Medical term:

Virazole

ribavirin

Copegus, Rebetol, Ribasphere, Virazole

Pharmacologic class: Synthetic nucleoside analog

Therapeutic class: Antiviral

Pregnancy risk category X

FDA Box Warning

• Ribavirin monotherapy isn't effective in treating chronic hepatitis C infection and shouldn't be used alone for this indication.

• Drug's main clinical toxicity is hemolytic anemia, which may worsen cardiac disease and lead to fatal and nonfatal myocardial infarctions. Don't administer to patients with history of significant or unstable cardiac disease.

• Drug is contraindicated in pregnant women and their male partners. Caution female patients and female partners of male patients receiving ribavirin to use extreme care to avoid pregnancy during therapy and for 6 months afterward.

Action

Unknown. Thought to inhibit RNA and DNA synthesis by depleting nucleotides and blocking replication and maturation of viral cells.

Availability

Capsules: 200 mg

Powder to be reconstituted for inhalation (Virazole): 6 g in 100-ml glass vial

Tablets: 200 mg

Indications and dosages

➣ Chronic hepatitis C infection

Note: Dosage calculated solely on basis of patient's weight.

Adults and children weighing 75 kg (165 lb) or more: 600 mg P.O. q morning and evening, given with interferon alfa-2b

Adults weighing less than 75 kg (165 lb) and children weighing more than 61 kg (134 lb): 400 mg P.O. q morning and 600 mg P.O. q evening, given with interferon alfa-2b

Children weighing 50 to 61 kg (110 to 134 lb): 400 mg P.O. b.i.d., given with interferon alfa-2b

Children weighing 37 to 49 kg (81 to 108 lb): 200 mg P.O. every morning and 400 mg P.O. every evening, given with interferon alfa-2b

Children weighing 25 to 36 kg (55 to 79 lb): 200 mg P.O. b.i.d., given with interferon alfa-2b

➣ Hospitalized children with severe lower respiratory infection caused by respiratory syncytial virus

Infants and young children: 20 mg/ml by inhalation as a starting solution in Viratek Small Particle Aerosol Generator (SPAG-2) for 12 to 18 hours daily for 3 to 7 days. Give by oxygen hood from SPAG-2 unit to infant who isn't mechanically ventilated.

Dosage adjustment

• Cardiovascular disease

• Chronic obstructive pulmonary disease (COPD)

• Renal impairment

• Hemoglobin below 10 g/dl

Off-label uses

• Influenza A or B

• Pneumonia caused by adenovirus

• Severe lower respiratory tract infection in adults

• Genital herpes

• Hemorrhagic fever

Contraindications

• Hypersensitivity to drug or its components

• Autoimmune hepatitis (oral combination therapy)

• Creatinine clearance below 50 ml/minute

• Significant or unstable cardiac disease

• Hemoglobinopathy (such as sickle cell anemia, thalassemia major)

• Females of childbearing age (inhalation form)

• Pregnancy, pregnant partner of male patient (oral drug)

• Breastfeeding

Precautions

Use cautiously in:

• decompensated hepatic disease, coinfection with hepatitis B or human immunodeficiency virus, COPD

• liver or other transplant recipients

• patients who don't respond to interferon.

Administration

☞ Be aware that oral form must be given with interferon alfa-2b injection.

• Give aerosol by Viratek SPAG-2 only. Don't use other aerosol-generating equipment.

• Dilute powder in sterile water for injection. Don't use solutions with antimicrobial ingredients.

• Know that drug may be given by oral or nasal inhalation.

• Discard solution in SPAG-2 every 24 hours before adding new solution.

☞ Avoid prolonged contact with aerosol, which can cause headache or eye irritation.

Adverse reactions

CNS: fatigue, headache, nervousness, depression, suicidal ideation

CV: hypotension, bradycardia (with inhalation form), cardiac arrest

EENT: conjunctivitis, eyelid erythema or rash

GI: nausea, dyspepsia, anorexia, pancreatitis

Hematologic: reticulocytosis, hemolytic anemia

Respiratory: bacterial pneumonia, pneumothorax, bronchospasm, pulmonary edema, apnea, worsening respiratory status (with inhalation form)

Skin: rash, pruritus

Interactions

Drug-drug. Abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine: potentially fatal lactic acidosis

Stavudine, zidovudine: decreased antiviral activity

Drug-diagnostic tests. Alanine aminotransferase, aspartate aminotransferase, bilirubin: increased levels

Hemoglobin: decreased level

Reticulocytes: increased count

Patient monitoring

☞ Carefully monitor patient's respiratory status. Check ventilator often to ensure that drug precipitates don't impede function.

☞ Monitor ECG and vital signs. Watch for hypotension, bradycardia, and other signs of impending cardiac arrest or worsening respiratory condition.

☞ Assess neurologic status. Stay alert for depression and suicidal ideation.

• Monitor liver function tests and CBC with white cell differential.

Patient teaching

• Explain drug delivery system and precautions carefully to patient or to parents of children receiving inhalation form.

☞ Tell patient or parents that drug may cause depression or suicidal thoughts, which should be reported immediately.

☞ Instruct patient or parents to immediately report new or worsening respiratory symptoms.

• Counsel sexually active patients (both males and females) about appropriate birth control. Tell them to use extreme care to avoid pregnancy. Stress importance of using two forms of effective contraception during and for 6 months after treatment (when using oral ribavirin).

• Advise female patient not to breastfeed.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

ribavirin

(rye-ba-vye-rin) ,

Copegus

(trade name),

Rebetol

(trade name),

Virazole

(trade name)

Classification

Therapeutic: antivirals
Pharmacologic: nucleoside analogues

Pregnancy Category: X

Indications

Inhalation: Treatment of severe lower respiratory tract infections caused by the respiratory syncytial virus (RSV) in infants and young children. Oral: Rebetol—with interferon alfa-2b (Intron A) or peginterferon alfa-2b (PegIntron) in the treatment of chronic hepatitis C in patients with compensated liver disease. Oral: Copegus—with peginterferon alfa-2a (Pegasys) in the treatment of chronic hepatitis C in patients with compensated liver disease who have not previously been treated with interferon alfa.Early (within 24 hr of symptoms) secondary treatment of influenza A or B in young adults.

Action

Inhibits viral DNA and RNA synthesis and subsequent replication.

Must be phosphorylated intracellularly to be active.

Therapeutic effects

Inhalation: Virustatic action.

Oral: Decreased progression and sequelae of chronic hepatitis C.

Pharmacokinetics

Absorption: Systemic absorption occurs following nasal and oral inhalation. Rapidly and extensively absorbed following oral administration, but undergoes first-pass hepatic metabolism (64% bioavailability).

Distribution: 70% of inhaled drug is deposited in the respiratory tract. Appears to concentrate in the respiratory tract and red blood cells. Enters breast milk.

Metabolism and Excretion: Eliminated from the respiratory tract by distribution across membranes, macrophages, and ciliary motion. Metabolized primarily by the liver; metabolites are renally excreted.

Half-life: Inhaln—9.5 hr (40 days in RBCs); oral—43.6 hr (single dose); 12 days (multiple dose).

Time/action profile (blood levels)

ROUTE	ONSET	PEAK	DURATION
Inhaln	unknown	end of inhaln	unknown
PO	unknown	1.7–3 hr	12 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity;Patients receiving mechanically assisted ventilation; Obstetric / Lactation: Pregnancy or lactation; Obstetric: Male partners of pregnant patients;CCr <50 mL/min;Significant/unstable cardiovascular disease;Hemoglobinopathies;Autoimmune hepatitis or hepatic decompensation before/during treatment (for combined therapy with interferon alfa-2b or peginterferon alfa-2a);Concurrent use of didanosine, stavudine, or zidovudine.

Use Cautiously in: Sarcoidosis (may exacerbate condition);Anemia (dose reduction/discontinuation may be required);Any pre-existing cardiac disease; Obstetric: Patients with childbearing potential. Pediatric: May result in ↓ growth.

Adverse Reactions/Side Effects

Inhalation

Central nervous system

dizziness
faintness

Ear, Eye, Nose, Throat

blurred vision
conjunctivitis
erythema of the eyelids
ocular irritation
photosensitivity

Cardiovascular

cardiac arrest (life-threatening)
hypotension

Dermatologic

rash

Hematologic

hemolytic anemia (with interferon alpha 2b) (most frequent)
reticulocytosis

Oral (may reflect combination with interferon)

Central nervous system

emotional lability (↑ in children)
fatigue (↓ in children)
impaired concentration (↓ in children)
insomnia (↓ in children)
irritability (↓ in children)

Ear, Eye, Nose, Throat

dry mouth
optic neuritis
papilledema
retinal artery/vein thrombosis
retinal detachment
retinal hemorrhage
retinopathy (with macular edema)
visual abnormalities

Respiratory

dyspnea (↓ in children)

Gastrointestinal

anorexia (↑ in children)
dyspepsia (↓ in children)
vomiting (↑ in children)

Hematologic

hemolytic anemia (most frequent)

Dermatologic

stevens-johnson syndrome (life-threatening)
pruritus (↓ in children)

Musculoskeletal

arthralgia (↓ in children)

Miscellaneous

fever (↑ in children)

Interactions

Drug-Drug interaction

Oral: May ↓ the antiretroviral action of stavudine and zidovudine.May ↑ hematologic toxicity of zidovudine.May ↑ risk of pancytopenia when used with azathioprine.May ↑ blood levels and risk of toxicity of didanosine.Although used together in the management of hepatitis, concurrent use with interferon alpha 2b ↑ risk of hemolytic anemia.

Route/Dosage

Inhalation (Infants and Young Children) 300 mL of 20 mg/mL solution delivered via mist for 12–18 hr/day.

Rebetol (with peginterferon alfa-2b [PegIntron])

If retreatment is necessary, duration of therapy is 48 wk, regardless of viral genotype

Oral (Adults >105 kg) 600 mg in the morning, then 800 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Adults 81–105 kg) 600 mg in the morning, then 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Adults 66–80 kg) 400 mg in the morning, then 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Adults ≤65 kg) 400 mg in the morning, then 400 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and >73 kg) 600 mg in the morning and 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and 60–73 kg) 400 mg in the morning and 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and 47–59 kg) 400 mg in the morning and 400 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and <47 kg) 15 mg/kg/day in 2 divided doses (as oral solution) for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Rebetol (with interferon alfa-2b [Intron A])

If retreatment is necessary, duration of therapy is 24 wk

Oral (Adults >75 kg) 600 mg in the morning, then 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Adults ≤75 kg) 400 mg in the morning, then 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and >73 kg) 600 mg in the morning and 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and 60–73 kg) 400 mg in the morning and 600 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and 47–59 kg) 400 mg in the morning and 400 mg in the evening for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Oral (Children 3–17 yr and <47 kg) 15 mg/kg/day in 2 divided doses (as oral solution) for 48 wk (viral genotype 1) or 24 wk (viral genotypes 2 and 3).

Copegus—viral genotype 1 or 4 (with peginterferon alfa-2a)

Oral (Adults ≥75 kg) 600 mg twice daily for 48 wk.

Oral (Adults <75 kg) 500 mg twice daily for 48 wk.

Oral (Children ≥5 yr and ≥75 kg) 600 mg in the morning, then 600 mg in the evening for 48 wk

Oral (Children ≥5 yr and 60–74 kg) 400 mg in the morning, then 600 mg in the evening for 48 wk

Oral (Children ≥5 yr and 47–59 kg) 400 mg in the morning, then 400 mg in the evening for 48 wk

Oral (Children ≥5 yr and 34–46 kg) 200 mg in the morning, then 400 mg in the evening for 48 wk

Oral (Children ≥5 yr and 23–33 kg) 200 mg in the morning, then 200 mg in the evening for 48 wk

Renal Impairment

Oral (Adults) CCr 30–50 mL/min—200 mg/day alternating with 400 mg/day every other day for 48 wk; CCr <30 mL/min or Hemodialysis—200 mg once daily for 48 wk

Copegus—viral genotype 2 or 3 (with peginterferon alfa-2a)

Oral (Adults) 400 mg twice daily for 24 wk.

Oral (Children ≥5 yr and ≥75 kg) 600 mg in the morning, then 600 mg in the evening for 24 wk

Oral (Children ≥5 yr and 60–74 kg) 400 mg in the morning, then 600 mg in the evening for 24 wk

Oral (Children ≥5 yr and 47–59 kg) 400 mg in the morning, then 400 mg in the evening for 24 wk

Oral (Children ≥5 yr and 34–46 kg) 200 mg in the morning, then 400 mg in the evening for 24 wk

Oral (Children ≥5 yr and 23–33 kg) 200 mg in the morning, then 200 mg in the evening for 24 wk

Renal Impairment

Oral (Adults) CCr 30–50 mL/min—200 mg/day alternating with 400 mg/day every other day for 24 wk; CCr <30 mL/min or Hemodialysis—200 mg once daily for 24 wk

Copegus—with HIV coinfection (regardless of viral genotype) (with peginterferon alfa-2a)

Oral (Adults) 800 mg daily for 48 wk.

Availability

Powder for reconstitution for aerosol use (Virazole): 6 g/vial

Capsules (Rebetol): 200 mg

Oral solution (Rebetol): 40 mg/mL

Tablets (Copegus): 200 mg

In combination with: Rebetrol with interferon alfa-2b (Intron A) as combination therapy for chronic hepatitis C (Rebetron). See combination drugs.

Nursing implications

Nursing assessment

RSV: Assess patient for infection (vital signs, sputum, WBC) at beginning and during therapy.
- Obtain specimens for culture and sensitivity prior to initiating therapy. First dose may be given before receiving results.
- Assess respiratory (lung sounds, quality and rate of respirations) and fluid status prior to and frequently throughout therapy.
Chronic Hepatitis C: Monitor symptoms of hepatitis during therapy.
Assess patient for signs of depression during therapy. Monitor closely for neuropsychiatric changes, including suicidal thoughts.
- Obtain ECG prior to therapy in patients with pre-existing cardiac disease. Assess patient for cardiovascular disorders (pulse, BP, chest pain). Reduce dose or discontinue therapy if cardiac disorders occur. May cause myocardial infarction.
- Assess for signs of colitis (abdominal pain, bloody diarrhea, fever) and pancreatitis (nausea, vomiting, abdominal pain) during therapy. Discontinue therapy if these occur; may be fatal.
- Assess pulmonary status (lung sounds, respirations) periodically during therapy. May require discontinuation.
- Monitor for hypersensitivity reactions (urticaria, angioedema, bronchoconstriction, anaphylaxis). Discontinue immediately and institute supportive therapy.
Lab Test Considerations: Chronic Hepatitis C: Monitor CBC with differential and platelet count prior to initiation, at week 2, and week 4, and regularly during therapy. If hemoglobin <10 g/dL in patients with no history of cardiac disease or ↓ more than 2 g/dL in any 4-wk treatment period in patients with history of stable cardiac disease, ↓ ribavirin dose to 600 mg (200 mg in AM and 400 mg in PM). If hemoglobin <8.5 g/dL in patients with no history of cardiac disease or <12 g/dL despite dose reduction in patients with history of stable cardiac disease, discontinue combination therapy permanently. If dose withheld in children, may restart with 1/2 original dose.
- Monitor biochemical tests and electrolytes prior to, after 4 wk, and periodically during therapy.
- Monitor liver function tests and thyroid stimulating hormone prior to and periodically during therapy.
- Monitor pregnancy tests prior to, monthly during, and for 6 mo following discontinuation of therapy in women of childbearing age. Ribavarin should be started following a negative pregnancy test.
- May cause ↑ serum bilirubin and uric acid levels.

Potential Nursing Diagnoses

Risk for infection (Indications, Side Effects)
Impaired gas exchange (Indications)

Implementation

Inhalation: Infants requiring assisted ventilation should be suctioned every 1–2 hr and pulmonary pressures monitored every 2–4 hr.
- Ribavirin treatment should begin within the first 3 days of RSV infection to be effective.
- Ribavirin aerosol should be administered using the Viratek SPAG model SPAG-2 only. Do not administer via other aerosol-generating devices. Usually administered using an infant oxygen hood attached to the SPAG-2 aerosol generator. Administration by face mask may be used if the oxygen hood cannot be used.
- Reconstitute ribavirin 6-g vial with preservative-free sterile water for injection or inhalation. Transfer to clean, sterilized Erlenmeyer flask of the SPAG-2 reservoir and dilute to a final volume of 300 mL. This recommended concentration (20 mg/mL) in the reservoir provides a concentration of aerosol ribavirin of 190 mcg/L of air over a 12-hr period. Solution should be discarded and replaced every 24 hr.
- Aerosol treatments should be administered continuously 12–18 hr/day for 3–7 days.
Oral: Administer with food. Capsules should be swallowed whole; do not open, crush, or chew.
- For children, determine if child is able to swallow 200-mg tablet.

Patient/Family Teaching

RSV: Explain the purpose and route of treatment to the patient and parents.
Inform patient and parents that ribavirin may cause blurred vision and photosensitivity.
Chronic Hepatitis C: Instruct patient to take ribavirin at the same time each day for the full course of therapy. Take missed doses as soon as remembered. If total day dose is missed, notify health care professional; do not double doses. Emphasize the importance of routine lab test to monitor for side effects.
- Advise patient to brush teeth twice daily, have regular dental examinations, and rinse mouth thoroughly after vomiting to prevent dental and periodontal disorders.
- May cause dizziness, confusion, fatigue, and drowsiness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
- Inform patient that ribavirin may not reduce the risk of transmission of HCV to others or prevent cirrhosis, liver failure, or liver cancer.
- Advise patient to consult health care professional before taking any other Rx, OTC, or herbal products.
- Advise patient to stop taking ribavirin and notify health care professional immediately if rash with fever; blisters or sores in mouth, nose, or eyes; or conjunctivitis occurs and to notify health care professional if trouble breathing, hives or swelling, chest pain, severe stomach pain or low back pain, bloody diarrhea or bloody or black stools, bruising or unusual bleeding, change in vision, fever >100.5°F, worsening psoriasis, worsening depression, or suicidal thoughts occur.
- Inform patient about teratogenic effects of ribavirin. Instruct women with childbearing potential, and men, to use 2 forms of effective contraception during and for at least 6 mo following conclusion of therapy. Men must use a condom. Avoid breast feeding during use.

Evaluation/Desired Outcomes

Resolution of the signs and symptoms of RSV.
Decreased progression and sequelae of chronic hepatitis C. Therapy with peginterferon alfa-2a and ribavirin should be discontinued if at least a 2-log 10 reduction from baseline in HCV RNA by 12 wk of therapy, or undetectable HCV RNA levels after 24 wk of therapy.

Virazole

(vîr′ə-zōl′)

A trademark for the drug ribavirin.

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