Ribavirin

(BAN, USAN, rINN)
Ribavirin Chemical formula
Synonyms: ICN-1229; Ribaviriini; Ribavirina; Ribavirinas; Ribavirine; Ribavirinum; RTCA; Tribavirin. 1carboxamide.
Cyrillic synonym: Рибавирин.

💊 Chemical information

Chemical formula: C8H12N4O5 = 244.2.
CAS — 36791-04-5.
ATC — J05AB04.
ATC Vet — QJ05AB04.

Pharmacopoeias.

In Chin., Eur., and US.

Ph. Eur. 6.2

(Ribavirin). A white or almost white crystalline powder. It exhibits polymorphism. Freely soluble in water; slightly soluble in alcohol; slightly soluble or very slightly soluble in dichloromethane. A 2% solution in water has a pH of 4.0 to 6.5. Protect from light.

USP 31

(Ribavirin). A white crystalline powder. Freely soluble in water; slightly soluble in dehydrated alcohol. Store in airtight containers.

💊 Adverse Effects

When given by inhalation, ribavirin has sometimes led
to worsening of lung function, bacterial pneumonia, and pneumothorax, to cardiovascular effects (including a fall in blood pressure and cardiac arrest), and, rarely, to anaemia, haemolysis, and reticulocytosis. Conjunctivitis and skin rash have also occurred. Precipitation of inhaled ribavirin and consequent accumulation of fluid has occurred in the tubing of ventilating equipment. The most common adverse effects reported by patients taking oral ribavirin, with either interferon alfa or peginterferon alfa, are psychiatric reactions (such as anxiety, depression, insomnia, and irritability) and flulike symptoms. Life-threatening or fatal adverse effects include severe depression, suicidal ideation, relapse of drug abuse or overdose, and bacterial infection. Severe adverse effects include haemolytic anaemia, leucopenia, thrombocytopenia, aplastic anaemia, diabetes mellitus, auto-immune disorders, gastrointestinal symptoms, pancreatitis, pulmonary embolism, chest pain, liver dysfunction, and interstitial pneumonitis. Lupus erythematosus, rash (including very rarely Stevens-Johnson syndrome and toxic epidermal necrolysis), and photosensitivity have also been reported. Growth retardation (including decrease in height and weight) has been reported in children. A wide range of other adverse effects may occur as a result of the use of ribavirin with interferon alfa.

Incidence of adverse effects.

A review1 of adverse effects reported in 110 patients with suspected or probable SARS who were treated with ribavirin found that 61% of the patients had evidence of haemolytic anaemia. In a smaller cohort of 76 patients hypocalcaemia and hypomagnesaemia were reported in 58% and 46% of patients, respectively, while 29% had evidence of both hypocalcaemia and hypomagnesaemia. A retrospective cohort study2 found that the adverse effects strongly associated with the use of ribavirin (mostly high-dose) in 306 patients with confirmed or probable SARS, were progressive anaemia, hypomagnesaemia, and bradycardia.
1. Knowles SR, et al. Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada. Clin Infect Dis 2003; 37: 1139–42
2. Muller MP, et al. Canadian SARS Research Network. Adverse events associated with high-dose ribavirin: evidence from the Toronto outbreak of severe acute respiratory syndrome. Pharmacotherapy 2007; 27: 494–503.

💊 Precautions

SPECIFIC CAUTIONS FOR INHALED TREATMENT. Standard supportive respiratory and fluid management should be maintained during aerosol treatment with ribavirin and electrolytes should be monitored closely. Equipment should be monitored for precipitation of ribavirin. Precautions should be taken to minimise atmospheric pollution with ribavirin during aerosol inhalation. SPECIFIC CAUTIONS FOR ORAL TREATMENT. Ribavirin should not be given orally to patients with pre-existing medical conditions that could be exacerbated by ribavirin-induced haemolysis, including significant or unstable cardiac disease or haemoglobinopathies (thalassaemia or sickle-cell anaemia). Blood cell counts and chemistry should be measured at the start of treatment, after 2 and 4 weeks of treatment, and periodically thereafter. Patients with renal impairment and a creatinine clearance of less than 50 mL/minute should not receive oral ribavirin. It should be avoided in patients with severe hepatic impairment or decompensated cirrhosis of the liver (Child-Pugh 6 or more). The potential for development of gout should be considered in predisposed patients. Patients should be monitored for signs and symptoms of psychiatric disorders. Ribavirin therapy is contra-indicated in children and adolescents with a history of, or existing, psychiatric disorders. The growth of children should be monitored and thyroid function should be tested every 3 months. Patients infected with hepatitis C virus and HIV should be carefully monitored for signs of mitochondrial toxicity and lactic acidosis. Dental and periodontal disorders have been reported and regular dental examinations and good oral hygiene are advised.

Contact lenses.

Report of damage to a nurse’s soft contact lenses after intermittent occupational exposure to aerosolised ribavirin over a period of 1 month.1
1. Diamond SA, Dupuis LL. Contact lens damage due to ribavirin exposure. DICP Ann Pharmacother 1989; 23: 428–9.

Pregnancy.

Oral ribavirin has been reported to be teratogenic and embryocidal in rodents and is contra-indicated in pregnancy or in those who may become pregnant. Ribavirin was not found to be teratogenic in baboons. Although there are no case reports of teratogenicity after exposure to aerosolised ribavirin during pregnancy, licensed product information advises that pregnant women and those planning pregnancy should avoid exposure to the aerosol. Pregnancy should also be avoided in partners of male patients taking ribavirin orally. Effective contraception should be used during treatment and for 6 months after the end of treatment. Male patients whose partners are pregnant should use a condom to minimise vaginal exposure to ribavirin.

💊 Interactions

Use of ribavirin with zidovudine is not recommended as patients are at increased risk of anaemia. Increased toxicity has also been seen with didanosine, and the combination should be avoided. Ribavirin inhibits the phosphorylation of NRTIs such as zidovudine, lamivudine, and stavudine, but although UK licensed product information suggests this may reduce their activity against HIV, US product information indicates that no such reduction has been seen in practice.

Anticoagulants.

For reference to the effect of ribavirin on the activity of warfarin, see under Antivirals.

💊 Antiviral Action

Ribavirin inhibits many viruses in vitro and in animal
models. However, this activity has not necessarily correlated with activity against human infections. Ribavirin is phosphorylated but its mode of action is still unclear; it may act at several sites, including cellular enzymes, to interfere with viral nucleic acid synthesis. The mono- and triphosphate derivatives are believed to be responsible for its antiviral activity. Susceptible DNA viruses include herpesviruses, adenoviruses, and poxviruses. Susceptible RNA viruses include Lassa virus, members of the bunyaviridae group, influenza, parainfluenza, measles, mumps, and RSV, and HIV.

💊 Pharmacokinetics

Aerosolised ribavirin is absorbed systemically, but local concentrations in the respiratory tract secretions are much higher than plasma concentrations. Plasma halflife is about 9.5 hours. The bioavailability of aerosolised ribavirin is unknown and may depend on the mode of delivery. Ribavirin is rapidly absorbed after oral doses and peak plasma concentrations have been reported within 1 to 2 hours. Absorption is extensive but oral bioavailability is about 45 to 65% as a result of first-pass metabolism. Steady state plasma concentrations are achieved after about 4 weeks with twice-daily oral doses resulting in peak plasma concentrations 6 times higher than that after single doses. On stopping dosing the plasma halflife is about 300 hours as a result of slow elimination from non-plasma compartments. Ribavirin does not bind to plasma proteins. Ribavirin is not metabolised by the cytochrome P450 system; it is metabolised by reversible phosphorylation and degradation involving deribosylation and amide hydrolysis to give a triazole carboxyacid metabolite. After a single oral dose the terminal half-life is about 120 to 170 hours. Ribavirin is mainly excreted in the urine as unchanged drug and metabolites. Insignificant amounts of the drug are removed by haemodialysis.
1. Kramer TH, et al. Hemodialysis clearance of intravenously administered ribavirin. Antimicrob Agents Chemother 1990; 34: 489–90
2. Glue P, et al. The single dose pharmacokinetics of ribavirin in subjects with chronic liver disease. Br J Clin Pharmacol 2000; 49: 417–21
3. Tsubota A, et al. Pharmacokinetics of ribavirin in combined interferon-alpha 2b and ribavirin therapy for chronic hepatitis C virus infection. Br J Clin Pharmacol 2003; 55: 360–7
4. Kamar N, et al. Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function. Am J Kidney Dis 2004; 43: 140–6
5. Uchida M, et al. Assessment of adverse reactions and pharmacokinetics of ribavirin in combination with interferon alpha-2b in patients with chronic hepatitis C. Drug Metab Pharmacokinet 2004; 19: 438–43
6. Wade JR, et al. Pharmacokinetics of ribavirin in patients with hepatitis C virus. Br J Clin Pharmacol 2006; 62: 710–14.

💊 Uses and Administration

Ribavirin is a synthetic nucleoside analogue structurally related to guanine. It is given by aerosol in the treatment of RSV infections; this route appears to give better results than the oral route although its efficacy is questionable. It is used orally with an interferon alfa or peginterferon alfa in the treatment of chronic hepatitis C, including HIV co-infection. Ribavirin has been tried in haemorrhagic fevers (such as haemorrhagic fever with renal syndrome and Lassa fever) and in SARS. For details of doses in children, see below. Ribavirin is used, with an interferon alfa or peginterferon alfa, for the treatment of chronic hepatitis C. Doses of ribavirin depend upon the product used, but are given orally, usually twice daily, and are determined according to body-weight. Duration of treatment, and sometimes also dose, may be influenced by the genotype of the hepatitis C virus. In those with hepatitis C infection alone (mono-infection), patients with viral genotype 1, and probably genotype 4, should generally be treated for 48 weeks and those with genotype 2 or 3 for 24 weeks; data on genotypes 5 or 6 are insufficient to make recommendations. In co-infection with HIV, treatment should generally be given for 48 weeks regardless of genotype. Rebetol (Schering-Plough) is used, with interferon alfa-2b or peginterferon alfa-2b for hepatitis C. The following doses are recommended in the UK:
adults up to 65 kg: 400 mg both in the morning and in the evening
65 to 85 kg: 400 mg in the morning and 600 mg in the evening
from 85 to 105 kg: 600 mg both in the morning and in the evening
over 105 kg: 600 mg in the morning and 800 mg in the evening In the USA, the doses are:
adults up to 75 kg: 400 mg in the morning and 600 mg in the evening
over 75 kg: 600 mg both in the morning and in the evening Copegus (Roche) is used in the UK with interferon alfa-2a or peginterferon alfa-2a and in the USA with peginterferon alfa-2a. The following doses are used with peginterferon alfa-2a for mono-infection in genotype 1 or 4:
adults up to 75 kg: 400 mg in the morning and 600 mg in the evening
over 75 kg: 600 mg both in the morning and in the evening For mono-infection in genotype 2 or 3 (with peginterferon alfa-2a):
all adults: 400 mg both in the morning and in the evening The following doses are used with interferon alfa-2a for mono-infection in genotype 1 to 4:
adults up to 75 kg: 400 mg in the morning and 600 mg in the evening
over 75 kg: 600 mg both in the morning and in the evening For co-infection with HIV:
all adults: 800 mg daily, irrespective of genotype Dose reductions of ribavirin may be necessary in patients who develop low haemoglobin concentrations. Ribavirin is contra-indicated in patients with a creatinine clearance less than 50 mL/minute.
1. Plosker GL, Keating GM. Peginterferon-α-2a (40kD) plus ribavirin: a review of its use in hepatitis C virus and HIV co-infection. Drugs 2004; 64: 2823–43
2. Keating GM, Plosker GL. Peginterferon α-2a (40KD) plus ribavirin: a review of its use in the management of patients with chronic hepatitis C and persistently ‘normal’ ALT levels. Drugs 2005; 65: 521–36
3. Gish RG. Treating HCV with ribavirin analogues and ribavirinlike molecules. J Antimicrob Chemother 2006; 57: 8–13
4. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2007 (accessed 13/06/08)
5. Keam SJ, Cvetković RS. Peginterferon-α-2a (40 kD) plus ribavirin: a review of its use in the management of chronic hepatitis C mono-infection. Drugs 2008; 68: 1273–1317.

Administration in children.

Preparations of ribavirin are available for aerosol administration to infants and children with severe RSV infection via a small particle aerosol generator. Solutions containing 20 mg/mL are used; 300 mL, representing 6 g of ribavirin, is delivered over a 12- to 18-hour period by aerosol at an average concentration of 190 micrograms/litre of air. Treatment is given for 3 to 7 days. Ribavirin is used, with an interferon alfa, for the treatment of chronic hepatitis C. Doses of ribavirin depend upon the product used, but are given orally, usually twice daily, and are determined according to body-weight. Duration of treatment, and sometimes also dose, may be influenced by the genotype of the hepatitis C virus. In hepatitis C mono-infection, patients with viral genotype 1 should be treated for 48 weeks and those with genotype 2 or 3 for 24 weeks. Rebetol (Schering-Plough) is used, with interferon alfa-2b or peginterferon alfa-2b, for hepatitis C. The following doses are recommended in the UK:
47 to 49 kg: 200 mg in the morning and 400 mg in the evening
50 to 65 kg: 400 mg both in the morning and in the evening
over 65 kg: the adult dose (above) In the USA, the doses are:
25 to 36 kg: 200 mg both in the morning and in the evening
37 to 49 kg: 200 mg in the morning and 400 mg in the evening
50 to 61 kg: 400 mg both in the morning and in the evening
over 61 kg: the adult dose Copegus (Roche) is not licensed for use in those less than 18 years of age.

Encephalitis.

A beneficial response to ribavirin was reported in a child with severe La Crosse encephalitis.1 Ribavirin was given intravenously in a dose of 25 mg/kg over the first 24 hours and then reduced to 15 mg/kg daily for a further 9 days. A small open-label study2 suggested that ribavirin might also be able to reduce mortality and neurological deficits in acute Nipah encephalitis. Intraventricular ribavirin (plus intraventricular interferon and oral isoprinosine) was found to be effective in 4 of 5 patients with subacute sclerosing panencephalitis.3 A concentration of ribavirin in the CSF of 50 to 200 micrograms/mL completely inhibited viral replication; doses of ribavirin given to achieve this concentration ranged from 1 to 9 mg/kg daily.
1. McJunkin JE, et al. Treatment of severe La Crosse encephalitis with intravenous ribavirin following diagnosis by brain biopsy. Pediatrics 1997; 99: 261–7
2. Chong HT, et al. Treatment of acute Nipah encephalitis with ribavirin. Ann Neurol 2001; 49: 810–13
3. Hosoya M, et al. Pharmacokinetics and effects of ribavirin following intraventricular administration for treatment of subacute sclerosing panencephalitis. Antimicrob Agents Chemother 2004; 48: 4631–5.

Haemorrhagic fevers.

The treatment of haemorrhagic fevers is primarily symptomatic. However, ribavirin has been reported to reduce mortality in patients with Lassa fever,1 haemorrhagic fever with renal syndrome,2 and possibly Crimean-Congo haemorrhagic fever3,4 and Bolivian haemorrhagic fever.5 Intravenous ribavirin has also been tried in the related hantavirus pulmonary syndrome,6,7 but a small randomised, double-blind, placebo-controlled study8 with intravenous ribavirin reported no significant difference in survival between the 2 groups. For treatment of Lassa fever, ribavirin has been given intravenously in a dose of 2 g initially, then 1 g every 6 hours for 4 days, then 500 mg every 8 hours for 6 days.1 Treatment is most effective if started within 6 days of the onset of fever. Experience has shown that rigors may occur if the drug is given as a bolus injection, but that this can be overcome by giving it as an infusion over 30 minutes.9 For prophylaxis, an oral dose of ribavirin 600 mg 4 times daily for 10 days has been suggested for adults,10although this was considered to be excessive by other commentators11 who suggested that oral doses of 1 g daily (after an intravenous loading dose for those in whom the start of prophylaxis is delayed) might be suitable.
1. McCormick JB, et al. Lassa fever: effective therapy with ribavirin. N Engl J Med 1986; 314: 20–6
2. Huggins JW, et al. Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 1991; 164: 1119–27
3. Fisher-Hoch SP, et al. Crimean Congo-haemorrhagic fever treated with oral ribavirin. Lancet 1995; 346: 472–5
4. Mardani M, et al. The efficacy of oral ribavirin in the treatment of crimean-congo hemorrhagic fever in Iran. Clin Infect Dis 2003; 36: 1613–18
5. Kilgore PE, et al. Treatment of Bolivian hemorrhagic fever with intravenous ribavirin. Clin Infect Dis 1997; 24: 718–22
6. Anonymous. Hantavirus pulmonary syndrome—northeastern United States, 1994. JAMA 1994; 272: 997–8
7. Prochoda K, et al. Hantavirus-associated acute respiratory failure. N Engl J Med 1993; 329: 1744
8. Mertz GJ, et al. Collaborative Antiviral Study Group. Placebocontrolled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America. Clin Infect Dis 2004; 39: 1307–13
9. Fisher-Hoch SP, et al. Unexpected adverse reactions during a clinical trial in rural West Africa. Antiviral Res 1992; 19: 139–47
10. Holmes GP, et al. Lassa fever in the United States: investigation of a case and new guidelines for management. N Engl J Med 1990; 323: 1120–23
11. Johnson KM, Monath TP. Imported Lassa fever—reexamining the algorithms. N Engl J Med 1990; 323: 1139–41.

Hepatitis.

For further discussion on the use of ribavirin with interferon alfa in the management of chronic hepatitis C, see under Interferon Alfa.

💊 Preparations

BP 2008: Ribavirin Nebuliser Solution; USP 31: Ribavirin for Inhalation Solution.

Proprietary Preparations

Arg.: Copegus; Laztie; Vibuzol; Xilopar; Austral.: Virazide; Austria: Copegus; Rebetol; Belg.: Copegus; Rebetol; Virazole; Braz.: Rebetol†; Ribav; Ribaviron C†; Viramid; Virazole†; Canad.: Virazole; Chile: Rebetol; Cz.: Copegus; Rebetol; Denm.: Copegus; Rebetol; Fin.: Copegus; Rebetol; Fr.: Copegus; Rebetol; Ger.: Copegus; Rebetol; Virazole; Gr.: Copegus; Rebetol; Hong Kong: Copegus; Rebetol; Virazole; Hung.: Copegus; Rebetol; Virazole†; India: Ribavin; Indon.: Rebetol; Virazide; Irl.: Copegus; Rebetol; Israel: Copegus; Rebetol; Ital.: Copegus; Rebetol; Virazole; Jpn: Copegus; Malaysia: Rebetol; Mex.: Copegus; Desiken; Trivorin; Vilona; Virazide; Neth.: Copegus; Rebetol; Virazole; Norw.: Copegus; Rebetol; NZ: Copegus; Rebetol; Philipp.: Ribazole; Pol.: Copegus; Rebetol; Port.: Copegus; Rebetol; Rus.: Arviron (Арвирон); Rebetol (Ребетол); Ribapeg (Рибапег); Virazole (Виразол); S.Afr.: Copegus; Singapore: Copegus; Rebetol; Virazole; Spain: Copegus; Rebetol; Virazole; Swed.: Copegus; Rebetol; Virazole; Switz.: Copegus; Rebetol; Virazole†; Thai.: Rebetol; UK: Copegus; Rebetol; Virazole; USA: Copegus; Rebetol; RibaPak; Ribaspheres; Ribatab; Virazole; Venez.: Rebetol. Multi-ingredient: Arg.: Bioferon Hepakit; Pegatron†; Rebetron†; Austral.: Pegasys RBV; Pegatron; Rebetron; Canad.: Pegasys RBV; Pegetron; Rebetron†; Mex.: Hepatron C; Pegtron Cotronak Kit; NZ: Pegasys RBV; Pegatron; Rebetron; Roferon-A RBV; Philipp.: Pegasys RBV; S.Afr.: Rebetron†; Switz.: Intron A/Rebetol†; USA: Rebetron†.
Published December 16, 2018.