ribavirin (Rebetol, Ribasphere, RibaPak, Copegus, Virazole, Moderiba)

Dosing and uses of Rebetol, Ribasphere (ribavirin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 200mg
• 400mg
• 600mg

inhalation solution

• 6g/vial

oral solution

• 40mg/mL

 

Chronic Hepatitis C

In combination with pegterferon alfa-2a (Pegasys)

Dose reductions/interruptions recommended if Hgb falls (see Mfr's PI for specifics)

Tablets (Copegus)

• In combination with peginterferon alfa-2a
• Genotype 1, 4; HIV-free (<75 kg): 1000 mg/day PO divided q12hr x48 weeks
• Genotype 1, 4; HIV-free (≥75 kg): 1200 mg/day PO divided q12hr x48 weeks
• Genotype 2/3; HIV-free: 800 mg/day PO divided q12hr x24 weeks
• Chronic hepatitis C coinfected with HIV: peginterferon alfa-2a 180 mcg SC qWeek plus ribavirin 800 mg PO divided q12hr (regardless of genotype)

Rebetol capsule, oral solution, Ribasphere combo with peginterferon alfa 2B

• <66 kg (145 lb): 800 mg/day (400 mg AM and 400 PM) + peginterferon 1.5 mcg/kg/Wk SC
• 66-80 kg (145-177 lb): 1000 mg/day (400 mg AM and 600 PM) + peginterferon 1.5 mcg/kg/Wk SC
• 81-105 kg (178-231 lb): 1200 mg/day (600 mg AM and 600 PM) + peginterferon 1.5 mcg/kg/Wk SC
• >105 kg (231 lb): 1400 mg/day (600 mg AM and 800 PM) + peginterferon 1.5 mcg/kg/Wk SC
• Recommended therapy duration
  • Genotype 1: 48 wks
  • Genotype 2,3: 24 wks
  • Patients who previously failed therapy: 48 wks, regardless of genotype

Ribavirin (Rebetol capsule and solution; Ribasphere) with interferon alfa 2B

• ≤75 kg: 400 mg PO qAM, 600mg PO qPM plus 3 million IU three times weekly SC for 24-48 wks
• >75 kg: 600 mg PO q12hr plus 3 million IU three times weekly SC for 24-48 wks
• Recommended therapy duration
  • Patients previously untreated with interferon: 24-48 wks
  • Patients who relapse following inteferon monotherapy: 24 wks

HIV/HCV coinfection: Copegus

• 800 mg/d PO divided q12h x48 weeks

RibaPak, Copegus, Ribasphere and equivalents used with peginterferon alfa-2a (Pegasys)

• Coadministered dose of peginterferon alfa-2a: 180 mcg qWeek

 

Renal Impairment

Rebetol capsules/solution, Ribasphere capsules

• CrCl < 50 mL/min: Use contraindicated
• CrC l ≥ 50 mL/min: Dose adjustment not necessary

Ribasphere tablets

• CrCl < 50 mL/min: Use contraindicated
• CrC l ≥ 50 mL/min: Dose adjustment not necessary

Copegus tablets

• CrCl <30 mL/min or hemodialysis: 200 mg PO qDay
• CrCl 30-50 mL/min: Alternating doses, 200 mg and 400 mg PO every other day
• CrCl ≥ 50 mL/min: Dose adjustment not necessary

 

Thyroid Cancer (Orphan)

Ribavirin elaidate: Treatment of follicular, medullary, and anaplastic thyroid carcinoma and metastatic or locally advanced papillary thyroid cancer

Orphan indication sponsor

• Translational Therapeutics, Inc; 163 Scituate Street; Arlington, MA 02476

 

Hemorrhagic Fever (Orphan)

Treatment of hemorrhagic fever (Lassa fever) with renal syndrome

Treatment: Load 30 mg/kg IV (up to 2 g), THEN 16 mg/kg IV (up to 1 g) q6hr x4 days, THEN 8 mg/kg IV (up to 500 mg) q8hr x6 days

IV form available from CDC on compassionate basis

Prophylaxis: 500-600 mg PO q6hr x7-10 days

Orphan indication sponsor

• Valeant Pharmaceuticals International; 3300 Hyland Avenue; Costa Mesa, CA 92626

 

Administration

Take with food

Take 1 dose AM and one at night (may not be equal)

 

Pediatric dosage forms and strengths

tablet

• 200mg
• 400mg
• 600mg

inhalation solution

• 6g/vial

oral solution

• 40mg/mL

 

Respiratory Syncytial Virus

Virazole: Put 20 mg/mL solution (6 g drug reconstituted with 300 mL sterile water for injection) in SPAG-2 unit

Continuous aerosolized administration for 12-18 hr/day x 3-7 days

Delivers 190 mcg/L of air for a 12-hr period

 

Chronic Hepatic C Virus Infection

Indicated in combination with peginterferon alfa-2a for treatment of chronic hepatitis C in patients with compensated liver disease and no prior history of interferon therapy

Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through completion of therapy

Length of treatment determined by genotype; genotypes 2 or 3 administer for 24 weeks, for genotype 1 is 48 weeks

Rebetol capsule, oral solution

• <47 kg (103 lb): 15 mg/kg/day, plus peginterferon alfa-2b 60 mcg/m² SC qWeek
• 47-59 kg (103-131 lb): 400 mgPO q12hr, plus peginterferon alfa-2b 60 mcg/m² SC qWeek
• 60-73 kg (132-162 lb): 400 mg PO qAM, 600 mg PO qPM plus peginterferon alfa-2b 60 mcg/m² SC qWeek
• >73 kg (162 lb): 600 mg PO q12hr plus peginterferon alfa-2b 60 mcg/m² SC qWeek

Copegus, Moderiba (tablets)

• <5 years: Safety and efficacy not established
• 5-17 years: ~15 mg/kg/day PO divided q12hr with weekly SC peginterferon alfa-2a
• 23-33 kg: 200 mg PO q12hr
• 34-46 kg: 200 mg PO qAM and 400 mg PO qPM
• 47-59 kg: 400 mg PO q12hr
• 60-74 kg: 400 mg PO qAM and 600 mg PO qPM
• ≥75 kg: 600 mg PO q12hr

 

Lassa Fever Prophylaxis

>9 years: As adult; Load 30 mg/kg IV (up to 2 g), THEN 16 mg/kg IV (up to 1 g) q6hr x4 days, THEN 8 mg/kg IV (up to 500 mg) q8hr x6 days

6-9 years: 400 mg PO q6hr

 

Rebetol, Ribasphere (ribavirin) adverse (side) effects

>10%

Fatigue (60-70%)

Headache (63-66%)

Hemolysis (61-64%)

Myalgia (61-64%)

Nausea (38-47%)

Rigors (40-43%)

Fever (32-41%)

Insomnia (26-39%)

Decreased Hgb (25-36%)

Depression (23-36%)

Hyperbilirubinemia (24-34%)

Arthralgia (29-33%)

Alopecia (27-32%)

Irritability (23-32%)

Musculoskeletal pain (20-28%)

Rash (20-28%)

Anorexia (21-27%)

Dizziness (17-26%)

Pruritus (13-21%)

Flu-like syndrome (13-18%)

Dyspnea (17-19%)

Nasal congestion (13-18%)

Dyspepsia (14-16%)

Impaired concentration (10-14%)

Thrombocytopenia (6-14%)

Sinusitis (9-12%)

Vomiting (9-12%)

Emotional lability (7-12%)

Decreased WBC; ANC <500 /cu.mm (5-11%)

 

1-10%

Hemolytic anemia (~10%)

Weakness (9-10%)

Chest pain (5-9%)

Taste perversion (6-8%)

Nervousness (~5%)

 

Postmarketing Reports

Combined with peginterferon alfa-2a

• Dehydration
• Hearing impairment
• Hearing loss
• Retinal detachment
• Pure red cell aplasia (PRCA)
• Serious skin reactions
• Liver and renal graft rejection
• Homicidal ideation
• Growth inhibition in pediatric patients

 

Warnings

Black box warnings

OraL

• Monotherapy not effective for treatment of chronic hepatitis C virus (HCV) infection and should not be used alone for this indication
• Hemolytic anemia is the primary toxicity, which may result in worsening of cardiac disease and lead to fatal and nonfatal MI; do not use if history of significant or unstable cardiac disease
• Significant teratogenic and/or embryocidal effects demonstrated in all animal species exposed to ribavirin
• Half-life is 12 days, and drug may persist in nonplasma compartments for as long as 6 months
• Contraindicated during pregnancy and in the male partners of pregnant women
• Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and female partners of male patients taking ribavirin
• At least 2 reliable forms of effective contraception must be used during treatment and during the 6-month posttreatment follow-up period

Inhalation

• Aerosolized ribavirin in patients requiring mechanical ventilator assistance should be administered only by health care providers and support staff familiar with this mode of administration and the specific ventilator being used
• Strictly follow procedures that minimize drug precipitate accumulation to avoid mechanical ventilator dysfunction
• Sudden respiratory function deterioration in infants may occur during initiation of aerosolized ribavirin
• Carefully monitor respiratory function during treatment
• If sudden deterioration of respiratory function occurs, stop treatment and reinstitute only with extreme caution, continuous monitoring, and possibly bronchodilator coadministration
• Aerosolized ribavirin not indicated for adults
• Produces testicular lesions in rodents and is teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits)

 

Contraindications

Women who are or may become pregnant

Men whose female partners are pregnant

Known hypersensitivity reactions to ribavirin (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme)

Autoimmune hepatitis

Hemoglobinopathies (eg, thalassemia major, sickle-cell anemia)

CrCl <50 mL/min

Coadministration with didanosine; exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) is increased; fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported with this combination

 

Cautions

Mechanically ventilated patients

Preexisting cardiac disease  

May need interruption if CV status deteriorates

Risk of hemolytic anemia

Do NOT use for influenza

Only Copegus studied in HCV/HIV coinfectees, however the modified dose is CDC recommended

Ribavirin may cause birth defects and/or death of unborn child (see Black box warnings and Contraindications)

There are significant adverse reactions caused by ribavirin/ interferon alfa therapy, including severe depression and suicidal or homicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes; suicidal ideation may occur more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up

Suspend ribavirin and alfa interferon combination therapy in patients with signs and symptoms of pancreatitis and discontinue in patients with confirmed pancreatitis

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, reported during therapy with ribavirin with alpha interferon combination therapy; occasional cases of fatal pneumonia have occurred; sarcoidosis or the exacerbation of sarcoidosis reported; closely monitor patient or if necessary discontinue therapy if pulmonary infiltrate or pulmonary function impairment observed

Dental and periodontal disorders reported in patients receiving ribavirin and interferon alfa combination therapy; dry mouth could have damaging effect on teeth and mucous membranes of mouth during long-term treatment with combination of ribavirin and interferon alfa; patients should brush teeth thoroughly twice daily and have regular dental examinations; if vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards

Take extreme care to avoid pregnancy

Risk of hemolytic anemia

Anemia associated with treatment may result in worsening of cardiac disease

Genotoxic and mutagenic: Potential carcinogen

Ocular disorders reported when ribavirin is used in combination therapy with alpha interferons (eg, decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages; cotton wool spots, optic neuritis, papilledema, serous retinal detachment)

Study in boys showed growth rate inhibited (ie, height percentile decreases) with peginterferon alfa-2b plus ribavirin

Pancytopenia and bone marrow suppression reported when coadministered with pegylated interferon and azathioprine

Hepatic decompensation

• Patients with chronic hepatitis C (CHC) and cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS
• Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART

 

Pregnancy and lactation

Pregnancy category: X

Lactation: unknown

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Rebetol, Ribasphere (ribavirin)

Mechanism of action

May inhibit the initiation and elongation of RNA fragments by inhibiting polymerase activity, which in turn results in the inhibition of viral protein synthesis

 

Absorption

Absorption (inhalation): Systemic maximal absorption occurs with use of aerosol generator via endotracheal tube; highest concentrations may occur in respiratory tract and erythrocytes

Peak plasma time: 3 hr (multiple doses; capsule at end of inhalation period)

Bioavailability: 64% (PO)

 

Distribution

Significantly prolonged in erythrocyte (16-40 days), which may use as marker for intracellular metabolism

Vd: 2825 L

Protein bound: None (PO)

 

Metabolism

Hepatically and intracellularly (forms active metabolites); may be necessary for drug action

 

Elimination

Half-life: 24 hr in healthy adults (capsule); 44 hr (chronic hepatitis C infection; increases to ~298 hr at steady state)

Excretion: Urine (61%); feces (12%)