RIBAVIRIN
DESCRIPTION:
WARNINGS:
USE OF AEROSOLIZED RIBAVIN IN PATIENTS
REQUIRING MECHANICAL VENTILATOR ASSISTANCE
SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND
SUPPORT STAFF FAMILIAR WITH THE SPECIFIC
VENTILATOR BEING USED AND THIS MODE OF
ADMINISTRATION OF THE DRUG. STRICT
ATTENTION MUST BE PAID TO PROCEDURES THAT
HAVE BEEN SHOWN TO MINIMIZE THE
ACCUMULATION OF DRUG PRECIPITATE, WHICH CAN
RESULT IN MECHANICAL VENTILATOR DYSFUNCTION
AND ASSOCIATED INCREASED PULMONARY
PRESSURES (SEE WARNINGS).
SUDDEN DETERIORATION OF RESPIRATORY
FUNCTION HAS BEEN ASSOCIATED WITH
INITIATION OF AEROSOLIZED RIBAVIN USE IN
INFANTS. RESPIRATORY FUNCTION SHOULD BE
CAREFULLY MONITORED DURING TREATMENT. IF
INITIATION OF AEROSOLIZED RIBAVIN
TREATMENT APPEARS TO PRODUCE SUDDEN
DETERIORATION OF RESPIRATORY FUNCTION,
TREATMENT SHOULD BE STOPPED AND
REINSTITUTED ONLY WITH EXTREME CAUTION,
CONTINUOUS MONITORING AND CONSIDERATION OF
CONCOMITANT ADMINISTRATION OF
BRONCHODILATORS (SEE WARNINGS).
RIBAVIN IS NOT INDICATED FOR USE IN
ADULTS. PHYSICIANS AND PATIENTS SHOULD BE
AWARE THAT RIBAVIRIN HAS BEEN SHOWN TO
PRODUCE TESTICULAR LESIONS IN RODENTS AND
TO BE TERATOGENIC IN ALL ANIMAL SPECIES IN
WHICH ADEQUATE STUDIES HAVE BEEN CONDUCTED
(RODENTS AND RABBITS); (SEE
CONTRAINDICATIONS).
Ribavin is a brand name for ribavirin, a synthetic nucleoside with antiviral
activity. RIBAVIN for inhalation solution is a sterile, lyophilized powder to
be reconstituted for aerosol administration. Each 100 mL glass vial contains 6
grams of ribavirin, and when reconstituted to the recommended volume of 300 mL
with sterile water for injection or sterile water for inhalation (no
preservatives added), will contain 20 mg of ribavirin per mL, pH approximately
5.5. Aerosolization is to be carried out in a Small Particle Aerosol Generator
(SPAG-2) nebulizer only.
Ribavirin is 1-beta-D-ribofuranosyl-1H- 1,2,4-triazole-3-carboxamide.
Ribavirin is a stable, white, crystalline compound with a maximum solubility in
water of 142 mg/mL at 25 deg C and with only a slight solubility in ethanol. The
empirical formula is C8H12N4O5 and the molecular weight is 244.21.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
In cell cultures the inhibitory activity of ribavirin for respiratory syncytial
virus (RSV) is selective. The mechanism of action is unknown. Reversal of the In
Vitro antiviral activity by guanosine or xanthosine suggests ribavirin may act
as an analogue of these cellular metabolites.
MICROBIOLOGY
Ribavirin has demonstrated antiviral activity against RSV In Vitro (REF. 1) and
in experimentally infected cotton rats. (REF. 2) Several clinical isolates of
RSV were evaluated for ribavirin susceptibility by plaque reduction in tissue
culture. Plaques were reduced 85-98% by 16 mcgm/mL; however, results may vary
with the test system. The development of resistance has not been evaluated In
Vitro or in clinical trials.
In addition to the above, ribavirin has been shown to have In Vitro activity
against influenza A and B viruses and herpes simplex virus, but the clinical
significance of these data is unknown.
IMMUNOLOGIC EFFECTS
Neutralizing antibody responses to RSV were decreased in aerosolized RIBAVIN
treated infants compared to placebo treated infants. (REF. 3) One study also
showed that RSV-specific IgE antibody in bronchial secretions was decreased in
patients treated with aerosolized RIBAVIN. In rats, ribavirin administration
resulted in lymphoid atrophy of the thymus, spleen, and lymph nodes. Humoral
immunity was reduced in guinea pigs and ferrets. Cellular immunity was also
mildly depressed in animal studies. The clinical significance of these
observations is unknown.
PHARMACOKINETICS
Assay for RIBAVIN in human materials is by a radioimmunoassay which detects
ribavirin and at least one metabolite.
RIBAVIN brand of ribavirin, when administered by aerosol, is absorbed
systemically. Four pediatric patients inhaling RIBAVIN aerosol administered by
face mask for 2.5 hours each day for 3 days had plasma concentrations ranging
from 0.44 to 1.55 microM, with a mean concentration of 0.76 microM. The plasma
half-life was reported to be 9.5 hours. Three pediatric patients inhaling
aerosolized RIBAVIN 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 microM, with a
mean concentration of 6.8 microM.
The bioavailability of aerosolized RIBAVIN is unknown and may depend on the
mode of aerosol delivery. After aerosol treatment, peak plasma concentrations of
ribavirin are 85% to 98% less than the concentration that reduced RSV plaque
formation in tissue culture. 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 it is unknown whether plasma concentrations or respiratory secretion
concentrations of the drug better reflect intracellular concentrations in the
respiratory tract.
In man, rats, and rhesus monkeys, accumulation of ribavirin and/or metabolites
in the red blood cells has been noted, plateauing in red cells in man in about 4
days and gradually declining with an apparent half-life of 40 days (the half-
life of erythrocytes). The extent of accumulation of ribavirin following
inhalation therapy is not well defined.
ANIMAL PHARMACOLOGY:
ANIMAL TOXICOLOGY
Ribavirin, when administered orally or as an aerosol, produced cardiac lesions
in mice, rats, and monkeys, when given at doses of 30, 36 and 120 mg/kg or
greater for 4 weeks or more (estimated human equivalent doses of 4.8, 12.3 and
111.4 mg/kg for a 5 kg child, or 2.5, 5.1 and 40 mg/kg for a 60 kg adult, based
on body surface area adjustment). Aerosolized ribavirin 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 in
the lungs following exposure at 131 mg/kg for 30 days. The significance of these
findings to human administration is unknown.
INDICATIONS AND USAGE:
RIBAVIN is indicated for the treatment of hospitalized infants and young
children with severe lower respiratory tract infections due to respiratory
syncytial virus. Treatment early in the course of severe lower respiratory tract
infection may be necessary to achieve efficacy.
Only severe RSV lower respiratory tract infection should be treated with
RIBAVIN. The vast majority of infants and children with RSV infection have
disease that is mild, self- limited, and does not require hospitalization or
antiviral treatment. Many children with mild lower respiratory tract involvement
will require shorter hospitalization than would be required for a full course of
RIBAVIN aerosol (3 to 7 days) and should not be treated with the drug. Thus the
decision to treat with RIBAVIN should be based on the severity of the RSV
infection.
The presence of an underlying condition such as prematurity, immunosuppression
or cardiopulmonary disease may increase the severity of clinical manifestations
and complications of RSV infection.
Use of aerosolized RIBAVIN in patients requiring mechanical ventilator
assistance should be undertaken only by physicians and support staff familiar
with this mode of administration and the specific ventilator being used (see
Warnings, and Dosage and Administration).
DIAGNOSIS
RSV infection should be documented by a rapid diagnostic method such as
demonstration of viral antigen in respiratory tract secretions by
immunofluorescence (REF. 3, 4) or ELISA (REF. 5) before or during the first 24
hours of treatment. Treatment may be initiated while awaiting rapid diagnostic
test results. However, treatment should not be continued without documentation
of RSV infection.
Non-culture antigen detection techniques may have false positive or false
negative results. Assessment of the clinical situation, the time of year and
other parameters may warrant reevaluation of the laboratory diagnosis.
DESCRIPTION OF STUDIES
NON-MECHANICALLY-VENTILATED INFANTS: In two placebo controlled trials in infants
hospitalized with RSV lower respiratory tract infection, aerosolized RIBAVIN
treatment had a therapeutic effect, as judged by the reduction in severity of
clinical manifestations of disease by treatment day 3. (REF. 3, 4) Treatment was
most effective when instituted within the first 3 days of clinical illness.
Virus titers in respiratory secretions were also significantly reduced with
RIBAVIN in one of these original studies. (REF. 4) Additional controlled
studies conducted since these initial trials of aerosolized RIBAVIN in the
treatment of RSV infection have supported these data.
MECHANICALLY-VENTILATED INFANTS: A randomized, double-blind, placebo controlled
evaluation of aerosolized RIBAVIN at the recommended dose was conducted in 28
infants requiring mechanical ventilation for respiratory failure caused by
documented RSV infection. (REF. 6) Mean age was 1.4 months (SD, 1.7 months).
Seven patients had underlying diseases predisposing them to severe infection and
21 were previously normal. Aerosolized RIBAVIN treatment significantly
decreased the duration of mechanical ventilation required (4.9 vs. 9.9 days,
p=0.01) and duration of required supplemental oxygen (8.7 vs 13.5 days, p=0.01).
Intensive patient management and monitoring techniques were employed in this
study. These included endotracheal tube suctioning every 1 to 2 hours; recording
of proximal airway pressure, ventilatory rate, and F1O2 every hour; and arterial
blood gas monitoring every 2 to 6 hours. To reduce the risk of RIBAVIN
precipitation and ventilator malfunction, heated wire tubing, two bacterial
filters connected in series in the expiratory limb of the ventilator (with
filter changes every 4 hours), and water column pressure release valves to
monitor internal ventilator pressures were used in connecting ventilator
circuits to the SPAG-2.
Employing these techniques, no technical difficulties with RIBAVIN
administration were encountered during the study. Adverse events consisted of
bacterial pneumonia in one case, staphylococcus bacteremia in one case and two
cases of post-extubation stridor. None were felt to be related to RIBAVIN
administration.
CONTRAINDICATIONS:
RIBAVIN is contraindicated in individuals who have shown hypersensitivity to
the drug or its components, and in women who are or may become pregnant during
exposure to the drug. Ribavirin has demonstrated significant teratogenic and/or
embryocidal potential in all animal species in which adequate studies have been
conducted (rodents and rabbits). Therefore, although clinical studies have not
been performed, it should be assumed that RIBAVIN may cause fetal harm in
humans. Studies in which the drug has been administered systemically demonstrate
that ribavirin is concentrated in the red blood cells and persists for the life
of the erythrocyte.
WARNINGS:
WARNINGS:
USE OF AEROSOLIZED RIBAVIN IN PATIENTS
REQUIRING MECHANICAL VENTILATOR ASSISTANCE
SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND
SUPPORT STAFF FAMILIAR WITH THE SPECIFIC
VENTILATOR BEING USED AND THIS MODE OF
ADMINISTRATION OF THE DRUG. STRICT
ATTENTION MUST BE PAID TO PROCEDURES THAT
HAVE BEEN SHOWN TO MINIMIZE THE
ACCUMULATION OF DRUG PRECIPITATE, WHICH CAN
RESULT IN MECHANICAL VENTILATOR DYSFUNCTION
AND ASSOCIATED INCREASED PULMONARY
PRESSURES (SEE WARNINGS).
SUDDEN DETERIORATION OF RESPIRATORY
FUNCTION HAS BEEN ASSOCIATED WITH
INITIATION OF AEROSOLIZED RIBAVIN USE IN
INFANTS. RESPIRATORY FUNCTION SHOULD BE
CAREFULLY MONITORED DURING TREATMENT. IF
INITIATION OF AEROSOLIZED RIBAVIN
TREATMENT APPEARS TO PRODUCE SUDDEN
DETERIORATION OF RESPIRATORY FUNCTION,
TREATMENT SHOULD BE STOPPED AND
REINSTITUTED ONLY WITH EXTREME CAUTION,
CONTINUOUS MONITORING AND CONSIDERATION OF
CONCOMITANT ADMINISTRATION OF
BRONCHODILATORS (SEE WARNINGS).
RIBAVIN IS NOT INDICATED FOR USE IN
ADULTS. PHYSICIANS AND PATIENTS SHOULD BE
AWARE THAT RIBAVIRIN HAS BEEN SHOWN TO
PRODUCE TESTICULAR LESIONS IN RODENTS AND
TO BE TERATOGENIC IN ALL ANIMAL SPECIES IN
WHICH ADEQUATE STUDIES HAVE BEEN CONDUCTED
(RODENTS AND RABBITS); (SEE
CONTRAINDICATIONS).
SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH INITIATION
OF AEROSOLIZED RIBAVIN USE IN INFANTS. Respiratory function should be carefully
monitored during treatment. If initiation of aerosolized RIBAVIN treatment
appears to produce sudden deterioration of respiratory function, treatment
should be stopped and reinstituted only with extreme caution, continuous
monitoring, and consideration of concomitant administration of bronchodilators.
USE WITH MECHANICAL VENTILATORS
USE OF AEROSOLIZED RIBAVIN IN PATIENTS REQUIRING MECHANICAL VENTILATOR
ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR
WITH THIS MODE OF ADMINISTRATION AND THE SPECIFIC VENTILATOR BEING USED. Strict
attention must be paid to procedures that have been shown to minimize the
accumulation of drug precipitate, which can result in mechanical ventilator
dysfunction and associated increased pulmonary pressures. These procedures
include the use of bacteria filters in series in the expiratory limb of the
ventilator circuit with frequent changes (every 4 hours), water column pressure
release valves to indicate elevated ventilator pressures, frequent monitoring of
these devices and verification that ribavirin crystals have not accumulated
within the ventilator circuitry, and frequent suctioning and monitoring of the
patient (see Clinical Studies).
Those administering aerosolized RIBAVIN in conjunction with mechanical
ventilator use should be thoroughly familiar with detailed descriptions of these
procedures as outlined in the SPAG-2 manual.
PRECAUTIONS:
GENERAL: Patients with severe lower respiratory tract infection due to
respiratory syncytial virus require optimum monitoring and attention to
respiratory and fluid status (see SPAG-2 manual).
DRUG INTERACTIONS
Clinical studies of interactions of RIBAVIN with other drugs commonly used to
treat infants with RSV infections, such as digoxin, bronchodilators, other
antiviral agents, antibiotics, or anti- metabolites have not been conducted.
Interference by RIBAVIN with laboratory tests has not been evaluated.
CARCINOGENESIS AND MUTAGENESIS
Ribavirin increased the incidence of cell transformations and mutations in mouse
Balb/c 3T3 (fibroblasts) and L5178Y (lymphoma) cells at concentrations of 0.015
and 0.03-5.0 mg/mL, respectively (without metabolic activation.) Modest
increases in mutation rates (3-4x) were observed at concentrations between 3.75-
10.0 mg/mL in L5178Y cells In Vitro with the addition of a metabolic activation
fraction. In the mouse micronucleus assay, ribavirin was clastogenic at
intravenous doses of 20-200 mg/kg, (estimated human equivalent of 1.67-16.7
mg/kg, based on body surface area adjustment for a 60 kg adult). Ribavirin was
not mutagenic in a dominant lethal assay in rats at intraperitoneal doses
between 50-200 mg/kg when administered for 5 days (estimated human equivalent of
7.14-28.6 mg/kg, based on body surface area adjustment; see Pharmacokinetics).
In Vivo carcinogenicity studies with ribavirin are incomplete. However, results
of a chronic feeding study with ribavirin in rats, at doses of 16-100 mg/kg/day
(estimated human equivalent of 2.3-14.3 mg/kg/day, based on body surface area
adjustment for the adult), suggest that ribavirin may induce benign mammary,
pancreatic, pituitary and adrenal tumors. Preliminary results of 2 oral gavage
oncogenicity studies in the mouse and rat (18-24 months; doses of 20-75 and 10-
40 mg/kg/day, respectively (estimated human equivalent of 1.67-6.25 and 1.43-
5.71 mg/kg/day, respectively, based on body surface area adjustment for the
adult)) are inconclusive as to the carcinogenic potential of ribavirin (see
Pharmacokinetics). However, these studies have demonstrated a relationship
between chronic ribavirin exposure and increased incidences of vascular lesions
(microscopic hemorrhages in mice) and retinal degeneration (in rats).
IMPAIRMENT OF FERTILITY
The fertility of ribavirin-treated animals (male or female) has not been fully
investigated. However, in the mouse, administration of ribavirin at doses
between 35-150 mg/kg/day (estimated human equivalent of 2.92-12.5 mg/kg/day,
based on body surface area adjustment for the adult) resulted in significant
seminiferous tubule atrophy, decreased sperm concentrations, and increased
numbers of sperm with abnormal morphology. Partial recovery of sperm production
was apparent 3-6 months following dose cessation. In several additional
toxicology studies, ribavirin has been shown to cause testicular lesions
(tubular atrophy), in adult rats at oral dose levels as low as 16 mg/kg/day
(estimated human equivalent of 2.29 mg/kg/day, based on body surface area
adjustment; see Pharmacokinetics). Lower doses were not tested. The reproductive
capacity of treated male animals has not been studied.
PREGNANCY: CATEGORY X
Ribavirin has demonstrated significant teratogenic and/or embryocidal potential
in all animal species in which adequate studies have been conducted. Teratogenic
effects were evident after single oral doses of 2.5 mg/kg or greater in the
hamster, and after daily oral doses of 0.3 and 1.0 mg/kg in the rabbit and rat,
respectively (estimated human equivalent doses of 0.12 and 0.14 mg/kg, based on
body surface area adjustment for the adult). Malformations of the skull, palate,
eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence
and severity of teratogenic effects increased with escalation of the drug dose.
Survival of fetuses and offspring was reduced. Ribavirin caused embryolethality
in the rabbit at daily oral dose levels as low as 1 mg/kg. No teratogenic
effects were evident in the rabbit and rat administered daily oral doses of 0.1
and 0.3 mg/kg, respectively with estimated human equivalent doses of 0.01 and
0.04 mg/kg, based on body surface area adjustment (see Pharmacokinetics). These
doses are considered to define the "No Observable Teratogenic Effects Level"
(NOTEL) for ribavirin in the rabbit and rat.
Following oral administration of ribavirin in the pregnant rat (1.0 mg/kg) and
rabbit (0.3 mg/kg), mean plasma levels of drug ranged from 0.10-0.20 microM
(0.024-0.049 mcgm/mL) at 1 hour after dosing, to undetectable levels at 24
hours. At 1 hour following the administration of 0.3 or 0.1 mg/kg in the rat and
rabbit (NOTEL), respectively, mean plasma levels of drug in both species were
near or below the limit of detection (0.05 microM; see Pharmacokinetics).
Although clinical studies have not been performed, RIBAVIN may cause fetal harm
in humans. As noted previously, ribavirin is concentrated in red blood cells and
persists for the life of the cell. Thus the terminal half-life for the systemic
elimination of ribavirin is essentially that of the half-life of circulating
erythrocytes. The minimum interval following exposure to RIBAVIN before
pregnancy may be safely initiated is unknown (see Contraindications, Warnings,
and Information for Health Care Personnel).
NURSING MOTHERS
RIBAVIN has been shown to be toxic to lactating animals and their offspring. It
is not known if RIBAVIN is excreted in human milk.
INFORMATION FOR HEALTH CARE PERSONNEL
Health care workers directly providing care to patients receiving aerosolized
RIBAVIN should be aware that ribavirin has been shown to be teratogenic in all
animal species in which adequate studies have been conducted (rodents and
rabbits). Although no reports of teratogenesis in offspring of mothers who were
exposed to aerosolized RIBAVIN during pregnancy have been confirmed, no
controlled studies have been conducted in pregnant women. Studies of
environmental exposure in treatment settings have shown that the drug can
disperse into the immediate bedside area during routine patient care activities
with highest ambient levels closest to the patient and extremely low levels
outside of the immediate bedside area. Adverse reactions resulting from actual
occupational exposure in adults are described below (see Adverse Events in
Health Care Workers). Some studies have documented ambient drug concentrations
at the bedside that could potentially lead to systemic exposures above those
considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the
most sensitive animal species). (REF. 7,8,9)
A 1992 study conducted by the National Institute of Occupational Safety and
Health (NIOSH) demonstrated measurable urine levels of ribavirin in health care
workers exposed to aerosol in the course of direct patient care. (REF. 7) Levels
were lowest in workers caring for infants receiving aerosolized RIBAVIN with
mechanical ventilation and highest in those caring for patients being
administered the drug via an oxygen tent or hood. This study employed a more
sensitive assay to evaluate ribavirin levels in urine than was available for
several previous studies of environmental exposure that failed to detect
measurable ribavirin levels in exposed workers. Creatinine adjusted urine levels
in the NIOSH study ranged from less than 0.001 to 0.140 microM of ribavirin per
gram of creatinine in exposed workers. However, the relationship between urinary
ribavirin levels in exposed workers, plasma levels in animal studies, and the
specific risk of teratogenesis in exposed pregnant women is unknown.
It is good practice to avoid unnecessary occupational exposure to chemicals
wherever possible. Hospitals are encouraged to conduct training programs to
minimize potential occupational exposure to RIBAVIN. Health care workers who
are pregnant should consider avoiding direct care of patients receiving
aerosolized RIBAVIN. If close patient contact cannot be avoided, precautions to
limit exposure should be taken. These include administration of RIBAVIN in
negative pressure rooms; adequate room ventilation (at least six air exchanges
per hour); the use of RIBAVIN aerosol scavenging devices; turning off the SPAG-
2 device for 5 to 10 minutes prior to prolonged patient contact, and wearing
appropriately fitted respirator masks. Surgical masks do not provide adequate
filtration of RIBAVIN particles. Further information is available from NIOSH's
Hazard Evaluation and Technical Assistance Branch and additional recommendations
have been published in an Aerosol Consensus Statement by the American
Respiratory Care Foundation and the American Association for Respiratory Care.
(REF. 10)
DRUG INTERACTIONS:
Clinical studies of interactions of RIBAVIN with other drugs commonly used to
treat infants with RSV infections, such as digoxin, bronchodilators, other
antiviral agents, antibiotics, or anti- metabolites have not been conducted.
Interference by RIBAVIN with laboratory tests has not been evaluated.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The description of adverse reactions is based on events from clinical studies
(approximately 200 patients) conducted prior to 1986, and the controlled trial
of aerosolized RIBAVIN conducted in 1989-1990. Additional data from spontaneous
post-marketing reports of adverse events in individual patients have been
available since 1986.
DEATHS
Deaths during or shortly after treatment with aerosolized RIBAVIN have been
reported in 20 cases of patients treated with RIBAVIN (12 of these patients
were being treated for RSV infections). Several cases have been characterized as
"possibly related" to RIBAVIN by the treating physician; these were in infants
who experienced worsening respiratory status related to bronchospasm while being
treated with the drug. Several other cases have been attributed to mechanical
ventilator malfunction in which RIBAVIN precipitation within the ventilator
apparatus led to excessively high pulmonary pressures and diminished
oxygenation. In these cases the monitoring procedures described in the current
package insert were not employed (see Description of Studies, Warnings, and
Dosage and Administration).
PULMONARY AND CARDIOVASCULAR
Pulmonary function significantly deteriorated during aerosolized RIBAVIN
treatment in six of six adults with chronic obstructive lung disease and in four
of six asthmatic adults. Dyspnea and chest soreness were also reported in the
latter group. Minor abnormalities in pulmonary function were also seen in
healthy adult volunteers.
In the original study population of approximately 200 infants who received
aerosolized RIBAVIN, several serious adverse events occurred in severely ill
infants with life-threatening underlying diseases, many of whom required
assisted ventilation. The role of RIBAVIN in these events is indeterminate.
Since the drug's approval in 1986, additional reports of similar serious, though
non-fatal, events have been filed infrequently. Events associated with
aerosolized RIBAVIN use have included the following:
PULMONARY: Worsening of respiratory status, bronchospasm, pulmonary edema,
hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea,
atelectasis and ventilator dependence.
CARDIOVASCULAR: Cardiac arrest, hypotension, bradycardia and digitalis toxicity.
Bigeminy, bradycardia and tachycardia have been described in patients with
underlying congenital heart disease.
Some subjects requiring assisted ventilation experienced serious difficulties,
due to inadequate 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.
Measures to avoid these complications should be followed carefully (see Dosage
and Administration).
HEMATOLOGIC
Although anemia was not reported with use of aerosolized RIBAVIN in controlled
clinical trials, most infants treated with the aerosol have not been evaluated 1
to 2 weeks post- treatment when anemia is likely to occur. Anemia has been shown
to occur frequently with experimental oral and intravenous RIBAVIN in humans.
Also, cases of anemia (type unspecified), reticulocytosis and hemolytic anemia
associated with aerosolized RIBAVIN use have been reported through post-
marketing reporting systems. All have been reversible with discontinuation of
the drug.
OTHER
Rash and conjunctivitis have been associated with the use of aerosolized
RIBAVIN. These usually resolve within hours of discontinuing therapy. Seizures
and asthenia associated with experimental intravenous RIBAVIN therapy have also
been reported.
ADVERSE EVENTS IN HEALTH CARE WORKERS
Studies of environmental exposure to aerosolized RIBAVIN in health care workers
administering care to patients receiving the drug have not detected adverse
signs or symptoms related to exposure. However, 152 health care workers have
reported experiencing adverse events through post-marketing surveillance. Nearly
all were in individuals providing direct care to infants receiving aerosolized
RIBAVIN. Of 358 events from these 152 individual health care worker reports,
the most common signs and symptoms were headache (51% of reports),
conjunctivitis (32%), and rhinitis, nausea, rash, dizziness, pharyngitis, or
lacrimation (10-20% each). Several cases of bronchospasm and/or chest pain were
also reported, usually in individuals with known underlying reactive airway
disease. Several case reports of damage to contact lenses after prolonged close
exposure to aerosolized RIBAVIN have also been reported. Most signs and
symptoms reported as having occurred in exposed health care workers resolved
within minutes to hours of discontinuing close exposure to aerosolized RIBAVIN
(also see Information for Health Care Personnel).
The symptoms of RSV in adults can include headache, conjunctivitis, sore throat
and/or cough, fever, hoarseness, nasal congestion and wheezing, although RSV
infections in adults are typically mild and transient. Such infections represent
a potential hazard to uninfected hospital patients. It is unknown whether
certain symptoms cited in reports from health care workers were due to exposure
to the drug or infection with RSV. Hospitals should implement appropriate
infection control procedures.
OVERDOSAGE:
No overdosage with RIBAVIN by aerosol administration has been reported in
humans. The LD50 in mice is 2 gm orally and is associated with hypoactivity and
gastrointestinal symptoms (estimated human equivalent dose of 0.17gm/kg, based
on body surface area conversion). The mean plasma half-life after administration
of aerosolized RIBAVIN for pediatric patients is 9.5 hours. RIBAVIN is
concentrated and persists in red blood cells for the life of the erythrocyte
(see Pharmacokinetics).
DOSAGE AND ADMINISTRATION:
BEFORE USE, READ THOROUGHLY THE ICN SMALL PARTICLE AEROSOL GENERATOR MODEL SPAG-
2 OPERATOR'S MANUAL FOR SMALL PARTICLE AEROSOL GENERATOR OPERATING INSTRUCTIONS.
AEROSOLIZED RIBAVIN SHOULD NOT BE ADMINISTERED WITH ANY OTHER AEROSOL
GENERATING DEVICE.
The recommended treatment regimen is 20 mg/mL RIBAVIN as the starting solution
in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration
for 12-18 hours per day for 3 to 7 days. Using the recommended drug
concentration of 20 mg/mL the average aerosol concentration for a 12 hour
delivery period would be 190 micrograms/liter of air. Aerosolized RIBAVIN
should not be administered in a mixture for combined aerosolization or
simultaneously with other aerosolized medications.
NON-MECHANICALLY VENTILATED INFANTS
RIBAVIN should be 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 and condensation
area are larger in a tent and this may alter delivery dynamics of the drug.
MECHANICALLY VENTILATED INFANTS
The recommended dose and administration schedule for infants who require
mechanical ventilation is the same as for those who do not. Either a pressure or
volume cycle ventilator may be used in conjunction with the SPAG-2. In either
case, patients should have their endotracheal tubes suctioned every 1-2 hours,
and their pulmonary pressures monitored frequently (every 2-4 hours). For both
pressure and volume ventilators, heated wire connective tubing and bacteria
filters in series in the expiratory limb of the system (which must be changed
frequently, i.e., every 4 hours) must be used to minimize the risk of RIBAVIN
precipitation in the system and the subsequent risk of ventilator dysfunction.
Water column pressure release valves should be used in the ventilator circuit
for pressure cycled ventilators, and may be utilized with volume cycled
ventilators (SEE SPAG-2 MANUAL FOR DETAILED INSTRUCTIONS).
METHOD OF PREPARATION
RIBAVIN brand of ribavirin is supplied as 6 grams of lyophilized powder per 100
mL vial for aerosol administration only. By sterile technique, reconstitute drug
with A MINIMAL OF 75ML OF STERILE USP WATER FOR INJECTION OR INHALATION in THE
ORIGINAL 100 mL glass vial. SHAKE WELL. Transfer to the clean, sterilized 500mL
SPAG-2 reservoir and further dilute to a final volume of 300 mL with Sterile
Water for Injection, USP, or Inhalation. The final concentration should be 20
mg/mL. IMPORTANT: This water should NOT have had any antimicrobial agent or
other substance added. The solution should be inspected visually for particulate
matter and discoloration prior to administration. Solutions that have been
placed in the SPAG-2 unit should be discarded at least every 24 hours and when
the liquid level is low before adding newly reconstituted solution.
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