, such as Crimean-Congo hemorrhagic fever. Ribavirin inhalation has shown some success against influenza A and B viruses and herpes simplex virus.

Contraindications

Women who are pregnant or men whose female partners are pregnant; hypersensitivity to ribavirin or any component of the product.

Capsules/Oral solution/Tablets

Patients with hemoglobinopathies (eg, thalassemia major or sickle cell anemia); CrCl less than 50 mL/min (capsules/oral solution); coadministration with didanosine.

Combination therapy with interferon alfa (additional contraindications)

Autoimmune hepatitis; in cirrhotic chronic HCV monoinfected patients with hepatic decompensation (Child-Pugh class B and C) before treatment; cirrhotic chronic HCV patients coinfected with HIV who have hepatic decompensation (Child-Pugh class B or C) before treatment.

Dosage and Administration

Chronic HCV
Capsules/Oral Solution Adults With interferon alfa-2b 75 kg or less

PO 400 mg in the morning and 600 mg in the evening.

76 kg or more

PO 600 mg in the morning and evening.

Duration of therapy

For patients previously untreated with ribavirin and interferon, duration is 24 to 48 weeks. For patients who relapsed following nonpegylated interferon monotherapy, duration is 24 weeks.

With peginterferon alfa-2b Less than 40 to 65 kg

400 mg in the morning and 400 mg in the evening.

66 to 80 kg

400 mg in the morning and 600 mg in the evening.

81 to 105 kg

600 mg in the morning and 600 mg in the evening.

More than 105 kg

600 mg in the morning and 800 mg in the evening.

Duration of therapy Interferon alpha–naive patients

48 weeks for patients with genotype 1; 24 weeks for genotypes 2 and 3.

Re-treatment of prior treatment failures

48 weeks.

Children 3 y and older Capsules/Oral solution

PO 15 mg/kg/day in divided doses in the morning and evening for children weighing less than 62 kg. For children with genotype 1, treat for 48 weeks. For genotypes 2 and 3, treat for 24 weeks.

Tablets Adults Genotype 1, 4

PO 1,000 mg/day in 2 divided doses for patients weighing 74 kg or less and 1,200 mg for patients weighing 75 kg or more. Duration is 48 weeks.

Genotype 2, 3

PO 800 mg/day in 2 divided doses for 24 weeks.

Dose Modification Tablets Adults

In patients whose Hgb levels fall below 10 g/dL, reduce the dosage to 600 mg/day (200 mg in the morning and 400 mg in the evening). Permanently discontinue in patients whose Hgb levels fall below 8.5 g/dL. In patients with a history of stable CV disease, a dosage reduction to 600 mg/day is required if the Hgb decreased by 2 g/dL or more during any 4-wk treatment period. Permanently discontinue therapy in patients with cardiac history if the Hgb remains less than 12 g/dL after 4 wk on a reduced dose. Once ribavirin has been withheld because of clinical manifestation or laboratory abnormality, an attempt may be made to restart ribavirin at 600 mg/day with a further increase in the dosage to 800 mg/day. Increasing the dose to the original assigned dose of 1,000 to 1,200 mg is not recommended.

Capsules/Oral solution Adults

In patients whose Hgb levels fall below 10 g/dL, reduce the dosage by 200 mg/day (in patients receiving the 1,400 mg dose, reduce dosage by 400 mg/day); the second dose reduction, if needed, is by 200 mg/day. Permanently discontinue in patients whose Hgb levels fall below 8.5 g/dL, WBC falls below 1 × 10 9 /L, neutrophils fall below 0.5 × 10 9 /L, or platelets fall below 25 × 10 9 /L. In patients with a history of stable CV disease, reduce dosage by 200 mg/day if the Hgb decreased by 2 g/dL or more during any 4-wk treatment period. Permanently discontinue therapy in patients with cardiac history if the Hgb remains less than 12 g/dL after 4 wk on a reduced dose.

Children

Modify the recommended dose from the original starting dosages of 15 mg/kg daily in a 2-step process to 12 mg/kg/day, then to 8 mg/kg/day if needed. Permanently discontinue in patients whose Hgb falls below 8.5 g/dL, WBC falls below 1 × 10 9 /L, neutrophils fall below 0.5 × 10 9 /L, creatinine is more than 2 mg/dL, or platelets fall below 50 × 10 9 /L.

Discontinuation of Therapy Ribavirin/Interferon alfa-2b

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.

Ribavirin/Peginterferon alfa-2b Adults

Consider discontinuation in HCV genotype 1 interferon alfa–naive patients who do not achieve at least a 2 log 10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable (greater than 10 to 20 units/mL) after 24 weeks of therapy. Regardless of genotype, previously treated patients who have a detectable HCV-RNA at 12 or 24 weeks should have treatment discontinued.

Children

Consider discontinuation in patients (excluding genotypes 2 and 3) who do not achieve at least a 2 log 10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable (greater than 10 to 20 units/mL) after 24 weeks of therapy.

Ribavirin/Peginterferon alfa-2a

Consider discontinuation in patients who do not achieve at least a 2 log 10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable (greater than 10 to 20 units/mL) after 24 weeks of therapy.

Chronic HCV With HIV Coinfection
Tablets Adults

PO 800 mg/day for 48 weeks.

Respiratory Syncytial Virus
Infants and Young Children

Inhalation 20 mg/mL as the starting solution in the drug reservoir of the small-particle aerosol generator (SPAG-2) unit, with continuous administration for 12 to 18 h per day for 3 to 7 days.

Renal function impairment
Copegus Adults PO CrCl 30 to 50 mL/min

Alternating doses, 200 and 400 mg every other day.

CrCl less than 30 mL/min and hemodialysis

200 mg daily.

Rebetol / Ribasphere

Do not use in patients with CrCl less than 50 mL/min.

General Advice

  • Administer with food. Do not open, crush, or break the capsules.
  • If severe adverse reactions or laboratory abnormalities develop during treatment, modify or discontinue the dose, if appropriate, until adverse reactions subside. If intolerance persists after dosage adjustment, discontinue therapy with these agents.
  • Inhalation
  • For use with the Valeant SPAG-2 only.
  • Reconstitute with a minimum of 75 mL of sterile 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 or inhalation. The final concentration should be 20 mg/mL.
  • Sterile water for injection or inhalation 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 h and when the liquid level is low before adding newly reconstituted solution.
  • Do not administer in a mixture for combined aerosolization or simultaneously with other aerosolized medications.
  • Mechanically ventilated infants — 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 to 2 h and their pulmonary pressures monitored frequently (every 2 to 4 h). For 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 [ie, every 4 h]) 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.
  • Nonmechanically ventilated infants — Deliver ribavirin 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. However, the volume and condensation area are larger in a tent, which may alter delivery dynamics of the drug.

Storage/Stability

Store capsules and tablets between 59° and 86°F. Store oral solution between 36° and 46°F or at 77°F. Store lyophilized powder in a dry place between 59° and 86°F. Reconstituted inhalation solutions may be stored under sterile conditions between 68° and 86°F for 24 h.

Drug Interactions

Antacids

Coadministration of ribavirin capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUC. The clinical importance is unknown.

Didanosine

Coadministration is contraindicated because of risk of fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis.

Lamivudine, stavudine, zidovudine

Ribavirin may antagonize the in vitro antiviral activity of lamivudine, stavudine, and zidovudine against HIV. Combination therapy with zidovudine, ribavirin, and peginterferon alfa-2a resulted in severe neutropenia and severe anemia. Use with caution. Monitor closely for treatment-associated toxicities.

Thiopurines (eg, azathioprine, mercaptopurine)

The risk of thiopurine-related myelosuppression (eg, pancytopenia) may be increased. If coadministration cannot be avoided, closely monitor for myelosuppression.

Warfarin

The anticoagulant action of warfarin may be decreased by oral ribavirin administration. Monitor INR closely during the first 4 weeks of combination therapy and upon discontinuation.

Adverse Reactions

The following adverse reactions were reported with combined use of ribavirin and peginterferon alfa-2a or interferon alfa-2b. The incidence is not specified for aerosolized ribavirin.

Cardiovascular

Bigeminy, bradycardia, tachycardia (in patients with underlying congenital heart disease); cardiac arrest; digitalis toxicity; hypotension; pulmonary hypertension (postmarketing).

CNS

Fatigue (70%); headache (69%); asthenia/fatigue (68%); rigors (48%); anxiety/emotional lability/irritability (47%); insomnia (41%); anxiety/irritability/nervousness (38%); depression (36%); dizziness (26%); impaired concentration (21%); mood alteration (9%); agitation (8%); impaired memory, malaise (6%); aggression (3%); anger, suicidal ideation or attempt (2%); seizures.

Dermatologic

Alopecia (36%); rash (34%); pruritus (29%); dry skin (24%); dermatitis (16%); increased sweating (11%); eczema (5%); flushing (4%); Stevens-Johnson syndrome, TEN (postmarketing).

EENT

Pharyngitis (13%); taste perversion (9%); rhinitis (8%); blurred vision (6%); conjunctivitis (5%); hearing disorder, hearing loss, serous retinal detachment, vertigo (postmarketing).

Endocrine

Hypothyroidism (5%); hyperthyroidism (3%); diabetes (postmarketing).

GI

Anorexia (51%); nausea (47%); vomiting (42%); decreased appetite, diarrhea (22%); abdominal pain (21%); dyspepsia (16%); dry mouth, upper abdominal pain (12%); constipation (5%); hepatomegaly (4%).

Hematologic-Lymphatic

Neutropenia (40%); anemia (35%); lymphopenia (14%); leukopenia (10%); thrombocytopenia (8%); aplastic anemia, pure red aplasia (postmarketing).

Lab Tests

Hyperuricemia (38%); decreased Hgb (30%); hyperbilirubinemia (14%).

Local

Injection-site reaction (58%); injection-site erythema (29%); injection-site inflammation (25%).

Musculoskeletal

Myalgia (64%); arthralgia (34%); musculoskeletal pain (28%); back pain (5%).

Respiratory

Dyspnea (26%); cough (23%); sinusitis (12%); exertional dyspnea (7%); apnea, atelectasis, bacterial pneumonia, bronchospasm, cyanosis, hypoventilation, pneumothorax, pulmonary edema, ventilator dependence, worsening of respiratory distress.

Miscellaneous

Pyrexia (80%); chills (39%); flu-like symptoms (31%); decreased weight (29%); pain (13%); resistance mechanism disorders, right upper quadrant pain, viral infection (12%); chest pain (9%); menstrual disorder (7%); fungal infection (6%); bacterial infection (5%); liver and renal graft rejection (postmarketing).

Precautions

Warnings

Inhalation

Use in patients requiring mechanical ventilation should only be undertaken by health care providers and staff familiar with this mode of administration and the ventilator being used. Pay strict attention to procedures shown to minimize accumulation of drug precipitate. Sudden deterioration of respiratory function has been associated with initiation of aerosolized ribavirin use in infants. Carefully monitor respiratory function. If treatment appears to produce sudden deterioration of respiratory function, stop treatment and reinstitute only with extreme caution, continuous monitoring, and consideration of coadministration of bronchodilators. Not indicated for use in adults. Ribavirin has been shown to produce testicular lesions in rodents and to be teratogenic in all animal species in which adequate studies have been conducted.

Oral

Ribavirin monotherapy is not effective for the treatment of chronic HCV infection and should not be used alone for this indication. Primary toxicity is hemolytic anemia that may result in worsening of cardiac disease and lead to fatal and nonfatal MIs. Do not use ribavirin to treat patients who have a history of significant or unstable cardiac disease. Contraindicated in women who are pregnant and in the male partners of women who are pregnant. Instruct patients to avoid pregnancy and to use at least 2 reliable forms of effective contraception during therapy and for 6 months after completion of treatment.


Monitor

Prior to starting therapy, screen women of childbearing potential for pregnancy and obtain baseline laboratory and hematologic values. Also, assess patients for underlying cardiac disease before initiation of therapy and periodically throughout therapy. Obtain CBC at 2 and 4 weeks of therapy or more frequently if indicated. Monitor ECG. Measure HCV-RNA periodically during treatment. Perform additional tests periodically. Carefully monitor respiratory function and fluid status during treatment with ribavirin inhalation.


Pregnancy

Category X .

Lactation

Undetermined.

Children

Capsule/Oral solution

Safety and efficacy not established in treatment with Ribasphere or in children younger than 3 y.

Tablets

Safety and efficacy not established.

Elderly

Administer with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity. Ribavirin inhalation is not indicated for use in adults.

Hypersensitivity

Severe acute hypersensitivity reactions have been rarely observed.

Renal Function

Adjust dose of Copegus ; do not use Rebetol or Ribasphere in patients with CrCl less than 50 mL/min.

Hepatic Function

Discontinue therapy in patients who develop hepatic decompensation during treatment.

Dental disorders

Dental and periodontal disorders have been reported.

Fatalities

Death during or shortly after treatment with aerosolized ribavirin has been reported.

Heath care workers

Avoid unnecessary occupational exposure. Pregnant health care workers should consider avoiding direct care of patients receiving aerosolized ribavirin.

Lab test abnormalities

Severe decreases in neutrophils and platelet count, and hematologic, endocrine (eg, TSH), and hepatic abnormalities may occur.

Pancreatitis

Discontinue therapy in patients with confirmed pancreatitis.

Pulmonary symptoms

Dyspnea, pneumonia, pneumonitis, pulmonary hypertension, and pulmonary infiltrates may occur. Occasional cases of fatal pneumonia have occurred, and sarcoidosis or exacerbations of sarcoidosis have been reported.

Severe reactions

Autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, diabetes, pulmonary dysfunction, colitis, and pancreatitis may occur.

Suicidal ideation/depression

Severe depression and suicidal ideation may occur. Suicidal ideation and attempts occurred more frequently among children, primarily adolescents, compared with adults.

Overdosage

Symptoms

Hypocalcemia, hypomagnesemia.

Patient Information

  • Advise patients to read Medication Guide before beginning therapy and with each refill of medication.
  • Caution patients that ribavirin is not effective by itself and to continue to take other medications for HCV infection as prescribed by their health care provider.
  • Advise patients that it is not known if this therapy will prevent transmission of hepatitis C to others, nor is it known if it can prevent cirrhosis, liver failure, or liver cancer that may develop as a result of hepatitis C infection.
  • Warn women of childbearing potential and female partners of male patients to take extreme care to avoid pregnancy during therapy and for 6 months after completion of therapy because of significant risk of birth defects and/or death of fetus. Instruct patient and his/her partner to use 2 reliable forms of effective contraception during treatment and for 6 months following completion of therapy.
  • Advise women of childbearing potential that pregnancy tests will have to be performed before starting therapy, monthly during therapy, and then monthly for 6 months following completion of therapy.
  • Instruct female patients or female partners of male patients to report suspected pregnancy immediately to health care provider.
  • Advise patients to take with food.
  • Instruct patients not to open, crush, or break the capsules.
  • Advise patients that laboratory evaluations are required prior to starting therapy and periodically thereafter.
  • Advise patients to be well hydrated, especially during the initial stages of treatment.
  • Inform patients that if they miss a dose, to take it as soon as possible during the same day. Instruct patients not to double the next dose.
  • Advise patients to immediately report any of the following to health care provider: bloody diarrhea or bloody bowel movements, bruising or unusual bleeding, change in vision, chest pain, depression or suicidal thoughts, high fever, hives or swelling, severe stomach or low back pain, trouble breathing.
  • Caution patients that therapy may cause confusion, dizziness, or drowsiness, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Caution patients to avoid alcoholic beverages because alcohol ingestion can make liver disease worse.

Copyright © 2009 Wolters Kluwer Health.

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