Virazole (Ribavirin)

Virazole (Lyophilized)

ICN

Ribavirin

Antiviral

Action And Clinical Pharmacology: Ribavirin is active against respiratory syncytial virus (RSV). In cell cultures, the inhibitory activity of ribavirin for RSV is selective. The mechanism(s) of action is unknown, although evidence exists that inhibition of other RNA and DNA viruses may be due to ribavirin competition with guanosine in formation of viral mRNA cap structures and/or interference with enzymes responsible for functional methylation of these molecules which are critical for production of structural viral proteins. tag_IndicationsIndications

Indications And Clinical Uses: RSV infection should be documented by a rapid diagnostic method such as demonstration of viral antigen in respiratory tract secretions by immunofluorescence or ELISA before or during the first 24 hours of treatment. Ribavirin aerosol is indicated only for lower respiratory tract infection due to RSV. Treatment may be initiated while awaiting rapid diagnostic test results. However, treatment should not be continued without documentation of RSV infection.

Limited clinical data indicate that ribavirin administered as a small particle aerosol may be beneficial in the treatment of severe respiratory syncytial virus infection in neonates and infants when associated with underlying cardiovascular, pulmonary or immune deficiency. Treatment should be confined to hospitalized patients and administration should be continuous during the period of therapy apart from the time required for ancillary care of the patient. Only severe RSV lower respiratory tract infection is to be treated with ribavirin aerosol.

Ribavirin aerosol treatment must be accompanied by and does not replace standard supportive respiratory and fluid management for infants and children with severe respiratory tract infection.

Contra-Indications: Ribavirin aerosol is contraindicated in women or girls who are or may become pregnant during exposure to the drug. Ribavirin may cause fetal harm, and respiratory syncytial virus infection is self-limited in this population. Ribavirin is not completely cleared from human blood even 4 weeks after administration. Although there are no pertinent human data, ribavirin has been found to be teratogenic and/or embryolethal in nearly all species in which it has been tested; however, pregnant baboons given up to 120 mg/kg/day of ribavirin over a 4 day period within the 20 days of organogenesis during gestation failed to exhibit any teratogenic effect. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Close monitoring of patients and respiratory equipment must be guaranteed when ribavirin is used in infants requiring assisted ventilation. Precipitation of ribavirin powder in respiratory equipment may interfere with safe and effective patient ventilation.

Bronchospasm was observed in a tolerance study with ribavirin aerosol in adults with chronic obstructive pulmonary disease and asthma.

Respiratory function should be carefully monitored during treatment. If initiation of ribavirin aerosol treatment appears to produce sudden deterioration of respiratory function, treatment should be stopped and only reinstituted with caution and continuous monitoring.

Pregnancy: Although ribavirin is not indicated in adults, the physician should be aware that it is teratogenic in animals (see Contraindications).

Ribavirin administered by aerosol produced cardiac lesions in mice and rats after 30 and 36 mg/kg, respectively, for 4 weeks, and after oral administration in monkeys at 120 mg/kg and rats at 154 to 200 mg/kg for 1 to 6 months. Ribavirin aerosol administered to developing ferrets at 60 mg/kg for 10 or 30 days resulted in inflammatory and possibly emphysematous changes in the lungs. Proliferative changes were seen at 131 mg/kg for 30 days. The significance of these findings to human administration is unknown.

Ribavirin lyophilized in 6 g vials is intended for use as an aerosol only.

It has been noted that ribavirin has shown some evidence of mutagenesis in some in vitro test systems. Carcinogenicity studies are incomplete and inconclusive. Some evidence for the production of benign tumors has been shown.

Precautions: Ribavirin has been in use for many years in human beings without any reported adverse effects in human fetuses. However, there are no adequate and well-controlled studies in pregnant women, and there is little published evidence of its safety in the early stages of human pregnancy. Since ribavirin is delivered in aerosolized form and because of known teratogenic effects in animals, pregnant women should not care for patients receiving ribavirin, although human teratogenic effects have not been proven.

Patients with lower respiratory tract infections due to respiratory syncytial virus require optimum monitoring and attention to respiratory and fluid status.

Drug Interactions: Interactions of ribavirin with other drugs such as digoxin, bronchodilators, other antiviral agents, antibiotics, or antimetabolites have not been evaluated. Interference by ribavirin with laboratory tests has not been evaluated. Appropriate attention should be given to the possibility of such interactions.

Adverse Reactions: The safety data from patients treated with ribavirin aerosol has been carefully evaluated in 26 studies. Bronchospasm was observed in a tolerance study with ribavirin aerosol (20 mg/mL) in adults. One of 6 adult patients with chronic obstructive pulmonary disease and 2 of 6 asthmatic adults became dyspneic during the period of ribavirin aerosol administration. These patients required chronic administration of bronchodilators which were discontinued 24 hours prior to ribavirin treatment. An inhalation of a bronchodilator by puffer produced symptomatic relief and return to baseline conditions.

Several serious adverse events occurred in severely ill infants with life-threatening underlying diseases, many of whom required assisted ventilation. These events include: worsening of respiratory status, bacterial pneumonia and pneumothorax. The role of ribavirin in these events is indeterminate.

There were 19 deaths during or shortly after treatment with ribavirin aerosol. No death was attributed to ribavirin aerosol by the investigators.

Some subjects requiring assisted ventilation have experienced serious difficulties, which may jeopardize adequate ventilation and gas exchange. Precipitation of drug within the ventilatory apparatus, including the endotracheal tube, has resulted in increased positive end expiratory pressure and increased positive inspiratory pressure. Accumulation of fluid in tubing “rain out” has also been noted.

Although anemia has not been reported with use of the aerosol, it occurs frequently with oral and i.v. ribavirin, and most infants treated with the aerosol have not been evaluated 1 to 2 weeks post-treatment when anemia is likely to occur. Reticulocytosis has been reported with aerosol use.

Conjunctivitis has been reported in controlled studies with ribavirin aerosol, however, no significant difference was observed between ribavirin treated and control groups.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No overdosage with ribavirin by aerosol administration has been reported in the human. In man, ribavirin is sequestered in red blood cells for weeks after dosing.

Dosage And Administration: Before use, read thoroughly the ICN Small Particle Aerosol Generator (SPAG) Model SPAG-2 Operator’s Manual for small particle aerosol generator operating instructions.

Treatment should be instituted as early as possible within the first 3 days of respiratory syncytial virus lower respiratory tract infection. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy. Treatment is carried out continuously, apart from the time required for ancillary care, for at least 3 and no more than 7 days, and is part of a total treatment program.

The aerosol is delivered to an infant oxygen hood from the SPAG-2 aerosol generator. Administration by face mask or oxygen tent may be necessary if a hood cannot be employed (see SPAG-2 manual). However, the volume of distribution and condensation area are larger in a tent and efficacy of this method of administering the drug has been evaluated in only a small number of patients. Ribavirin aerosol is not to be administered with any other aerosol generating device or from the same reservoir with other aerosolized medications.

Aerosolized bronchodilators, when clinically indicated, should be administered with the ribavirin SPAG-2 generator shut down.

Using the recommended drug concentration of 20 mg/mL ribavirin as the starting solution in the drug reservoir of the SPAG unit, the average aerosol concentration for a 12 hour period is 190 g/L (0.19 mg/L) of air.

Reconstitution: By sterile technique, reconstitute drug with a minimum of 70 mL sterile water USP for injection or inhalation in the original 100 mL glass vial. Shake well. Transfer to the clean, sterilized 500 mL widemouth Erlenmeyer flask (SPAG-2 Reservoir) and further dilute to a final volume of 300 mL with sterile USP water for injection or inhalation. The final concentration should be 20 mg/mL.

Important: This water should not have any antimicrobial agent or other substance added. The solution should be inspected visually for particulate matter and discoloration prior to administration. When the liquid level in the SPAG-2 unit is low, it should be discarded before adding newly reconstituted solution. Solutions that have been placed in the SPAG-2 unit should be discarded at least every 24 hours.

Stability and Storage of Solution: Reconstituted solutions should be prepared immediately before use or may be stored in 100 mL glass vials under sterile conditions at 2 to 6°C for 24 hours. Further diluted solutions should not be stored.

Availability And Storage: Each 100 mL glass vial of sterile, lyophilized powder contains: ribavirin 6 g. The drug is administered only by a small particle aerosol generator (SPAG-2). Store in a dry place at 15 to 25°C. Packs of 4.

Virazole (Lyophilized) ICN Ribavirin Antiviral

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