RIBAZOLE 500 MG TABLETS

Indications

• Chronic hepatitis C in combination with interferon alfa or peginterferon alfa
• Respiratory syncytial virus (RSV) infection in immunocompromised children
• Other viral infections as indicated by clinician

Dosage

Adults: The usual adult dose for chronic hepatitis C is 400 mg twice daily for patients weighing up to 65 kg. For patients weighing 65

Mechanism of action

Ribavirin exerts its antiviral effects through multiple mechanisms. After phosphorylation by adenosine kinase, it is converted into ribavirin mono-, di-, and triphosphate metabolites, with ribavirin triphosphate (RTP) being the most active. RTP inhibits viral mRNA polymerase by binding to its nucleotide binding site, hindering the correct nucleotide binding and leading to decreased viral replication and defective virion production. Additionally, ribavirin disrupts the posttranslational capping of viral mRNA and inhibits inosine monophosphate dehydrogenase (IMPDH), reducing intracellular GTP pools and further limiting viral protein synthesis.

Pharmacodynamics

Ribavirin demonstrates direct antiviral activity against various DNA and RNA viruses by increasing the mutation frequency in viral genomes. As a nucleoside antimetabolite, it interferes with the duplication of viral genetic material and inhibits RNA-dependent RNA polymerase, resembling the building blocks of RNA molecules, which leads to a decrease in viral load and replication.

Pharmacokinetics

Ribavirin is administered orally, and following absorption, it undergoes extensive hepatic metabolism to its active metabolites. The drug exhibits a long half-life, allowing for twice-daily dosing in adults. It is predominantly eliminated via the kidneys, and renal impairment may lead to accumulation of the drug. Monitoring of renal function is advised during treatment, particularly in patients with existing renal conditions.

Contra-indications

• Severe cardiac disease (in adults)
• Severe uncontrolled cardiac disease in children with chronic hepatitis C
• Unstable or uncontrolled cardiac disease in previous 6 months (in adults)
• Hemoglobinopathies
• Decompensated liver disease

Adverse effects

• Anaemia
• Fatigue
• Weakness
• Nausea
• Vomiting
• Jaundice
• Elevation of ALT levels
• Lack of appetite

Interactions

• Severe interaction with zidovudine (increases risk of anaemia and/or leucopenia)

Precautions

• Hepatic effects should be monitored, discontinue if ALT elevation occurs with signs of hepatic impairment
• Assess cardiac status prior to use, especially in patients with a history of cardiac disease
• Monitor haemoglobin concentration during treatment

Pregnancy

Ribavirin is contraindicated in pregnancy due to the risk of teratogenicity and fetal harm. Effective contraception is recommended during treatment and for 6 months after discontinuation.

Breast-feeding

Ribavirin should be avoided during breastfeeding as it may be excreted in breast milk and could affect the infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Capsules (Rebetol)
• Oral solution (Rebetol)
• Intravenous preparation (not licensed for use)

Mechanism of action

Ribavirin is reported to have several mechanism of actions that lead to inhibition of viral RNA and protein synthesis. After activation by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites. Ribavirin triphosphate (RTP) is the predominant metabolite which directly inhibits viral mRNA polymerase by binding to the nucleotide binding site of the enzyme. This prevents the binding of the correct nucleotides, leading to a reduction in viral replication or to the production of defective virions. RTP also demonstrates an inhibitory action on viral mRNA guanylyltransferase and mRNA 2′-O-methyltransferase of dengue virus. Inhibition of these enzymes disrupts the posttranslational capping of the 5′ end of viral mRNA through ribavirin being incorporated at the 5′ end in place of guanosine and preventing the cap methylation step. Inhibition of host inosine monophosphate dehydrogenase (IMPDH) and subsequent depletion of GTP pool is proposed to be another mechanism of action of ribavirin. IMPDH catalyzes the rate-limiting step where inosine 5′-monophosphate is converted to xanthine monophosphate during guanosine monophosphate (GMP) synthesis. GMP is later converted to guanosine triphoshpate (GTP). Ribavirin monophosphate mimics inosine 5′-monophosphate and acts as a competitive inhibitor of IMPDH. Inhibited de novo synthesis of guanine nucleotides and decreased intracellular GTP pools leads to a decline in viral protein synthesis and limit replication of viral genomes. Ribavirin acts as a mutagen in the target virus to cause an 'error catastrophe' due to increased viral mutations. RTP pairs with cytidine triphosphate or uridine triphosphate with equal efficiency and to block HCV RNA elongation. It causes premature termination of nascent HCV RNA and increases mutagenesis by producing defective virions. Ribavirin also exerts an immunomodulatory action of the host to the virus by shifting a Th2 response in favor of a Th1 phenotype. Th2 response and production of type 2 cytokines such as IL-4, IL-5, and IL-10 stimulates the humoral response which enhances immunity toward the virus. Ribavirin enhanced induction of interferon-related genes, including the interferon-α receptor, and down-regulation of genes involved in interferon inhibition, apoptosis, and hepatic stellate cell activation in vitro. The exact mechanism of action of the antiviral activity of ribavirin has not been fully elucidated, but the drug appears to exert its antiviral activity by interfering with RNA and DNA synthesis and subsequently inhibiting protein synthesis and viral replication. The antiviral activity of the drug results principally in an intracellular virustatic effect in cells infected with ribavirin sensitive RNA or DNA viruses; however, specific mechanisms of action of the drug may vary depending on the virus. In virus infected cells in vitro, ribavirin generally exhibits a greater affinity for inhibition of viral DNA and RNA synthesis than cellular (host cell) DNA and RNA synthesis. However, in vesicular stomatitis virus infected cells in vitro, the drug appeared to exhibit a greater affinity for inhibition of cellular than viral RNA synthesis. Inhibition of cellular RNA synthesis usually occurs only at in vitro concentrations higher than those necessary for inhibition of cellular DNA synthesis. The antiviral activity of ribavirin appears to depend principally on intracellular conversion of the drug to ribavirin-5'-triphosphate and -monophosphate. Ribavirin-5'-diphosphate exhibits minimal antiviral activity compared with the monophosphate or triphosphate. Ribavirin is readily absorbed across the cellular plasma membrane, probably via a nucleoside transport mechanism. The drug is then converted via cellular enzymes to deribosylated ribavirin (the 1,2,4-triazole-3-carboxamide) and phosphorylated to ribavirin-5'-monophosphate, -diphosphate, and -triphosphate. Phosphorylation of ribavirin occurs principally in virus infected cells, but also occu

Pharmacodynamics

Ribavirin mediates direct antiviral activity against a number of DNA and RNA viruses by increasing the mutation frequency in the genomes of several RNA viruses. It is a member of the nucleoside antimetabolite drugs that interfere with duplication of the viral genetic material. The drug inhibits the activity of the enzyme RNA dependent RNA polymerase, due to its resemblence to building blocks of the RNA molecules.