Ribavirin (Systemic)


VA CLASSIFICATION
Primary: AM890

Commonly used brand name(s): Virazole.

Another commonly used name is
tribavirin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—
Note: Ribavirin is a broad-spectrum antiviral active in vitro against a wide variety of DNA and RNA viruses. {01} {03}



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Respiratory syncytial virus (RSV) infection, lower respiratory tract (treatment)—Ribavirin inhalation solution is indicated as a primary agent in the treatment of lower respiratory tract disease (including bronchiolitis and pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and young children who are at high risk for severe or complicated RSV infection; this category includes premature infants and infants with structural or physiologic cardiopulmonary disorders, bronchopulmonary dysplasia, immunodeficiency, or imminent respiratory failure. {01} {20} {22} {46} {47} Ribavirin is indicated in the treatment of RSV infections in infants requiring mechanical ventilator assistance. {46} {49} {50} {51} {62} {66}

[Influenza A (treatment)]1 or
[Influenza B (treatment)]1—Ribavirin inhalation solution is used as a secondary agent in the treatment of influenza A and B in young adults when treatment is started early (e.g., within 24 hours of initial symptoms) in the course of the disease. {07} {08} {17} {23} {24} {25} {26} {27} {29}

[Lassa fever (prophylaxis and treatment)]1or
[Viral hemorrhagic fever (prophylaxis and treatment)]1—Oral and intravenous ribavirin are used in the treatment of Lassa fever and as post-exposure prophylaxis in contacts at high risk. It may be similarly effective with other viral hemorrhagic fevers, including hemorrhagic fever with renal syndrome, Crimean-Congo hemorrhagic fever, and Rift Valley fever. {11} {19} {54} {55} {63}

Unaccepted
Ribavirin is not indicated in children with mild RSV lower respiratory tract involvement who require a shorter hospitalization than that required for completion of a full course of ribavirin treatment (i.e., 3 to 7 days). {01}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    244.21

Mechanism of action/Effect:

Virustatic {02} {03} {21} {28} {30}; mechanism not completely understood {01} {04} {08} {09} {10} {13} {24} {28}, but does not alter viral attachment, penetration, or uncoating {16} {28} {30} and does not induce cellular production of interferon {02} {03} {28} {30} {35}; however, reversal of its antiviral action by guanosine and xanthosine suggests that ribavirin may act as a competitive inhibitor of cellular enzymes that act on these metabolites {01} {03} {08} {09} {16} {23} {31}. Ribavirin is rapidly transported into cells and acts within virus-infected cells {01} {30} {36}. Ribavirin is readily phosphorylated intracellularly by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites {02} {03} {06} {09} {15} {23} {25}. Ribavirin triphosphate (RTP) is a potent competitive inhibitor of inosine monophosphate (IMP) dehydrogenase {03} {09} {12} {13} {15} {16} {17} {23} {28} {31} {35}, influenza virus RNA polymerase {03} {08} {10} {13} {17} {23} {28}, and messenger RNA (mRNA) guanylyltransferase {03} {09} {13} {17}, the latter resulting in inhibition of the capping of mRNA {02} {03} {09} {17} {23} {28}. These diverse effects result in a marked reduction of intracellular guanosine triphosphate (GTP) pools {03} {08} {17} {23} {28} {31} and inhibition of viral RNA and protein synthesis {02} {03} {06} {08} {10} {14} {15} {24} {30} {31} {35}. Ultimately, viral replication and spreading to other cells are prevented or greatly inhibited {24}.


Other actions/effects:

May have immunologic effects; decreases in neutralizing antibody responses to respiratory syncytial virus (RSV) infection have been reported in ribavirin-treated patients. The clinical significance of this effect is unknown. Ribavirin has also been shown to significantly reduce viral shedding in RSV-infected patients. {01} {18} {20} {21}

Absorption:

Inhalation—A small amount is systemically absorbed following inhalation. {01} {37} {42}

Oral—Rapidly absorbed from the gastrointestinal tract following oral administration {10} {36}; bioavailability is approximately 45%. {60} {65}

Distribution:

Distributed to plasma, respiratory tract secretions, and erythrocytes (RBCs) {01} {21} {23} {36}. Large amounts of ribavirin triphosphate are sequestered in RBCs, reaching a plateau in approximately 4 days and remaining sequestered for weeks after administration {01} {23}. Significant concentrations (greater than 67%) may be found in the cerebrospinal fluid after prolonged administration. {59}

Vol D=Approximately 647 to 802 liters. {60} {65}

Protein binding:

No significant plasma protein binding. {60}

Biotransformation:

Hepatic (probable) {10} {36}; phosphorylated intracellularly to mono-, di-, and triphosphate metabolites, the latter being active {10} {16} {17}; metabolized also to 1,2,4-triazole carboxamide metabolite {36}; secondary metabolic pathway involves amide hydrolysis to tricarboxylic acid, deribosylation, and breakdown of the triazole ring. {03} {06}

Half-life:


Distribution:


Intravenous—

Approximately 0.2 hours. {60}




Elimination:

Inhalation: 9.5 hours. {01}

Intravenous and oral (single dose): 0.5 to 2 hours. {03} {06} {60} {65}

In erythrocytes: 40 days. {01} {03} {06}



Terminal:


Intravenous and oral—

Single dose—27 to 36 hours. {60} {65}

Steady state—Approximately 151 hours. {65}



Time to peak plasma concentration

Intravenous—End of infusion.

Oral—1 to 1.5 hours. {03} {10} {65}

Therapeutic plasma concentration

Therapeutically effective concentrations depend primarily on the duration of exposure and patient minute volume. {36} Concentrations in respiratory tract secretions are much higher than corresponding plasma concentrations. {37}

Mean peak plasma concentration


Inhalation:

Approximately 0.2 mcg per mL (0.8 micromoles) in pediatric patients receiving ribavirin aerosol by face mask 2.5 hours per day for 3 days. {01}

Approximately 1.7 mcg per mL (6.8 micromoles) in pediatric patients receiving ribavirin aerosol by face mask or mist tent 20 hours per day for 5 days. {01}



Intravenous:

Approximately 43 micromoles per liter after a single 600 mg dose. {60}

Approximately 72 micromoles per liter after a single 1200 mg dose. {60}



Oral:

Approximately 5 micromoles per liter at the end of the first week of administration of 200 mg every 8 hours. {56}

Approximately 11 micromoles per liter at the end of the first week of administration of 400 mg every 8 hours. {56}


Elimination:


Inhalation—
        Renal: Approximately 30 to 55% excreted as the 1,2,4-triazole carboxamide metabolite in urine within 72 to 80 hours. {03} {06} {10} {36}
        Fecal: Approximately 15% excreted in feces within 72 hours. {03} {06} {10} {36}



Intravenous—
        Approximately 19% excreted unchanged in 24 hours; approximately 24% excreted unchanged in 48 hours. {60}



Oral—
        Approximately 7% excreted unchanged in 24 hours; approximately 10% excreted unchanged in 48 hours. {60}



In dialysis—
        Significant amounts of ribavirin are not removed by hemodialysis. {64}



Precautions to Consider

Carcinogenicity/Tumorigenicity

Studies have shown that ribavirin induces cell transformation in a mammalian system (Balb/C 3T3 cell line). Although carcinogenicity studies are incomplete and inconclusive, results thus far suggest that chronic feeding of ribavirin to rats in doses of 16 to 60 mg per kg of body weight (mg/kg) can induce benign mammary, pancreatic, pituitary, and adrenal gland tumors. {01}

Mutagenicity

Studies have shown that ribavirin is mutagenic to mammalian cells (L5178Y) in culture. However, microbial mutagenicity assays and dominant lethal assays in mice have not shown that ribavirin is mutagenic. {01} {03}

Pregnancy/Reproduction
Fertility—
Although the effects of lower doses have not been studied, studies have shown that ribavirin causes testicular lesions (tubular atrophy) in adult rats given oral doses as low as 16 mg/kg daily. However, the fertility of ribavirin-treated animals (male or female) has not been adequately investigated. {01}

Pregnancy—
Ribavirin is contraindicated during pregnancy. Studies in humans have not been done. Although ribavirin is not indicated for use in adults in the U.S., healthcare workers and visitors who spend time at the patient's bedside may become environmentally exposed to ribavirin. Female healthcare workers and visitors who are pregnant, or may become pregnant, should be advised of the potential risks of exposure. {44}

Studies in primates (e.g., baboons) have not shown that ribavirin causes adverse effects on the fetus {01}; however, ribavirin crosses the placenta and studies in other animals have shown that it is teratogenic and/or embryocidal in nearly all species tested; studies in hamsters given daily oral doses of 2.5 mg/kg and studies in rats given daily oral doses of 10 mg/kg have shown teratogenicity. Malformations of the skull, palate, eye, jaw, skeleton, and gastrointestinal tract have been observed in animal studies, and survival of fetuses and offspring was reduced. Studies in rabbits given daily oral doses as low as 1 mg/kg have shown that ribavirin is embryocidal. {01}

FDA Pregnancy Category X.

Breast-feeding

It is not known whether ribavirin is excreted in human breast milk. However, ribavirin is excreted in the breast milk of animals and has been shown to be toxic to lactating animals and their offspring. Ribavirin aerosol is not indicated in the treatment of nursing mothers since respiratory syncytial virus (RSV) infection is self-limited in this population. {01}

Pediatrics

Ribavirin inhalation solution is indicated in the treatment of RSV infection only in children.


Geriatrics


Ribavirin inhalation solution is not indicated for use in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Zidovudine    (in vitro studies have shown that when combined, ribavirin and zidovudine are reproducibly antagonistic and should not be used concurrently; ribavirin inhibits the phosphorylation of zidovudine to its active triphosphate form {52} {53})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Anemia, severe{19}{56}{57}{58}    (intravenous and oral ribavirin may cause anemia that is reversible when the drug is discontinued)


Hypersensitivity to ribavirin

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hematocrit{19}{56}{57}{58}    (hematocrit should be monitored periodically since intravenous and oral ribavirin may cause anemia)




Side/Adverse Effects

Note: Although the manufacturer's literature includes a number of side effects, most studies indicate that ribavirin inhalation solution causes little or no systemic toxicity.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
—intravenous and oral only {01} {19} {56} {57} {58} {61}    
Anemia (unusual tiredness or weakness)
Note: Anemia is reversible with discontinuation of ribavirin.





Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
—intravenous and oral only {56} {61}    
CNS effects (fatigue; headache; insomnia)— usually with higher doses
    
gastrointestinal effects (anorexia; nausea)

Incidence rare
—inhalation only {45}In patients
    
Skin irritation due to prolonged drug contact
    
skin rash

In healthcare worker
{45}    
Headache
    
itching, redness, or swelling of eye






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ribavirin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Ribavirin is contraindicated during pregnancy. Female healthcare workers and visitors who are pregnant or may become pregnant may become environmentally exposed to ribavirin and should be advised of the potential risks of exposure

Proper use of this medication
» Importance of receiving medication for full course of therapy and on regular or continuous schedule

» Proper dosing


General Dosing Information
Before using, become thoroughly familiar with the Viratek Small Particle Aerosol Generator (SPAG) Model SPAG-2 Operator's Manual for operating instructions. {01}

According to the manufacturer, ribavirin inhalation solution should be administered using the Viratek SPAG Model SPAG-2 only. It should not be administered using any other aerosol-generating device. Ribavirin inhalation solution is usually administered using an infant oxygen hood attached to the SPAG-2 aerosol generator. However, administration by face mask may be necessary if an oxygen hood cannot be utilized (see SPAG-2 manual). With use of the recommended concentration (20 mg per mL) of ribavirin in the SPAG reservoir, the average ribavirin inhalation solution concentration over a 12-hour period is approximately 190 micrograms per liter of air. {01}

Use of ribavirin inhalation solution in infants requiring mechanical ventilation should be undertaken only by health care workers familiar with this mode of administration and the specific ventilator being used. The dose for infants requiring mechanical ventilation is the same as for those who do not. Precipitation of ribavirin within the ventilator apparatus, including endotracheal tubes, may cause obstruction, resulting in increased positive end expiratory pressure and increased positive inspiratory pressure. Accumulation of fluid in the tubing (“rain out”) has also been observed. To try to avoid this, instructions must be followed carefully. Either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2. Patients should have their endotracheal tubes suctioned every 1 to 2 hours, and their pulmonary pressures monitored frequently (every 2 to 4 hours). For both pressure and volume ventilators, heated wire connective tubing and bacteria filters in series in the expiratory limb of the system must be used to minimize the risk of ribavirin precipitation in the system and the subsequent risk of ventilator dysfunction. Bacteria filters must be changed frequently, i.e., every 4 hours. Water column pressure release valves should be used in the ventilator circuit for pressure cycled ventilators, and may be utilized with volume cycled ventilators. Refer to the SPAG-2 manual for detailed instructions. {66}

Ribavirin aerosolization, using a small particle aerosol generator, produces particles of 1.2 to 1.6 microns (mass mean diameter) in size. Ribavirin inhalation solution has been administered by this method at the rate of 12.5 liters per minute via an infant oxygen hood or mask, tent, or tubing of a respirator. Using a ribavirin concentration of 20 mg per mL, this method delivers approximately 1.8 mg per kg of body weight (mg/kg) per hour in infants and children up to 6 years of age. {07} {18} {20} {21} {22} {25} {27} {29} {48}

Although ribavirin inhalation solution has been administered using a tent, the volume of distribution and the condensation area are larger and the efficacy of this method has been evaluated in only a small number of patients. {01}

Although ribavirin treatment may be initiated before the results of diagnostic tests are received, treatment should not be continued without laboratory confirmation of respiratory syncytial virus (RSV) infection. {01}

Ribavirin inhalation solution treatment is generally effective when initiated within the first 3 days of RSV pneumonia. Early treatment may be necessary to achieve efficacy and to avoid further damage to the patient's lungs. {01} {24}


Inhalation Dosage Forms

RIBAVIRIN FOR INHALATION SOLUTION USP

Usual adult and adolescent dose
Respiratory syncytial virus (RSV) infection, lower respiratory tract
Dosage has not been established.


Usual pediatric dose
Respiratory syncytial virus (RSV) infection, lower respiratory tract
Oral inhalation, via a Viratek Small Particle Aerosol Generator (SPAG) Model SPAG-2 utilizing a 20-mg-per-mL ribavirin concentration in the reservoir, over a twelve- to eighteen-hour period per day for at least three to a maximum of seven days. {01} {20} {22}


Note: Various ribavirin dosage regimens have been utilized in RSV pneumonia and other infections, including virtually continuous aerosolization for three to six days {12} {18} {20} {22} and aerosolization over a four-hour period three times a day for three days. {07} {29}


Size(s) usually available:
U.S.—


6 grams (Rx) [Virazole]

Canada—


6 grams (Rx) [Virazole]

Packaging and storage:
Prior to reconstitution, store between 15 and 25 °C (59 and 78 °F), in a dry place.

Preparation of dosage form:
To prepare initial dilution for oral inhalation, add a measured quantity of sterile water for injection (without antimicrobial agents or other added substances) or sterile water for inhalation, sufficient for dissolution, to each 6-gram vial. Transfer the resulting solution to a clean, sterilized 500-mL wide-mouth Erlenmeyer flask (SPAG-2 reservoir). Further dilute the solution to a final volume of 300 mL with sterile water for injection or sterile water for inhalation to provide a final concentration of 20 mg per mL. {01}

Prior to administration, visually inspect the final solution for particulate matter and discoloration. {01}

When the solution level in the SPAG-2 reservoir is low, discard the remaining solution before adding freshly reconstituted solution to the reservoir. {01}

Stability:
The stability of ribavirin for inhalation solution (lyophilized powder) is unaffected by temperature, light, and moisture. {36}

After reconstitution, solutions retain their potency at room temperature (20 to 30 °C [68 to 86 °F]) for 24 hours. {01}

Ribavirin solutions are colorless. {18} {20}

Incompatibilities:
Ribavirin for inhalation solution should not be administered concurrently with other medications administered by aerosolization. {01}



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

RIBAVIRIN FOR ORAL SOLUTION

Note: Ribavirin for Inhalation Solution USP is the dosage form being used because an oral solution is not commercially available.


Usual adult and adolescent dose
[Lassa fever (prophylaxis)]1
Oral, 500 mg every six hours for seven to ten days. {55} {63}


Usual pediatric dose
Children 10 years of age and older—See Usual adult and adolescent dose {55} {63}.

Children 6 to 9 years of age—Oral, 400 mg every six hours for seven to ten days. {55} {63}

Children less than 6 years of age—Dosage has not been established. {55} {63}

Strength(s) usually available
U.S.—
Dosage form not commercially available. Compounding required for prescription.

Canada—
Dosage form not commercially available. Compounding required for prescription.

Packaging and storage:
Prior to reconstitution, store between 15 and 25 °C (59 and 78 °F), in a dry place.

Preparation of dosage form:
To prepare initial dilution for oral solution, add a measured quantity of sterile water for injection (without antimicrobial agents or other added substances) or sterile water for inhalation, sufficient for dissolution, to each 6-gram vial. Add dissolved solution to 0.9% sodium chloride or 5% dextrose in water.

Stability:
The stability of ribavirin for inhalation solution (lyophilized powder) is unaffected by temperature, light, and moisture. {36}

After reconstitution, solutions retain their potency at room temperature (20 to 30 °C [68 to 86 °F]) for 24 hours. {01}

Ribavirin solutions are colorless.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

RIBAVIRIN FOR INJECTION

Note: Ribavirin for Inhalation Solution USP is the dosage form being used because a parenteral solution is not commercially available.


Usual adult and adolescent dose
[Lassa fever (treatment)]1
Intravenous infusion, 30 mg per kg of body weight loading dose, then 16 mg per kg of body weight every six hours for four days, then 8 mg per kg of body weight every eight hours for six more days. Infuse over 15 to 20 minutes. {19} {63}


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—
Dosage form not commercially available. Compounding required for prescription.

Canada—
Dosage form not commercially available. Compounding required for prescription.

Packaging and storage:
Prior to reconstitution, store between 15 and 25 °C (59 and 78 °F), in a dry place.

Preparation of dosage form:
To prepare initial dilution for parenteral use, add a measured quantity of sterile water for injection (without antimicrobial agents or other added substances) or sterile water for inhalation, sufficient for dissolution, to each 6-gram vial. Add to 0.9% sodium chloride or 5% dextrose in water and infuse over 15 to 20 minutes. {19}

Stability:
The stability of ribavirin for inhalation solution (lyophilized powder) is unaffected by temperature, light, and moisture. {36}

After reconstitution, solutions retain their potency at room temperature (20 to 30 °C [68 to 86 °F]) for 24 hours. {01}

Ribavirin solutions are colorless.



Revised: 06/08/1994



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