Ribavirin (Virazole)
Ribavirin is indicated in the treatment of carefully selected hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). In addition, ribavirin (600 to 1800 mg / day for 10 to 14 days) has shown effectiveness in acute and chronic hepatitis, herpes genitalis, measles, and Lassa fever.
Ribavirin has antiviral inhibitory activity in vitro against respiratory syncytial virus, influenza virus, and herpes simplex virus.
The antiviral mechanism of action of ribavirin relates to alteration of cellular nucleotide pools and inhibition of viral messenger RNA synthesis. Intracellular phosphorylation to the mono-, di-, and triphosphate derivatives is mediated by host cell enzymes. In both uninfected and RSV-infected cells, the predominant derivative (>80%) is the triphosphate, which has an intracellular t1/2 of elimination of less than 2 hours.
Ribavirin monophosphate competitively inhibits cellular inosine-5′-phosphate dehydrogenase and interferes with the synthesis of guanosine triphosphate (GTP) and, thus, nucleic acid synthesis in general. Ribavirin triphosphate also competitively inhibits the GTP-dependent 5′-capping of viral messenger RNA and, specifically, influenza virus transcriptase activity. Ribavirin appears to have multiple sites of action, and some of these (e.g., inhibition of GTP synthesis) may potentiate others (e.g., inhibition of GTP-dependent enzymes).
Ribavirin, which is teratogenic, gonadotoxic, embryotoxic, and oncogenic, has caused malformation of skull, palate, eye, jaw, skeleton, and GI tract, and hence is con-traindicated in female subjects who are or intend to become pregnant during exposure to the drug.
Aerosolized ribavirin has been well tolerated but may cause mild conjunctival irritation, rash, transient wheezing, and occasional reversible deterioration in pulmonary function. When used in conjunction with mechanical ventilation, equipment modifications and frequent monitoring are required to prevent plugging of ventilator valves and tubing with ribavirin.
Systemic ribavirin causes dose-related anemia due to extravascular hemolysis and dose-related suppression of bone marrow. Reversible increases of serum bilirubin, serum iron, and uric acid concentrations occur during short-term oral administration. Bolus intravenous infusion may cause rigors. In HIV-infected patients, chronic oral therapy is also associated with dose-related lymphopenia and gastrointestinal and CNS complaints, including headache, lethargy, insomnia, and mood alteration.
Ribavirin: Organs and Systems
Hematologic
Ribavirin accumulates in erythrocytes, resulting in hemolysis by an unknown mechanism, perhaps related to oxidative damage to the erythrocyte membrane. Time-dependent and dose-dependent hemolytic anemia (eventually associated with hyperbilirubinemia and a high reticulocyte count) is the only major toxic effect associated with oral or intravenous ribavirin and is reversible on withdrawal. There was a fall in hemoglobin concentrations below 10.0 g/dl in 9% of patients with hepatitis C treated with ribavirin and interferon alfa.
In 140 patients with Nipah virus infection there was no difference in the incidence of adverse effects between those who elected to have ribavirin treatment and those who refused. Dosing was based on recommendations used to achieve the same approximate concentrations as those seen with 100-1200 mg/day in the treatment of hepatitis C. Anemia occurred in 37% of the ribavirin-treated patients and in the same number of controls, suggesting that ribavirin was equally well tolerated in the two groups.
In patients taking ribavirin plus interferon alfa-2b the average fall in hemoglobin is 2-3 g/dl. Of 57 patients taking ribavirin 800 mg/day 28 were randomized to a high dose of peginterferon alfa-2b once a week (3 micro-grams/kg for 1 week, 1.5 micrograms/kg for 3 weeks, and 1.0 microgram/kg for 44 weeks) and 27 patients were randomized to receive a low dose (0.5 micrograms/kg) for 48 weeks; three patients required reduced doses of ribavirin because of anemia.
In a randomized controlled trial of high-dose interferon alfa-2b plus oral ribavirin for 6 or 12 months in 50 patients with chronic hepatitis C, the sequential effects of treatment on hemoglobin, leukocytes, and platelets were recorded. There was a fall in hemoglobin, and the lowest concentrations were recorded after 6 months of treatment in both groups. All hematological measurements returned to normal after the end of treatment.
Detailed studies of the effects of ribavirin on erythrocyte Adenosine and adenosine triphosphate content and on the hexose monophosphate shunt have been conducted in vitro. Adenosine and adenosine triphosphate concentrations were significantly reduced and the hexose monophosphate shunt increased, suggesting erythrocyte susceptibility to oxidation. In vivo, ribavirin, alone or in combination with interferon, was associated with significant reductions in hemoglobin concentrations and a marked increase in absolute reticulocyte counts. Erythrocyte Na/ K pump activity was significantly reduced, whereas K/Cl co-transport and its dithiothreitol-sensitive fraction and malondialdehyde and methemoglobin concentrations increased significantly. Ribavirin-treated patients showed an increase in aggregated band 3, which was associated with significantly increased binding of auto-logous antibodies and complement C3 fragments, suggesting erythrophagocytic removal by the reticuloen-dothelial system.
A low pretreatment platelet count, the dose of inter-feron alfa, and the haptoglobin phenotype are risk factors for ribavirin-induced anemia, and the fall in hemoglobin is independent of dose in the therapeutic range. In five patients with chronic hepatitis C on hemodialysis who received subcutaneous interferon alfa-2b and oral ribavirin for 40 weeks, the dose of ribavirin was titrated based on hemoglobin, with bone marrow support by erythro-poietin. There was significant bone marrow toxicity in all five. A dose of 200 mg/day produced a steady-state AUC comparable to that obtained with 1000-1200 mg/ day in historical controls with normal renal function. More severe anemia was possibly due to chronic renal insufficiency in addition to the prolonged effects of ribavirin.
Treatment of ribavirin-induced hemolytic anemia with recombinant human erythropoietin has been described in 13 patients. The hemoglobin concentration increased from a nadir of 10.2 g/dl to a median of 11.5 g/dl and ribavirin treatment did not have to be withdrawn.
Liver
As part of a multicenter, randomized, double-blind, placebo-controlled trial of ribavirin in 59 patients with hepatitis C virus infection, liver biopsies were studied for iron deposition. Increased total iron deposition, preferentially in hepatocytes, occurred during a 9-month course of ribavirin. The deposition had no apparent effect on the biochemical or histological response to ribavirin therapy.
Skin
Photosensitivity after administration of ribavirin has been described. A well-documented photoallergic reaction in a woman who was taking both ribavirin and interferon alfa provided evidence that ribavirin is a potential photo-sensitizer for UVB, a problem that may become increasingly relevant in patients with chronic hepatitis C taking combination therapy for 6-12 months with interferon alfa and ribavirin.
Transient acantholytic dermatosis (Grover’s disease) was first described by Grover in 1970 as a pruritic, self-limiting, popular, or papulovesicular eruption, mainly distributed on the trunk of white middle-aged men. The histopathological hallmark is suprabasal acantholysis at different levels of the epidermis. Its origin is uncertain; most cases are related to sunlight, heat, or sweating. Grover’s disease has been attributed to ribavirin.
A 55-year-old man with chronic hepatitis C presented with a pruritic papular eruption on the trunk lasting 2 weeks. He had multiple, erythematous, excoriated papules on the neck, trunk, upper arms, and thighs. The lesions appeared 2 weeks after combination therapy with oral ribavirin and subcutaneous interferon alfa-2b. He had previously been treated with interferon alfa alone (in the same dosage). On withdrawal of ribavirin the lesions gradually faded, but they returned 1 week after reintroduction.
Ribavirin: Side Effects
The synthetic triazole nucleoside, ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, tribavirin, virazole), has a broad spectrum of antiviral activity, including DNA as well as RNA viruses. Ribavirin closely resembles guanosine and is converted intracellularly to mono-, di-, and triphosphate derivatives, which inhibit the virally induced enzymes involved in viral nucleic acid synthesis by different mechanisms that are not fully understood. Of the DNA viruses, ribavirin is active against Herpes simplex virus and hepatitis B virus; among the RNA viruses, good activity has been observed against hepatitis C virus, orthomyxoviruses, paramyxoviruses, arenaviruses, and bunyaviruses. Although active against HIV in vitro and in vivo, ribavirin is not widely used in the treatment of HIV infection. So far, drug resistance has not been described.
Oral ribavirin has been successfully used in the treatment of Lassa fever, Crimean Congo hemorrhagic fever, and in combination therapy with interferon alfa for hepatitis C infection. Several publications have suggested enhanced efficacy of the combination of interferon alfa with ribavirin when compared with mono-therapy with interferon alfa. There is also evidence that re-treatment with the combination may succeed in controlling or eliminating viremia when monotherapy has failed. Although the combination may lead to some increase in the adverse effects normally associated with interferon alfa (dyspnea, pharyngitis, pruritus, nausea, insomnia, and anorexia), there is no doubt that oral ribavirin adds to the overall toxicity of the combination by causing hemolytic anemia, which is usually mild.
Ribavirin is well absorbed orally, but it can be given in aerosol form for the treatment of respiratory syncytial virus (RSV) infections in immunocompromised patients, and in those with cardiopulmonary abnormalities, or in infants receiving mechanical ventilation.
The adverse effects and other safety aspects of interferon and ribavirin in the treatment of hepatitis C infection have been reviewed.
Comparative studies
Two, large, randomized, placebo-controlled comparisons of interferon alfa-2b alone with the combination of interferon alfa-2b plus ribavirin have been published. In the initial treatment of chronic hepatitis C, 912 patients were randomly assigned to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg/day orally, depending on body weight) for 24 or 48 weeks. As expected, dosage reduction for anemia was necessary in 8% of patients taking the combination therapy and in none of those treated with interferon alone. Dyspnea, pharyngitis, pruritus, rash, nausea, insomnia, and anorexia were adverse effects that were reported more often during combination therapy with ribavirin. In patients whose chronic hepatitis had relapsed after therapy with interferon alfa-2b alone, 345 patients were randomized to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg/day orally, depending on body weight) for 6 months. Dosage reduction for anemia was required in 12/173 patients assigned to combination therapy and in none assigned to interferon alone. As was the case in the initial therapy study, dyspnea, nausea, and rash were significantly more common in patients treated with the combination of interferon and ribavirin.
Ribavirin 15 mg/kg/day plus interferon alfa in 12 teenagers has been compared with interferon alone in 10. There was no difference in dropout rate, but viral clearance was achieved in 50% of the patients who took the combination treatment versus 30% of those who took monotherapy. Adverse events were similar in the two groups. There was mild hemolytic anemia at the end of the first month in most of the children who took ribavirin, but four had moderate to severe hemolysis and two had to stop taking ribavirin. Severe hemolysis in a patient with thalassemia warranted withdrawal of ribavirin within 3 months.
Ribavirin: Organs and Systems
Second-Generation Effects
Teratogenicity
Ribavirin is teratogenic and embryotoxic in laboratory animals and should not be given to pregnant women. Concern has been expressed about the safety of people in the same room as patients being treated with ribavirin by aerosol, particularly women of child-bearing age. However, no ribavirin was detected in the urine, plasma, or erythrocytes of 19 nurses exposed to ribavirin administered via ventilator, oxygen tent, or oxygen hood over 3 days.
Drug-Drug Interactions
Didanosine
Multisystem organ dysfunction and lactic acidemia occurred in two of 15 patients with HIV and hepatitis C infections who received interferon alfa, didanosine, and ribavirin. Co-administration of didanosine with ribavirin can lead to increased toxicity secondary to raised intracellular concentrations of phosphorylated didanosine (ddA-TP). Thus, the evidence suggests that the combination of didanosine plus ribavirin increases the risk of lactic acidosis.
Warfarin
An interaction of warfarin with ribavirin has been reported.
In a 61-year-old white man with chronic hepatitis C, who took interferon plus ribavirin, the dosage of warfarin had to be increased by about 40% (from 45 to 63 mg/week) in order to maintain the desired degree of anticoagulation. This effect was reproduced on rechallenge with ribavirin.
The mechanism of this supposed interaction is not known. For example, ribavirin is cleared by intracellular phosphorylation and its metabolites by the kidneys, warfarin by cytochrome P450 isozymes in the liver; warfarin is highly protein bound, ribavirin is not. However, an effect on warfarin absorption or its action on clotting factor synthesis is possible.
| Dosage forms of Ribavirin: | |||
|---|---|---|---|
| Rebetol 40 mg/ml Solution | Ribavirin powder | Ribasphere 200 mg tablet | Ribavirin 200 mg tablet |
| Ribasphere 200 mg capsule | Ribavirin 200 mg capsule | Rebetol 200 mg capsule | Copegus 200 mg tablet |
| Ribasphere 400 mg tablet | Ribavirin 400 mg tablet | Ribavirin 500 mg tablet | Ribatab 400 mg tablet |
| Ribasphere 600 mg tablet | Ribavirin 600 mg tablet | Ribatab 600 mg tablet | Virazole 6 gm vial |
Synonyms of Ribavirin:
RBV, Ribavirin Triphosphate, Ribavirina [INN-Spanish], Ribavirine [INN-French], Ribavirinum [INN-Latin]
How can i get Ribavirin online over the counter?
You can buy Ribavirin OTC in online drugstore with low cost.
Therapeutic classes of Ribavirin:
Antimetabolites, Antiviral Agents
Delivery
Australia, Canada, Mexico, New Zealand, USA, Europe [Belgium, France, Norway, Holland, Ireland, Spain, Switzerland, Great Britain (UK), Italy] and etc.