RIBAVIRIN
- Ribavirin
- Ribavirin is an antiviral agent that is used to treat hepatitis C virus
- In the past, ribavirin was combined with interferon to treat HCV. Ribavirin-interferon regimens had many side effects and were only about 50% effective.
- New generation hepatitis C treatments are much more effective and better tolerated. Ribavirin is still recommended with some of these regimens because it enhances their
efficacy.
- Ribavirin has a number of trade names including Rebetol®, Ribasphere®, and Copegus®
- Ribavirin
- The mechanism by which ribavirin inhibits HCV viral replication is not
completely understood
- The following mechanisms have been proposed:
- Ribavirin inhibits HCV RNA polymerase
- Ribavirin depletes intracellular GTP pools
- Ribavirin induces mutations in the virus that lead to viral death or
production of virus with diminished infectivity
- Ribavirin alters T-cell profiles in favor of T-helper 1 cells that are
more antiviral [12]
- Hemolytic anemia
- The most concerning side effect of ribavirin is hemolytic anemia
- The initial drop in hemoglobin typically occurs within 1 - 2 weeks of starting therapy
- Ribavirin-induced anemia tends to be dose-related meaning it is worse with higher doses
- In trials where ribavirin was added to Zepatier and Viekira Pak, average hemoglobin decreased by 2.2 g/dl and 2.4 g/dl, respectively, over the course of therapy
- See monitoring therapy below for recommendations on managing ribavirin-induced anemia
- Pancytopenia
- Pancytopenia has been reported in a small number of patients when
PegIFN was coadministered with ribavirin and boceprevir
- Pancytopenia has also occurred when PegIFN was coadministered with
ribavirin and azathioprine (Imuran®)
- Hair loss
- Hair loss or thinning is common during treatment with 20 - 40% of patients being affected
- Symptoms typically resolves when therapy is over
- Rashes
- Rashes have been reported in up to 25% of patients during combination therapy with PegIFN and ribavirin [12]
- Worsening liver function
- Liver function tests (AST, ALT, bilirubin, etc.) may worsen and hepatic decompensation may occur when patients are treated with combinations of
PegIFN, ribavirin, and protease inhibitors
- Elevated uric acid
- Ribavirin-induced hemolysis can raise uric acid levels and precipitate gout attacks in susceptible individuals
- In studies, 33 - 38% of patients developed hyperuricemia in association with ribavirin-induced hemolysis
- It may be necessary to monitor uric acid levels in high-risk patients
- Overview
- One of the most concerning side effects of ribavirin is hemolytic anemia
- The Rebetol PI recommends that a CBC be checked before the start of treatment and at Week 2 and Week 4 of therapy. Continued monitoring and/or more frequent checks may be appropriate in some patients.
- Recommendations for therapy adjustments based on lab results are presented below
- Adjusting therapy
- Patients without cardiac disease
- Hemoglobin ≥ 10 g/dl: No dose adjustment necessary. If patient had prior dose reduction, may consider increasing ribavirin gradually in 200 mg increments.
- Hemoglobin 8.5 - 9.9 g/dl: Reduce ribavirin dose by 200 mg/day. If patient is receiving 1400 mg/day, reduce dose by 400 mg.
Recheck hemoglobin within 2 weeks as clinically indicated.
- Hemoglobin < 8.5: Discontinue therapy
- Patients with stable coronary artery disease
- Hemoglobin reduction ≥ 2 g/dl during any 4 week period and hemoglobin is still ≥ 12 g/dl: Reduce ribavirin dose by 200 mg/day. If patient is receiving 1400 mg/day,
reduce dose by 400 mg. Recheck hemoglobin within 2 weeks as clinically indicated.
- Hemoglobin 8.5 - 11.9 g/dl: Reduce ribavirin dose by 200 mg/day. If patient is receiving 1400 mg/day, reduce dose by 400 mg.
Recheck hemoglobin within 2 weeks as clinically indicated. If hemoglobin remains < 12 g/dl despite 4 weeks at the reduced dose, discontinue therapy.
- Hemoglobin < 8.5: Discontinue therapy [14,15]
- Pregnancy (including female partners of males receiving ribavirin)
- Ribavirin causes birth defects, and pregnant women or women hoping to become pregnant should not take ribavirin
- Ribavirin may be passed to female partners of ribavirin-treated males through intercourse. If these women become pregnant, the fetus may be
exposed to ribavirin. Female partners of ribavirin-treated males should take precautions to avoid pregnancy.
- Pregnancy should also be avoided for 6 months after ribavirin has been stopped in both female patients and female partners of ribavirin-treated males [1]
- Known hypersensitivity
- Women who are pregnant or trying to become pregnant
- ribavirin causes birth defects. Women who are pregnant or trying to become pregnant should not take ribavirin. Women who take ribavirin should avoid
pregnancy for at least 6 months after stopping ribavirin. [13]
- Men whose female partners are pregnant or may become pregnant
- it is not known whether ribavirin contained in sperm will exert a
potential teratogenic effect upon fertilization of the ova. 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. Potential pregnancy should be avoided for at least 6 months after stopping ribavirin. [13]
- 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
- Patients with autoimmune hepatitis
- Kidney disease - CrCl < 50 ml/min (See
kidney disease for more)
- Kidney disease
- Ribavirin undergoes significant renal (kidney) clearance
- When CrCl is < 50 ml/min, ribavirin levels rise sharply and the
incidence of side effects (anemia, neutropenia) also increases
- The Rebetol and Ribasphere package inserts say that ribavirin is contraindicated in patients with a CrCl < 50 ml/min
- The Copegus PI gives dosing recommendations for patients with CrCl < 50 ml/min
- Copegus® PI
- CrCl 30 - 50 ml/min: alternating doses, 200 mg one day followed by 400 mg the next
- CrCl < 30 ml/min: 200 mg daily
- Rebetol® PI
- CrCl < 50 ml/min: DO NOT USE
- Ribasphere® PI
- CrCl < 50 ml/min: DO NOT USE
- Liver disease
- Dose reductions or discontinuing ribavirin should be considered if
hepatic decompensation occurs (Child-Pugh B or C)
- Heart disease
- Ribavirin-induced anemia may adversely affect patients with heart
disease
- Patients with unstable heart disease should not receive ribavirin
- Patients with stable heart should have their therapy adjusted appropriately. See monitoring therapy below.
- Autoimmune hepatitis
- Ribavirin should not be used in patients with autoimmune hepatitis
- Hematological disorders (ex. thalassemia major, sickle cell
disease, cirrhosis, HIV disease)
- Ribavirin may cause anemia in a significant number of patients
- Many patients with liver disease have hematological abnormalities
- Caution should be exercised when choosing to treat patients with pre-existing blood disorders
- Patients with pre-existing blood disorders should be monitored closely while undergoing treatment [1,11]
- Pregnancy (including female partners of males receiving treatment)
- Ribavirin causes birth defects, and pregnant women or women hoping to become pregnant should not take ribavirin. Pregnancy should also be avoided for 9 months after ribavirin is stopped.
- Ribavirin may be passed to female partners of ribavirin-treated males through intercourse. If these women become pregnant, the fetus may be exposed to ribavirin. Female partners of ribavirin-treated males should take
precautions to avoid pregnancy during treatment and for 6 months after therapy is stopped. [14]
- Gout
- Ribavirin-induced hemolysis can raise uric acid levels and precipitate gout attacks in susceptible individuals
- In studies, 33 - 38% of patients developed hyperuricemia in association with ribavirin-induced hemolysis
- It may be necessary to monitor uric acid levels in high-risk patients
- NOTE: Drug
interactions presented here are NOT all-inclusive. Other interactions may
exist. The interactions presented here are meant to encompass commonly
prescribed medications and/or interactions that are well-documented. Always
consult your physician or pharmacist before taking medications concurrently.
CLICK HERE for more information on drug interactions.
- Drug interactions
- Azathioprine (Imuran®) - when ribavirin and azathioprine are taken together, severe decreases in
blood cells have occurred. 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.
- Didanosine (Videx®) - Ribavirin increases blood levels of didanosine and they should not be taken together
- HIV medications - Ribavirin may inhibit the metabolism of certain HIV medications
called Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (e.g. lamivudine, stavudine, zidovudine). This may lead to increased toxic effects including liver
decompensation and worsening anemia. Patients on NRTIs should be monitored closely.
- Metabolism and clearance
- Ribavirin undergoes no known liver metabolism
- Dosage forms
- Capsule
- Names: Rebetol®, Ribasphere®
- Dosage forms: 200 mg
- Generic/Cost: YES / $100 - $150 for 150 capsules
- Tablet
- Names: Copegus®
- Dosage forms: 200 mg
- Generic/Cost (200 mg): YES / $100 - $150 for 150 tablets
- Weight-based ribavirin dosing
- Take ribavirin with food. Food increases absorption.
- For current HCV treatment regimens that include ribavirin, weight-based dosing is recommended (see hepatitis c treatment regimens for more)
- The two weight-based regimens detailed below are typically recommended
- Regimen 1 (Daklinza, Epclusa, Harvoni, Sovaldi, Technivie, Viekira Pak/XR)
- < 165 lbs (75 kg): 1000 mg a day given in 2 divided doses
- > 165 lbs (75 kg): 1200 mg a day given in 2 divided doses
- A starting dose of 600 mg/day with titration as tolerated may be appropriate in patients with decompensated cirrhosis (Child-Pugh B and C)
- Regimen 2 (Zepatier)
- < 66 kg (145 pounds): 800 mg a day given in 2 divided doses
- 66 - 80 kg (145 - 176 pounds): 1000 mg a day given in 2 divided doses
- 81 - 105 kg (177 - 231 pounds): 1200 mg a day given in 2 divided doses
- > 105 kg (231 pounds): 1400 mg a day given in 2 divided doses
- A starting dose of 600 mg/day with titration as tolerated may be appropriate in patients with decompensated cirrhosis (Child-Pugh B and C)
- Ribavirin has been used since the late 1990s
- Ribavirin is only used for a short period during which it can have many side effects
- No long-term adverse effects have been identified
- 1 - PegIntron PI
- 2 - PMID 12324553
- 3 - PMID 19625712
- 4 - PMID 19330875
- 5 - PMID 21898493
- 6 - PMID 21316497
- 7 - PMID 21449783
- 8 - Telaprevir PI
- 9 - Boceprevir PI
- 10 - Ribavirin PI
- 11 - Pegasys PI
- 12 - PMID 18161743
- 13 - AASLD HCV website
- 14 - Rebetol PI
- 15 - PMID 24795200 - ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV, NEJM (2014)
