Oral Ribavirin for RSV

The Pharmacy and Therapeutics Committee voted to add oral ribavirin to the in inpatient formulary in the spring of 2014 after a request was made for use in the immunocompromised adult oncology patient population for the treatment of respiratory syncytial virus (RSV). A multi-disciplinary group met and evaluated the published effectiveness of various ribavirin formulations. Additionally the costs and safety of administration of each formulation were evaluated and the result of this process was a request to add oral ribavirin to the formulary with publication of guidelines for its use.

  • Oral ribavirin was restricted to the oncology and infectious disease services when used for off label indications (i.e., RSV). Thus, continuation of home therapy for the treatment of Hepatitis C would not be included in the restriction.

In the fall of 2015, an additional request was made for use in lung transplant patients. A multi-disciplinary group met to review the published effectiveness of ribavirin for RSV in this patient population. After a review of the literature and groups discussion it was decided that lung transplant recipients infected with RSV represent another high risk group and should be considered for treatment with oral ribavirin. Decisions on the use of ribavirin in this population will be a joint decision involving both the lung transplant group and infectious disease.

Oral Ribavirin Guidelines Treatment Guidelines

Pharmacology

  • Ribavirin is categorized as an antihepaciviral, nucleoside (Anti-HCV); it inhibits replication of RNA and DNA viruses. It inhibits RNA polymerase activity and inhibits the initiation and elongation of RNA fragments which prevents viral protein synthesis.

FDA Approved Indications

  • Ribavirin is FDA approved for treatment of hepatitis C infection and respiratory syncytial virus (RSV) infection in children. There are different formulations of ribavirin (inhalation, capsule/solution, tablet); specific FDA approved indications for each formulation are different.

Mechanism of action:

  • Ribavirin inhibits replication of RNA and DNA viruses. It inhibits RNA polymerase activity and inhibits the initiation and elongation of RNA fragments which prevents viral protein synthesis.6

Pharmacokinetics:6, 16, 17

  • Ribavirin’s absolute bioavailability is reduced due to first-pass metabolism. Administering ribavirin with a high fat meal increases the AUC and the peak concentrations by 70%. Ribavirin is “metabolized via a reversible phosphorylation pathway in nucleated cells and a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite.”16 The metabolites, triazole carboxamide and triazole carboxylic acid, and unchanged ribavirin are excreted renally.
  • In patients with renal dysfunction, AUCtf values (time zero to last measured concentration) after a single oral dose are increased 2 fold when CrCl is 30-60ml/min and increased 3 fold when CrCl is 10-30ml/min. The increase in AUCtf values in renal insufficiency were thought to be due to alteration of both renal and non-renal clearance of ribavirin.

Dosing:

  • 15-20mg/kg/day divided into TID administration for 7-10 days
Table 4: Pharmacokinetics
Absorption/bioavailability 64%
Distribution 2825L
Prolonged in erythrocyte, Does not bind to plasma proteins
Metabolism Hepatic, intracellular
Half-life of elimination 24h (single dose), 298h (multiple doses, BID)
Time to peak serum concentration Capsule: 3h
Tablet: 2h
Excretion Urine 61%, Feces 12% (in 336h); unchanged ribavirin 17% of administered dose; ribavirin and triazole metabolites excreted renally

Administration:

  • Oral ribavirin should be taken with food.6

Contraindications to oral ribavirin formulations:6

  • Hypersensitivity to the ribavirin product, pregnant women or women who may become pregnant, males with pregnant female partners, patients with hemoglobinopathies, patients with autoimmune hepatitis, concomitant use with didanosine, and some specific products have contraindications for use in patients with CrCl<50ml/min

Warnings/precautions:6

  • A boxed warning exists for hemolytic anemia which may occur with oral therapy. Patients with significant or unstable cardiac disease should avoid use of ribavirin due to the potential for the hemolytic anemia leading to a myocardial infarction. Elderly patients may be more prone to adverse events such as anemia. Experience with the use of ribavirin for treatment of hepatitis C indicates that anemia usually occurs within 1-2 weeks after initiation of oral ribavirin therapy.
  • For those patients that have renal impairment, dose adjustments or discontinuation of therapy may be needed.
  • A boxed warning also exists regarding the teratogenic effects of ribavirin observed in animal studies. Pregnancy should be avoided during and for 6 months after treatment in both female patients and the female partners of male patients treated with ribavirin.
  • This is a hazardous agent and special handling and disposal is required.

Adverse reactions (oral therapy):2, 7,8

  • Hemolytic anemia, nephrotoxicity, drug rash, lactic acidosis, altered mental status

Monitoring:6

  • CBC (baseline, twice weekly while on therapy)23
  • In patients with new onset anemia, a blood smear should be evaluated for schistocytes.
  • Renal function (e.g., serum creatinine)