Virazole (Ribavirin) Aerosol

Ribavirin 6 g

International non-proprietary name (INN): Ribavirin

Chemical Name: 1-Beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide

Powder for inhalation solution.

Virazole is indicated in the treatment of infants and children with severe respiratory syncytial virus (RSV) bronchiolitis.

Important: Ribavirin aerosol is more effective when instituted within the first 3 days of the treatment of bronchiolitis. Treatment early in the course of the disease may be necessary to achieve efficacy.

Treatment with Virazole must be accompanied by, and does not replace, standard supportive respiratory and fluid management for infants and children with severe respiratory tract infection.

Nebulised bronchodilators, when clinically indicated, should be administered with the small particle aerosol generator (SPAG) generator or Aiolos nebuliser turned off.

Ribavirin aerosol is only recommended for use in infants and children.

Aerosol administration or nebulisation should be carried out in a SPAG or Aiolos nebuliser. Before use read the relevant Operator's Manual for instructions.

Treatment is carried out for 12 to 18 hours per day for at least 3 and no more than 7 days and is part of a total treatment programme.

The daily dose is prepared by dissolving 6 g of ribavirin in a minimum of 75 ml Water for Injection BP. Shake well. Transfer dissolved drug and dilute to a total volume of 300 ml of Water for Injection BP to give a 20 mg/ml ribavirin solution.

In the SPAG unit and Aiolos nebuliser the average concentration for a 7 hour period is 190 µg/l of air.

Method of administration

Please see point 6.6 for instructions on preparation of the aerosol solution.

The aerosol is delivered to an infant oxygen hood from the SPAG aerosol generator or Aiolos nebuliser. Administration by face mask or oxygen tent may be necessary if a hood cannot be employed (see Operator's Manual). However, the volume of distribution and condensation area are larger in a tent and the efficacy of this method of administration has been evaluated only in a small number of patients.

Ribavirin is contraindicated in females who are or may become pregnant and it should be noted that ribavirin can be detected in human blood even four weeks after oral administration has ceased.

Precipitation of the drug in respiratory equipment and consequent accumulation of fluid in the tubing has caused difficulties for patients requiring assisted ventilation.

In infants requiring assisted ventilation, Virazole should only be used when there is constant monitoring of both patients and equipment.

Directions for use during assisted ventilation are given in the SPAG or Aiolos manual, which should be read carefully before such administration.

Occupational exposure

Nebulised Virazole may potentially escape into the hospital environment during therapy. However, ribavirin was not detected in the erythrocytes, plasma or urine of subjects exposed for a mean of 25 hours during 5 consecutive days. Reports of occupational asthma have been reported rarely although the causal link to ribavirin is unknown since respiratory viruses may induce reactive airways disease in addition to other symptoms including headache, fever, nasal congestion and wheezing. However, care should be exercised, particularly in healthcare workers with pre-existing reactive airways diseases.

Health care workers directly providing care to patients receiving aerosolised Virazole should be aware that ribavirin has been shown to be teratogenic in rabbits and rodents but not in baboons. However, no reports of teratogenicity in the offspring of mothers who were exposed to Virazole aerosol during pregnancy have been confirmed and the teratogenic risk of Virazole to humans is unknown. As a precaution, women who are pregnant or trying to become pregnant should avoid exposure to the Virazole aerosol.

It is good practice to avoid unnecessary occupational exposure to chemicals whenever possible. Several methods have been employed to lower environmental exposure during Virazole use. The most practical of these is to turn the SPAG or Aiolos Nebuliser off for 5 to 10 minutes prior to prolonged contact.

None known.

Ribavirin is contraindicated in females who are or may become pregnant, and in nursing mothers. Ribavirin can be detected in human blood four weeks after administration has ceased. Although there are no pertinent human data, oral ribavirin has been found to be teratogenic in tested rodent species. Pregnant baboons given up to 120 mg/kg/day orally over a 4 week period and within 20 days of gestation failed to exhibit any teratogenic effects.

None known.

Side-effects: Several serious adverse events occurred in severely ill infants with life-threatening underlying disease, many of whom required assisted ventilation. These events included worsening of respiratory status, bacterial pneumonia and pneumothorax. The role of ribavirin aerosol in these events has not been determined.

Anaemia (often of a haemolytic variety) and reticulocytosis have been reported with oral and intravenous administration. Rarely, cases of non-specific anaemia and haemolysis have been reported spontaneously in association with the aerosol administration of Virazole.

No overdoses have been reported.

Ribavirin has anti-viral inhibitory activity in vitro against respiratory syncytial virus, influenzae virus and herpes simplex virus. Ribavirin is also active against respiratory syncytial virus in experimentally infected cotton rats.

The inhibitory activity of ribavirin on RSV in cell cultures is selective. The mechanism of action is unknown, but there is evidence that ribavirin interferes with protein translation by mRNA of several other RNA viruses, possibly the result of interference with formation of the 5' cap structure of mRNA.

Assay for ribavirin in human materials is by a radioimmunoassay which detects ribavirin and at least one metabolite.

Ribavirin administered by aerosol is absorbed systemically. Four paediatric patients inhaling ribavirin aerosol administered by face mask for 2.5 hours each day had plasma concentrations ranging from 0.44 to 1.44 µM, with a mean concentration of 0.76 µM. The plasma half-life was reported to be 9.5 hours. Three paediatric patients inhaling ribavirin aerosol administered by face mask or mist tent for 20 hours each day for 5 days had plasma concentrations ranging from 1.5 to 14.3 µM, with a mean concentration of 6.8 µM.

It is likely that the concentration of ribavirin in respiratory tract secretions is much higher than plasma concentrations in view of the route of administration.

The bioavailability of ribavirin is unknown and may depend on the mode of aerosol delivery. After aerosol treatment, peak plasma concentrations are less than the concentration that reduced RSV plaque formation in tissue cultures by 85 to 98%. After aerosol treatment, respiratory tract secretions are likely to contain ribavirin in concentrations many fold higher than those required to reduce plaque formation. However, RSV is an intracellular virus and serum concentrations may better reflect intracellular concentrations in the respiratory tract than respiratory secretion concentrations.

Pertinent information is included in the Pregnancy and Lactation section.

Not applicable.

None known.

5 years. After reconstitution in Water for Injections, Virazole should be used within 24 hours.

Store in a dry place. Store below 25°C.

100 ml type 1 glass serum bottle with butyl rubber closure and aluminium seal with tear-off septum. Each bottle contains 6 g ribavirin as a lyophilised white cake. Virazole is packaged in cartons of three bottles.

By aseptic technique dissolve the powder in a minimum of 75 ml Water for Injections BP in the 100 ml vial. The solution should be adequately mixed to ensure complete dissolution. Shake well. It is not recommended that this solution is heated during dissolution. When using the SPAG generator, transfer the solution to the clean, sterilised 500 ml flask and dilute to a final volume of 300 ml with Water for Injections BP. When using the Aiolos nebuliser, transfer the solution into an infusion bag and dilute to a final volume of 300 ml with Water for Injections BP. The final concentration should be 20 mg/ml.

The Water for Injections BP used to make up the Virazole solution should not have any antimicrobial agent or any other substance added and all solutions should be inspected for particulate matter and discoloration prior to administration.

See guidelines for avoiding unwanted exposure to Virazole aerosol under 4.4. Special warnings and special precautions for use.

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

11 March 1996

June 2009