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Ribavirin Adverse Effects

By , MD, PhD

Ribavirin represents a nucleotide analogue of guanosine and a broad-spectrum direct antiviral agent. Although its usage has been associated with a number of adverse effects, most of them are mild, and all are reversible with cessation or dose reduction of the drug.

Patients with a history of any significant cardiac disease should avoid this drug, as its administration can result in worsening of cardiac disease and lead to myocardial infarctions. The same is recommended for patients with spherocytosis and history of gastrointestinal bleeding. The reason behind this is hemolytic anemia – the most common adverse effect of ribavirin.

Hemolytic anemia

The major dose-limiting toxicity of ribavirin is hemolytic anemia, which is observed in 10-13% of all the patients. The underlying mechanism is significant accumulation and lack of dephosphorylation of ribavirin 5'-triphosphate (RTP) in the erythrocytes, which is an active metabolite that interacts with viral RNA polymerases.

As a result, high levels of RTP accumulate in the erythrocyte, reaching approximately 100x the concentration found in the serum. This extreme intracellular concentration of the nucleotide depletes ATP in the cell and leads to oxidative stress, ultimately damaging the cell membrane and resulting in lysis of the erythrocyte.

Some reports have also demonstrated that ribavirin-induced hemolysis is influenced by the pretreatment platelet level, the haptoglobin phenotype and the combination therapy of ribavirin and interferon-α. Depending on the severity of anemia, this toxicity may result in either dose reduction or permanent discontinuation of the treatment.

Erythropoietin and darbepoietine, two well-known erytrhocyte stimulating agents, are sometimes used to counter the anemia associated with pegylated interferon and ribavirin. Although their usage reduces the requirement for ribavirin dose reduction and improves patient's general well-being, the improvement of sustained virological response rates has not been consistently shown. Furthermore, these agents are not approved for use in chronic hepatitis C patients.

Other adverse effects

Although no deaths from the use of oral ribavirin have been recorded, chest pain as a result of coronary ischemia exacerbated by hemolytic anemia has been reported. Furthermore, as this agent is eliminated via kidney, it should be used with extreme caution in patients with chronic kidney disease.

Ribavirin is teratogenic and embryotoxic in rodents, and significant embryocidal effects have been observed in all animal species exposed to ribavirin (except for baboons). Consequently, this drug is contraindicated during pregnancy and breastfeeding, but also in all males and females who are attempting conception. A washout period of six months is also recommended before trying to get pregnant.

Other adverse effects associated with ribavirin include nausea and vomiting, metallic taste, dry mouth, cough, myalgia, fatigue, abdominal pain, diarrhea, headache, jaundice, skin rash, tachycardia, thrombocytosis, elevated lipase levels, hyperuricemia, itching, rigors and certain neurological perturbations (including mood and sleep disturbances).

Sources

  1. http://cid.oxfordjournals.org/content/51/12/1435.long
  2. https://www.jstage.jst.go.jp/article/dmpk/19/6/19_6_438/_pdf
  3. www.hepatitis.va.gov/provider/reviews/treatment-side-effects.asp
  4. www.intmedpress.com/serveFile.cfm
  5. De Clerq E. Antiviral Drugs. In: Stromgaard K, Krogsgaard-Larsen P, Madsen U. Textbook of Drug Design and Discovery, Fourth Edition. CRC Press, 2009; pp. 393-418.

Further Reading

Last Updated: Jun 15, 2015

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