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RIBAVIRIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ribavirin is a synthetic triazole nucleoside antiviral agent, structurally related to guanosine and xanthosine used against a wide variety of DNA and RNA viruses.

Specific Substances

    1) ICN 1229
    2) RTCA
    3) Viramid
    4) Virazole(R) (ICN)
    5) CAS 36791-04-5

Available Forms Sources

    A) FORMS
    1) Copegus(R) is available as a 200 mg light pink colored, flat, oval-shaped, film-coated tablet (Prod Info COPEGUS(R) oral tablets, 2015).
    2) Rebetol(R) is available as 200 mg capsules and 40 mg/mL oral solution (Prod Info REBETOL(R) oral capsules solution, 2009).
    3) Ribasphere(R) is available as 200 mg capsules, and 200 mg, 400 mg, and 600 mg tablets (Prod Info RIBASPHERE(R) oral tablets, 2005).
    4) Virazole(R) is available as 6 g inhalation powder for solution (Prod Info Virazole(R) inhalation solution, 2013).
    B) USES
    1) Ribavirin oral tablet (Copegus(R)) is used in combination with peginterferon alfa-2a to treat chronic hepatitis C (CHC) in patients 5 years and older with compensated liver disease, not previously treated with interferon alfa and in adult CHC patients coinfected with HIV (Prod Info COPEGUS(R) oral tablets, 2015).
    2) Ribavirin oral capsule (Rebetrol(R)) is used in combination with peginterferon alfa-2b or interferon alfa-2b to treat chronic hepatitis C in patients 3 years and older with compensated liver disease (Prod Info REBETOL(R) oral capsules solution, 2009; Prod Info PegIntron(TM)/REBETOL(R) Combo Pack oral capsules, subcutaneous injection, 2008).
    3) Ribavirin is also used to treat hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (Prod Info Virazole(R) inhalation solution, 2013; Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009). It is not recommended for routine use due to the lack of consistent efficacy data and risks to healthcare workers administering the aerosol (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009).
    4) The Working Group on Civilian Biodefense recommends the use of ribavirin for the treatment of hemorrhagic fever of unknown etiology or secondary to Arenaviruses or Bunyaviruses in the event these viruses are used as a biological weapon. Intravenous ribavirin is recommended in a contained casualty situation and oral ribavirin is recommended in a mass casualty situation (a high number of casualties making intravenous (therapy impossible) (Borio et al, 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ribavirin oral tablet is used in combination with peginterferon alfa-2a to treat chronic hepatitis C (CHC) in patients 5 years and older with compensated liver disease, not previously treated with interferon alfa and in adult CHC patients coinfected with HIV. Ribavirin oral capsule is used in combination with peginterferon alfa-2b or interferon alfa-2b to treat chronic hepatitis C in patients 3 years and older with compensated liver disease. Ribavirin for inhalation solution is also used to treat hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus.
    B) PHARMACOLOGY: Ribavirin is a nucleoside analogue with antiviral activity. Although the mechanism is not fully understood, ribavirin has direct antiviral activity in tissue culture against many RNA viruses. It increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.
    C) EPIDEMIOLOGY: Exposure can occur via several routes. During postmarketing surveillance, healthcare workers providing direct patient care to infants receiving aerosolized ribavirin have experienced adverse effects. The most common events were headache and conjunctivitis.
    D) WITH THERAPEUTIC USE
    1) INHALATION: In some cases, ribavirin has led to worsening pulmonary function (e.g., bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis and ventilator dependence). Rarely, cardiac abnormalities (ie, cardiac arrest, hypotension, and bradycardia) have developed in patients following aerosolized ribavirin.
    2) ORAL: Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction. It may also be associated with increased serum concentrations of bilirubin and uric acid. Other effects have included reticulocytosis, gastrointestinal disturbances (eg, anorexia, dyspepsia, nausea), dizziness, insomnia, irritability, dyspnea, pharyngitis, skin rashes and pruritus.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Clinical studies indicate that the primary effects are increases in bilirubin and anemia followed by a rebound reticulocytosis. Hypocalcemia and hypomagnesemia have been reported following intravenous administration of ribavirin at doses that were up to and exceeded 4 times the recommended maximum oral daily dose. Headache, nausea and dizziness are also reported. Ribavirin becomes generally cytotoxic at greater than 100 times the ordinary serum levels produced by therapeutic doses.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever is a common adverse event.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Rarely, cardiac abnormalities have developed in patients following aerosolized ribavirin. Alterations in cardiac rhythm have occurred in patients with underlying congenital heart disease.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) A transient rise in serum unconjugated bilirubin may occur during therapy.
    0.2.17) METABOLISM
    A) WITH THERAPEUTIC USE
    1) An increase in uric acid levels may occur with oral administration of this agent.
    0.2.20) REPRODUCTIVE
    A) Ribavirin is classified as FDA pregnancy category X. Developmental abnormalities (ie, malformations of the skull, palate, eye, jaw, limb, skeleton, and gastrointestinal tract), and reduced fetal survival have been reported with animal studies. It is possible for a male patient being treated with oral ribavirin to expose a sexual partner who is pregnant to the drug. Ribavirin is excreted into breast milk.

Laboratory Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Monitor CBC with differential and platelet count and serum bilirubin following in symptomatic patients.
    C) In symptomatic patients, obtain a baseline ECG and institute continuous cardiac monitoring. Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction.
    D) Monitor calcium and magnesium levels following a significant intravenous exposure or as indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose experience. Clinical overdose events are anticipated to be similar to adverse events. Monitor vital signs. Hemolytic anemia is the primary toxicity of ribavirin; obtain a baseline CBC as indicated and repeat as needed. Pediatric patients are more likely to develop vomiting with therapy. Monitor fluids and electrolytes in symptomatic patients. Replace fluids and correct electrolyte abnormalities as necessary. Hypocalcemia and hypomagnesemia have occurred following excessive doses of IV ribavirin; monitor as indicated following a significant exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In some cases, fatal and nonfatal myocardial infarction have been reported in patients that developed anemia with ribavirin therapy. Obtain a baseline ECG and institute continuous cardiac monitoring as necessary. Pulmonary symptoms (ie, dyspnea, pneumonitis, pneumonia) have occurred when ribavirin has been combined with interferon. Assess respiratory function, pulse oximetry, and begin oxygen therapy as indicated. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is unlikely to be necessary following a minor ingestion. Activated charcoal may be indicated following a recent, significant ingestion, the patient is not vomiting and the airway can be protected.
    2) HOSPITAL: Toxicity after an acute minor ingestion is unlikely. Based on limited experience, gastrointestinal decontamination is unlikely to be necessary. Consider activated charcoal following a recent, large ingestion and the airway can be protected or coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor exposure. Ensure adequate ventilation and perform endotracheal intubation early in patients that develop significant toxicity (ie, life-threatening cardiac toxicity, respiratory depression, hemodynamic instability).
    E) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with an inadvertent minor (1 to 2 tablets) exposure, that remain asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess CBC, electrolytes and fluid balance. Patients that remain asymptomatic can be discharged; appropriate laboratory follow-up may be needed in some patients.
    3) ADMISSION CRITERIA: Patients should be admitted for evidence of cardiac or pulmonary toxicity or instability, hematologic abnormalities, severe vomiting, severe abdominal pain (ie, pancreatitis), dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    F) PITFALLS
    1) When managing a suspected ribavirin overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are likely to be similar to reported side effects of ribavirin. Early symptoms of overdose may be delayed or not evident (ie, hemolytic anemia, thrombocytopenia), so reliable follow-up is necessary.
    G) PHARMACOKINETICS
    1) ORAL: Average time to reach Cmax is 2 hours. It does not bound to plasma proteins; volume of distribution is extensive. Terminal half-life of a single oral dose of ribavirin is approximately 120 to 170 hours.
    2) INHALATION: Ribavirin administered by aerosol is absorbed systemically.
    3) TOXIC CONCENTRATION: A 3 mg/kg dose is expected to produce a peak level of 1 to 2 mcg/mL. Ribavirin becomes cytotoxic at levels of 200 to 1,000 mcg/mL
    H) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hemolytic anemia.
    2) Patients with underlying cardiac disease may develop more severe symptoms.

Range Of Toxicity

    A) TOXICITY: Aerosol administration of 2 g over 3 days was well tolerated without effects. A 3 mg/kg dose is expected to produce a peak level of 1 to 2 mcg/mL. Ribavirin becomes cytotoxic at levels of 200 to 1,000 mcg/mL. Hypocalcemia and hypomagnesemia have been reported following IV administration of ribavirin at doses that were up to and exceeded 4 times the recommended maximum oral daily dose. THERAPEUTIC DOSE: ORAL: ADULT: 400 to 1400 mg orally in divided doses daily. CHILD: Refer to adult dosing if greater than 61 kg; or 400 to 800 mg orally in divided doses daily. INHALATION: GENERAL: Dose delivered cannot be precisely determined. ADULT: Based on a particle size of 1.3 microns in diameter and retention factor of 0.7, it is estimated that an adult receives 0.82 mg/kg/hr. CHILD: Initial 20 mg/mL in the drug reservoir of a small particle aerosol generator (SPAG-2) unit, with continuous aerosol administration for 12 to 18 hours/day for 3 to 7 days.

Clinical Effects

Summary Of Exposure

    A) USES: Ribavirin oral tablet is used in combination with peginterferon alfa-2a to treat chronic hepatitis C (CHC) in patients 5 years and older with compensated liver disease, not previously treated with interferon alfa and in adult CHC patients coinfected with HIV. Ribavirin oral capsule is used in combination with peginterferon alfa-2b or interferon alfa-2b to treat chronic hepatitis C in patients 3 years and older with compensated liver disease. Ribavirin for inhalation solution is also used to treat hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus.
    B) PHARMACOLOGY: Ribavirin is a nucleoside analogue with antiviral activity. Although the mechanism is not fully understood, ribavirin has direct antiviral activity in tissue culture against many RNA viruses. It increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.
    C) EPIDEMIOLOGY: Exposure can occur via several routes. During postmarketing surveillance, healthcare workers providing direct patient care to infants receiving aerosolized ribavirin have experienced adverse effects. The most common events were headache and conjunctivitis.
    D) WITH THERAPEUTIC USE
    1) INHALATION: In some cases, ribavirin has led to worsening pulmonary function (e.g., bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis and ventilator dependence). Rarely, cardiac abnormalities (ie, cardiac arrest, hypotension, and bradycardia) have developed in patients following aerosolized ribavirin.
    2) ORAL: Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction. It may also be associated with increased serum concentrations of bilirubin and uric acid. Other effects have included reticulocytosis, gastrointestinal disturbances (eg, anorexia, dyspepsia, nausea), dizziness, insomnia, irritability, dyspnea, pharyngitis, skin rashes and pruritus.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Clinical studies indicate that the primary effects are increases in bilirubin and anemia followed by a rebound reticulocytosis. Hypocalcemia and hypomagnesemia have been reported following intravenous administration of ribavirin at doses that were up to and exceeded 4 times the recommended maximum oral daily dose. Headache, nausea and dizziness are also reported. Ribavirin becomes generally cytotoxic at greater than 100 times the ordinary serum levels produced by therapeutic doses.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever is a common adverse event.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) The most common adverse reactions occurring in greater than 40% of patients (adults) receiving combination ribavirin and interferon therapy include headache, pyrexia, fatigue/asthenia, and myalgia (Prod Info COPEGUS(R) oral tablets, 2015). Fever was also commonly (greater than 25%) reported in pediatric patients treated with combination therapy (Prod Info REBETOL(R) oral capsules, oral solution, 2015)

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CONJUNCTIVITIS may occur following aerosolized treatment (Hall, 1985).
    2) BLURRED VISION has occurred infrequently following combination oral therapy with interferon (Prod Info COPEGUS(R) oral tablets, 2015)

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rarely, cardiac abnormalities have developed in patients following aerosolized ribavirin. Alterations in cardiac rhythm have occurred in patients with underlying congenital heart disease.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Cardiac abnormalities (ie, cardiac arrest, hypotension, bradycardia, and digitalis toxicity) have been reported infrequently following therapeutic use of aerosolized ribavirin (Prod Info Virazole(R) inhalation solution, 2013).
    b) Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction (Prod Info COPEGUS(R) oral tablets, 2015).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Alterations in cardiac rhythm (ie, bigeminy, bradycardia, tachycardia) have developed in patients with a history of congenital heart disease following therapeutic use of aerosolized ribavirin (Prod Info Virazole(R) inhalation solution, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY FUNCTION STUDIES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) SUMMARY: The following pulmonary events have been reported with therapeutic use of aerosolized ribavirin: worsening of respiratory status, bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis and ventilator dependence (Prod Info Virazole(R) inhalation solution, 2013).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea is a relatively common adverse event reported following therapeutic use of oral ribavirin and interferon therapy. Exertional dyspnea has been reported infrequently (Prod Info COPEGUS(R) oral tablets, 2015).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough is a relatively common adverse event reported following therapeutic use of oral ribavirin in combination with interferon. Exertional dyspnea has been reported infrequently (Prod Info COPEGUS(R) oral tablets, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Neuropsychiatric adverse events (e.g., depression, anxiety, insomnia, irritability) have occurred frequently following oral ribavirin therapy in combination with interferon. Other events may include impaired concentration and mood alteration (Prod Info COPEGUS(R) oral tablets, 2015).
    2) WITH POISONING/EXPOSURE
    a) Headache and dizziness have been reported by health care workers providing direct patient care to infants receiving aerosolized therapy (Prod Info Virazole(R) inhalation solution, 2013).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) The most common adverse reactions occurring in greater than 40% of patients (adults) receiving combination ribavirin and interferon therapy include headache, pyrexia, fatigue/asthenia, and myalgia (Prod Info COPEGUS(R) oral tablets, 2015). Headache was also commonly (greater than 25%) reported in pediatric patients treated with combination therapy (Prod Info REBETOL(R) oral capsules, oral solution, 2015).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures and asthenia were reported following experimental intravenous administration of ribavirin (Prod Info Ribavirin (Virazole), 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a chronic hepatitis C clinical trial combining oral ribavirin and interferon therapy, nausea and vomiting were common adverse events (Prod Info COPEGUS(R) oral tablets, 2015).
    b) Vomiting is one of the most common (greater than 25%) adverse effects reported in pediatric patients treated with oral ribavirin in combination with interferon (Prod Info REBETOL(R) oral capsules, oral solution, 2015).
    2) WITH POISONING/EXPOSURE
    a) Nausea has developed in health care workers providing direct patient care to infants receiving aerosolized ribavirin (Prod Info Virazole(R) inhalation solution, 2013).
    B) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Abdominal pain, diarrhea, dry mouth and dyspepsia may develop with combination oral therapy with interferon(Prod Info COPEGUS(R) oral tablets, 2015). Anorexia was also commonly (greater than 25%) reported in pediatric patients treated with combination therapy (Prod Info REBETOL(R) oral capsules, oral solution, 2015).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) A transient rise in serum unconjugated bilirubin may occur during therapy.
    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Increases in serum concentrations of both bilirubin and uric acid, associated with hemolysis, have occurred with during clinical trials with oral use of ribavirin (Prod Info REBETOL(R) oral capsules, oral solution, 2015).
    1) A transient rise in serum unconjugated bilirubin occurred in approximately 25% of volunteers given 1,000 mg/day (Magnussen et al, 1977).
    2) One study reported the general range of elevated bilirubins to be 1.5 to 2.2 mg/100 mL, with the highest values being 4.3 and 3.8 (Smith et al, 1980).
    3) Since other liver enzymes appear not to be affected, the increase in bilirubin is more likely due to inhibition of uptake and processing, rather than hepatic cell toxicity (Smith et al, 1980).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia is relatively common following combination oral therapy with interferon (Prod Info COPEGUS(R) oral tablets, 2015). Neutropenia was also commonly (greater than 25%) reported in pediatric patients treated with combination therapy (Prod Info REBETOL(R) oral capsules, oral solution, 2015).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia occurs relatively frequently following combination oral therapy with interferon (Prod Info COPEGUS(R) oral tablets, 2015).
    C) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia is the primary toxicity of ribavirin and occurred in about 13% of patients treated with a combination of oral ribavirin and interferon. This event typically occurs within 1 to 2 weeks of beginning therapy (Prod Info COPEGUS(R) oral tablets, 2015).
    D) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Lymphopenia is a relatively common laboratory finding following combination oral therapy with interferon (Prod Info COPEGUS(R) oral tablets, 2015).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has occurred infrequently following combination oral therapy with interferon (Prod Info COPEGUS(R) oral tablets, 2015).
    F) MYELOPROLIFERATIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) SUMMARY: During postmarketing experience, reticulocytosis has been reported with aerosolized ribavirin. The events were reversible with the discontinuation of drug therapy (Prod Info Virazole(R) inhalation solution, 2013).
    b) Reticulocyte count has increased in cases where 1 g/day was used therapeutically (Nicholson, 1984). One study which recorded reticulocyte count had an average value of 2 to 3% (Smith et al, 1980). This occurs after withdrawal of the drug in conjunction with correction of anemia.
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) MONKEYS: Chronic studies in rhesus monkeys have demonstrated normochromic normocytic anemia secondary to increased red cell destruction and decreased production. Hyperplasia of bone marrow megakaryocytes results in thrombocytosis.
    1) Examination of bone marrow revealed dose-related erythroid hypoplasia, red cell phagocytosis by bone marrow histocytes, marrow cell vacuolization, and occasional megaloblastoid erythroid precursors (Cosgriff et al, 1984).
    2) LACK OF EFFECT
    a) Other non-primate animal species studied, such as rats, guinea pigs, and dogs, do not demonstrate adverse hematologic effects, even after doses of up to 60 mg/kg/day in dogs and 120 mg/kg/day in rats (Canonico, 1985).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash and pruritus have been reported following therapeutic use of aerosolized and oral formulations of ribavirin (Prod Info COPEGUS(R) oral tablets, 2015; Prod Info Virazole(R) inhalation solution, 2013).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has been frequently observed following oral ribavirin (Prod Info COPEGUS(R) oral tablets, 2015).
    C) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Dermatitis is relatively common adverse event with oral ribavirin therapy. Eczema has developed infrequently with oral therapy (Prod Info COPEGUS(R) oral tablets, 2015).
    D) TOXIC EPIDERMAL NECROLYSIS DUE TO DRUG
    1) WITH THERAPEUTIC USE
    a) During postmarketing experience, toxic epidermal necrolysis (TEN) has been reported in patients treated with oral ribavirin in combination with interferon (Prod Info COPEGUS(R) oral tablets, 2015).
    E) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing experience, Stevens-Johnson syndrome has been reported in patients treated with oral ribavirin in combination with interferon (Prod Info COPEGUS(R) oral tablets, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) The most common adverse reactions occurring in greater than 40% of patients (adults) receiving oral ribavirin in combination with interferon include headache, pyrexia, fatigue/asthenia, and myalgia (Prod Info COPEGUS(R) oral tablets, 2015).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia is relatively common adverse event following oral ribavirin when combined with interferon therapy (Prod Info COPEGUS(R) oral tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Ribavirin is classified as FDA pregnancy category X. Developmental abnormalities (ie, malformations of the skull, palate, eye, jaw, limb, skeleton, and gastrointestinal tract), and reduced fetal survival have been reported with animal studies. It is possible for a male patient being treated with oral ribavirin to expose a sexual partner who is pregnant to the drug. Ribavirin is excreted into breast milk.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Preliminary results from the Ribavirin Pregnancy Registry (December 23, 2003 through August 8, 2009) could not definitively link human teratogenicity with direct (via maternal use) or indirect exposure (via the male sexual partner) to the drug. The registry enrolled 118 live births (49 from direct exposure and 69 from indirect exposure) and 6 outcomes with birth defects were reported. Ventricular septal defect and cyst of fourth ventricle of the brain (n=1), torticollis (n=1), and glucose-6-phosphate dehydrogenase deficiency (n=1) were reported in infants from direct exposure (6.1%; 95% CI: 1.2, 16.9). Torticollis (n=1), hypospadias (n=1), and polydactyly and a neonatal tooth (n=1) were reported in infants from indirect exposure (4.3%; 95% CI: 0.9, 12.2). In two cases of indirect exposure, paternal family history of the defects was reported. Because the registry enrollment was far short of the desired sample size, researchers hesitated to estimate the risk of teratogenicity and draw conclusions following ribavirin use at this time (Roberts et al, 2010).
    2) Because the estimated amount of ribavirin absorbed during a typical nursing work shift exceeds 1/100 of the teratogenic dose in hamsters and embryolethal dose in rabbits, it is recommended that pregnant or potentially pregnant healthcare workers be advised of the risk and minimize exposure. Wearing of surgical masks is not likely to prevent absorption (Harrison et al, 1988).
    B) LACK OF EFFECT
    1) PRIMATES: No teratogenicity was noted in baboons given massive amounts, up to 120 mg/kg/day (Demers, 1988).
    C) ANIMAL STUDIES
    1) Developmental abnormalities, including skull, palate, eye, jaw, limb, skeleton, and gastrointestinal tract malformations, occurred in animals following oral maternal administration of ribavirin. Teratogenic effects increased in incidence and severity with larger drug doses (Prod Info REBETOL(R) oral capsules, oral solution, 2014; Prod Info Virazole(R) inhalation solution, 2013).
    2) HAMSTERS: Single intraperitoneal doses as low as 2.1 mg/kg produced malformations of the skull, palate, eye, jaw, skeletal muscle, and gastrointestinal tract in hamsters (Kilham & Ferm, 1977). A single oral dose of 2.5 mg/kg or greater resulted in teratogenetic effects (Prod Info ribavirin oral tablets, 2014).
    3) RABBITS/RATS: Teratogenic effects were evident after daily oral doses of 0.3 and 1.0 mg/kg in rabbits and rats, respectively (an estimated human equivalent doses of 0.12 and 0.14 mg/kg, based on body surface area adjustment for the adult) (Prod Info Virazole(R) inhalation solution, 2013).
    4) MICE: Studies in mice demonstrated that all single intraperitoneal doses greater than 25 mg/kg/day given during organogenesis were teratogenic.
    a) Abnormalities included all parts of the skeleton, the site influenced by the dose and stage of development.
    b) Cleft palate was a common defect. Doses of 10 mg/kg had no effect, and doses of 200 mg/kg were embryolethal (Kochar et al, 1980).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified ribavirin as FDA pregnancy category X (Prod Info COPEGUS(R) oral tablets, 2015; Prod Info REBETOL(R) oral capsules, oral solution, 2014; Prod Info Virazole(R) inhalation solution, 2013).
    2) It is possible for a male patient being treated with ribavirin to expose a sexual partner who is pregnant to the drug (Prod Info REBETOL(R) oral capsules, oral solution, 2014; Prod Info ribavirin oral tablets, 2014).
    3) Ribavirin is contraindicated in pregnant women and men whose female partners are pregnant (Prod Info COPEGUS(R) oral tablets, 2015; Prod Info REBETOL(R) oral capsules, oral solution, 2014).
    4) Ribavirin use during pregnancy is contraindicated. It is also contraindicated in men whose female partners are pregnant. A ribavirin pregnancy registry has been established to track maternal and fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during therapy and for 6 months after cessation of therapy. Physicians and patients are encouraged to report these cases to the registry at 1-800-593-2214. Ribavirin therapy should not be started until pregnancy is ruled out. Pregnancy testing should be done monthly while on ribavirin and for 6 months after cessation of therapy. In both female patients and in female partners of male patients on ribavirin, extreme care must be taken to avoid pregnancy during therapy and for 6 months after cessation of therapy. Women of childbearing potential must use 2 effective forms of contraception while on ribavirin therapy, and for an additional 6 months after the cessation of therapy (Prod Info COPEGUS(R) oral tablets, 2015).
    5) Women who are or who may become pregnant should avoid environmental exposure (inhalation of aerosolized drug emanating from infant treatment). Nurses, respiratory therapists, and other caregivers should preferably not administer ribavirin if they are pregnant. If pregnant health care workers cannot avoid close patient contact, ribavirin should be administered in a negative pressure room with adequate ventilation (at least 6 air exchanges/hour). Administer ribavirin in aerosol scavenging devices, turn off the SPAG-2 for 5 to 10 minutes before prolonged patient contact, and wear an appropriate respiratory filter mask. Surgical masks will not adequately filter ribavirin particles. Administering ribavirin at a high dose (60 mg/mL) over a 2-hour period 3 times per day for up to 5 days may reduce environmental exposure (Prod Info Virazole(R), 2002; Shults et al, 1996).
    B) ANIMAL STUDIES
    1) RATS/RABBITS: For fetal effects in rats and rabbits, the no-effect oral dose of ribavirin was 0.3 mg/kg/day (approximately .06 times the maximum recommended human daily dose). The no-effect dose in a peri/postnatal rat study was up to 1 mg/kg/day (approximately 0.01 times the maximum recommended human daily dose) (Prod Info REBETOL(R) oral capsules, oral solution, 2014).
    2) RABBITS: Chronic oral doses as low as 1 mg/kg were embryolethal in rabbits (Prod Info Virazole(R) inhalation solution, 2013; Prod Info Virazole(R), 1996).
    3) RATS: Ribavirin doses up to 200 mg/kg (up to 1.7 times the maximum recommended human daily dose) for 5 days did not induce dominant lethality in rats (Prod Info REBETOL(R) oral capsules, oral solution, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Lactation studies with ribavirin have not been conducted in humans, and it is unknown whether ribavirin is excreted in human breast milk. Nursing mothers should not receive ribavirin (Prod Info COPEGUS(R) oral tablets, 2015; Prod Info REBETOL(R) oral capsules, oral solution, 2014; Prod Info Virazole(R) inhalation solution, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Tubular atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology were observed in male mice and rats receiving between 16 and 150 mg/kg/day; lower doses were not tested (Prod Info Virazole(R) inhalation solution, 2013).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) BENIGN TUMORS
    1) Although carcinogenicity studies are incomplete, chronic feeding studies in animals at doses of 16 to 100 mg/kg (estimated human equivalent of 2.3 to 14.3 mg/kg/day based on body surface area adjustment for the adult) suggest that ribavirin may induce benign tumors (ie, mammary, pancreatic, pituitary and adrenal tumors) (Prod Info Virazole(R) inhalation solution, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status following significant overdose.
    B) Monitor CBC with differential and platelet count and serum bilirubin following in symptomatic patients.
    C) In symptomatic patients, obtain a baseline ECG and institute continuous cardiac monitoring. Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction.
    D) Monitor calcium and magnesium levels following a significant intravenous exposure or as indicated.
    4.1.2) SERUM/BLOOD
    A) Monitor CBC with differential and platelet count and serum bilirubin following in symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) Hypocalcemia and hypomagnesemia have been reported following intravenous administration of ribavirin at doses that were up to and exceeded 4 times the recommended maximum oral daily dose (Prod Info COPEGUS(R) oral tablets, 2015).
    2) In symptomatic patients, obtain a baseline ECG and institute continuous cardiac monitoring.
    a) Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction (Prod Info COPEGUS(R) oral tablets, 2015).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Ribavirin can be assayed in biological materials by radioimmunoassay (Prod Info Virazole(R) inhalation solution, 2013) or HPLC (Harrison et al, 1988).
    2) The detection limit for the RIA method was 0.002 mcg/mL and for the HPLC method was 1 to 1.4 mcg/sample (Conner, 1990).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for evidence of cardiac or pulmonary toxicity or instability, hematologic abnormalities, severe vomiting, severe abdominal pain (ie, pancreatitis), dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with an inadvertent minor (1 to 2 tablets) exposure, that remain asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess CBC, electrolytes and fluid balance. Patients that remain asymptomatic can be discharged; appropriate laboratory follow-up may be needed in some patients.

Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Monitor CBC with differential and platelet count and serum bilirubin following in symptomatic patients.
    C) In symptomatic patients, obtain a baseline ECG and institute continuous cardiac monitoring. Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction.
    D) Monitor calcium and magnesium levels following a significant intravenous exposure or as indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Gastrointestinal decontamination is unlikely to be necessary following a minor ingestion.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Limited overdose experience. Clinical overdose events are anticipated to be similar to adverse events. Monitor vital signs. Hemolytic anemia is the primary toxicity of ribavirin; obtain a baseline CBC as indicated and repeat as needed. Pediatric patients are more likely to develop vomiting with therapy. Monitor fluids and electrolytes in symptomatic patients. Replace fluids and correct electrolyte abnormalities as necessary. Hypocalcemia and hypomagnesemia have occurred following excessive doses of IV ribavirin; monitor as indicated following a significant exposure.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. In some cases, fatal and nonfatal myocardial infarction have been reported in patients that developed anemia with ribavirin therapy. Obtain a baseline ECG and institute continuous cardiac monitoring as necessary. Pulmonary symptoms (ie, dyspnea, pneumonitis, pneumonia) have occurred when ribavirin has been combined with interferon. Assess respiratory function, pulse oximetry, and begin oxygen therapy as indicated. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status following significant overdose.
    2) Monitor CBC with differential and platelet count and serum bilirubin following in symptomatic patients.
    3) In symptomatic patients, obtain a baseline ECG and institute continuous cardiac monitoring.
    a) Following ingestion, some patients have developed hemolytic anemia which may result in worsening cardiac disease and lead to fatal and nonfatal myocardial infarction (Prod Info COPEGUS(R) oral tablets, 2015).
    4) Monitor calcium and magnesium levels following a significant intravenous exposure or as indicated.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis and peritoneal dialysis are not effective in the treatment of a ribavirin overdose (Prod Info REBETOL(R) oral capsules, oral solution, 2015).
    HEMODIALYSIS
    2) Plasma ribavirin is removed by hemodialysis with an extraction ratio of approximately 50%; however, based on its large volume of distribution hemodialysis is unlikely to be effective because plasma exposure is not anticipated to change (Prod Info COPEGUS(R) oral tablets, 2015).

Range Of Toxicity

Summary

    A) TOXICITY: Aerosol administration of 2 g over 3 days was well tolerated without effects. A 3 mg/kg dose is expected to produce a peak level of 1 to 2 mcg/mL. Ribavirin becomes cytotoxic at levels of 200 to 1,000 mcg/mL. Hypocalcemia and hypomagnesemia have been reported following IV administration of ribavirin at doses that were up to and exceeded 4 times the recommended maximum oral daily dose. THERAPEUTIC DOSE: ORAL: ADULT: 400 to 1400 mg orally in divided doses daily. CHILD: Refer to adult dosing if greater than 61 kg; or 400 to 800 mg orally in divided doses daily. INHALATION: GENERAL: Dose delivered cannot be precisely determined. ADULT: Based on a particle size of 1.3 microns in diameter and retention factor of 0.7, it is estimated that an adult receives 0.82 mg/kg/hr. CHILD: Initial 20 mg/mL in the drug reservoir of a small particle aerosol generator (SPAG-2) unit, with continuous aerosol administration for 12 to 18 hours/day for 3 to 7 days.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) INHALATION SOLUTION
    a) Ribavirin inhalation solution is NOT indicated for use in adults (Prod Info Virazole(R) inhalation solution, 2013).
    2) ORAL TABLET
    a) CHRONIC HEPATITIS C MONOINFECTION: 800 to 1200 mg in 2 divided doses daily with food for 24 to 48 weeks. Dose may be individualized based on viral genotype, patient weight, response to therapy, and tolerability to the regimen (Prod Info COPEGUS(R) oral tablets, 2013).
    b) CHRONIC HEPATITIS C WITH HIV COINFECTION: 800 mg daily with food for 48 weeks regardless of viral genotype (Prod Info COPEGUS(R) oral tablets, 2013).
    3) ORAL CAPSULE OR SOLUTION
    a) CHRONIC HEPATITIS C: 800 to 1400 mg daily with food based on patient's body weight for 12 to 48 weeks. Capsules should never be opened, crushed, or broken (Prod Info REBETOL(R) oral capsules, oral solution, 2013).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) INHALATION SOLUTION
    a) HOSPITALIZED INFANTS AND YOUNG CHILDREN:
    1) SEVERE LOWER RESPIRATORY TRACT INFECTION DUE TO RESPIRATORY SYNCYTIAL VIRUS (RSV): The recommended dose is 20 mg/mL as the starting solution in the drug reservoir of the small particle aerosol generator (SPAG-2) unit with continuous aerosol administration for 12 to 18 hours/day for 3 to 7 days. Do NOT administer in a mixture for combined aerosolization or simultaneously with other aerosolized medications. The recommended dose and administration schedule for infants requiring mechanical ventilation is the same as for those who do not (Prod Info Virazole(R) inhalation solution, 2013).
    2) MANUFACTURER WARNING: Read thoroughly the particle aerosol generator operating instructions prior to use; ribavirin should NOT be administered with any other aerosol generating device (Prod Info Virazole(R) inhalation solution, 2013).
    2) ORAL TABLET
    a) CHILDREN 5 YEARS OF AGE AND OLDER WITH CHRONIC HEPATITIS C: 400 to 1200 mg daily with food based on patient's body weight for 24 to 48 weeks (Prod Info COPEGUS(R) oral tablets, 2013).
    b) CHILDREN YOUNGER THAN 5 YEARS OF AGE: Safety and efficacy have not been established (Prod Info COPEGUS(R) oral tablets, 2013).
    3) ORAL CAPSULE OR SOLUTION
    a) CHILDREN 3 YEARS OF AGE AND OLDER WITH CHRONIC HEPATITIS C
    1) BODY WEIGHT LESS THAN 47 KG: 15 mg/kg/day in 2 divided doses daily with food for 24 or 48 weeks. The oral solution should be used for children in this age and weight group (Prod Info REBETOL(R) oral capsules, oral solution, 2013).
    2) BODY WEIGHT 47 KG OR GREATER: 800 to 1200 mg in 2 divided doses daily with food for 24 or 48 weeks. Capsules should never be opened, crushed, or broken (Prod Info REBETOL(R) oral capsules, oral solution, 2013).
    b) CHILDREN YOUNGER THAN 3 YEARS OF AGE: Safety and efficacy have not been established (Prod Info REBETOL(R) oral capsules, oral solution, 2013).

Maximum Tolerated Exposure

    A) SUMMARY
    1) A 3 mg/kg dose is expected to produce a peak level of 1 to 2 mcg/mL. Ribavirin becomes cytotoxic at levels of 200 to 1,000 micrograms/milliliter (Nicholson, 1984).
    B) INTRAVENOUS
    1) Hypocalcemia and hypomagnesemia have been reported following intravenous administration of ribavirin at doses that were up to and exceeded 4 times the recommended maximum oral daily dose (Prod Info COPEGUS(R) oral tablets, 2015).
    C) INHALATION
    1) Aerosol administration of 2 g in 36 to 39 hours over 3 days was tolerated without pulmonary or other symptoms (Hall et al, 1983).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) A 3 mg/kg dose is expected to produce a peak level of 1 to 2 mcg/mL. Ribavirin becomes cytotoxic at levels of 200 to 1,000 micrograms/milliliter (Nicholson, 1984).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1.3 g/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 2.7 g/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) This agent is rapidly transported into cells where it is converted by cellular enzymes to monophosphate, diphosphate, and triphosphate derivatives which inhibit viral or virally induced enzymes involved with viral nucleic acid synthesis.
    B) The herpes viruses are the most sensitive of the DNA viruses (Nicholson, 1984).

Toxicologic Mechanism

    A) Plasma ribavirin is removed by hemodialysis with an extraction ratio of approximately 50%; however, based on its large volume of distribution hemodialysis is unlikely to be effective because plasma exposure is not anticipated to change (Prod Info COPEGUS(R) oral tablets, 2015).
    B) Ribavirin has a modest effect on cellular DNA synthesis, but is cytotoxic to resting cells only at a concentration of 200 to 1,000 mcg/mL (Nicholson, 1984).

Physicochemical

Physical Characteristics

    A) Ribavirin is a white crystalline compound (Prod Info Virazole(R) inhalation solution, 2013)

Molecular Weight

    A) 244.2 (Prod Info COPEGUS(R) oral tablets, 2015)

References

General Bibliography

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