广谱抗病毒药。体外具有抑制呼吸道合胞病毒、流感病毒、甲肝病毒、腺病毒等多种病毒生长的作用，其机制不全清楚。本品并不改变病毒吸附、侵入和脱壳，也不诱导干扰素的产生。药物进入被病毒感染的细胞后迅速磷酸化，其产物作为病毒合成酶的竞争性抑制剂，抑制肌苷单磷酸脱氢酶、流感病毒RNA多聚酶和mRNA鸟苷转移酶，从而引起细胞内鸟苷三磷酸的减少，损害病毒RNA和蛋白合成，使病毒的复制与传播受抑。对呼吸道合胞病毒也可能具免疫作用及中和抗体作用。
动物实验发现本品可诱发乳房、胰腺、垂体和肾上腺良性肿瘤，但对人体的致癌性并未肯定。药物对仓鼠等动物可引起头颅、腭、眼、颌、骨骼和胃肠道的畸形，子代成活减少，但灵长类动物实验并未发现药物对胎仔的影响。
给予小鼠、大鼠和猴口服利巴韦林，剂量分别为30、36和120mg/kg或持续4周以上(相当于人用剂量：给予体重为5kg的儿童4.8、12.3和111.4mg/kg，或者体重为60kg成人2.5、5.1和40mg/kg。以上均按体表面积折算)，出现心脏损伤。
口服吸收迅速，生物利用度(F)约45%，少量可经气溶吸入。口服后1.5小时血药浓度达峰值，血药峰浓度(Cmax)约1～2mg/L。小儿每日以面罩吸药2.5小时共3天，平均血药峰浓度(Cmax)为0.2mg/L；每日吸药20小时共5天，平均血药峰浓度(Cmax)为1.7mg/L，与血浆蛋白几乎不结合。药物在呼吸道分泌物中的浓度大多高于血药浓度。药物能进入红细胞内，且蓄积量大。长期用药后脑脊液内药物浓度可达同时期血药浓度的67%。本品可透过胎盘，也能进入乳汁。在肝内代谢。血药消除半衰期(t1/2β)约为0.5～2小时。本品主要经肾排泄。72～80小时尿排泄率为30%～55%。72小时粪便排泄率约15%。药物在红细胞内可蓄积数周。
常见的不良反应有贫血、乏力等，停药后即消失。较少见的不良反应有疲倦、头痛、失眠、食欲减退、恶心、呕吐、轻度腹泻、便秘等，并可致红细胞、白细胞及血红蛋白下降。
2．少量药物由乳汁排泄，且对母子二代动物均具毒性，因此哺乳期妇女在用药期间需暂停哺乳，乳汁也应丢弃。由于哺乳期妇女呼吸道合胞病毒感染具自限性，故本品不用于此种病例。
REBETOL ORAL SOL 100ML RIBAVIRIN MERCK SHARP & DOHME 00085-1318-01
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Rebetol, Ribasphere (ribavirin) dosing, indications, interactions, adverse effects, and more
Dosing Forms & Strengths
(tablet)
•200mg
•400mg
•600mg
(capsule)
•200mg
(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 BID x48 weeks
•Genotype 1, 4; HIV-free (>75 kg): 1200 mg/day PO div BID x48 weeks
•Genotype 2/3; HIV-free: 800 mg/day PO divided BID x24 weeks
•Chronic hepatitis C coinfected with HIV: peginterferon alfa-2a 180 mcg SC qWeek plus ribavirin 800 mg PO qDay (regardless of genotype)
•Renal impairment (CrCl 30-50 mL/min): Alternating doses, 200 mg and 400 mg PO every other day)
•Renal impairment (<30 mL/min or hemodialysis): 200 mg PO qDay
Capsules or oral solution (in combination with interferon alfa-2b)
•<75 kg: 400 mg PO qAM, 600mg PO qPM
•>75 kg: 600 mg PO BID
HIV/HCV Coinfectee: Copegus
•800 mg/d div BID PO x48 weeks
RibaPak, Copegus, Ribasphere & equivalents used with peginterferon alfa-2a (Pegasys)
•Coadministered dose of peginterferon alfa-2a: 180 mcg qWeek
•Renal impairment (CrCl <30 mL/min or hemodialysis): 135 mcg SC qWeek
Rebetol
Rebetol: Combo with peginterferon-alfa-2b (PegIntron)
•<40-65 kg: 800 mg/d div 2 doses (400 mg AM & 400 PM) +Peginterferon 1.5 mcg/kg/Week SC
•66-85 kg: 1000 mg/d div 2 doses (400 mg AM & 600 PM) +Peginterferon 1.5 mcg/kg/Week SC
•86-105 kg: 1200 mg/d div 2 doses (600 mg AM & 600 PM) +Peginterferon 1.5 mcg/kg/Week SC
•>105 kg: 1400 mg/d div 2 doses (600 mg AM & 800 PM) +Peginterferon 1.5 mcg/kg/Week SC)
•Patients with CrCl <50 mL/min should not take Rebetol
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 d, THEN 8 mg/kg IV (up to 500 mg) q8hr x6 d
IV form available from CDC on compassionate basis
Prophylaxis: 500-600 mg PO q6hr x7-10 d
Orphan indication sponsor
•Valeant Pharmaceuticals International; 3300 Hyland Avenue; Costa Mesa, CA 92626
Administration
Take with food
Take 1 dose AM & one at night (may not be equal)
Other Indications & Uses
Virazole: severe RSV infection
PO forms: hepatitis C
Off-label: Lassa fever, other viral hemorrhagic fevers
Dosing Forms & Strengths
(tablet)
•200mg
•400mg
•600mg
(capsule)
•200mg
(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 x3-7 d
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 the completion of therapy
Length of treatment determined by genotype; genotypes 2 or 3 administer for 24 weeks, other genotypes for 48 weeks
Rebetol
•<3 years old: Safety and efficacy not established
•Rebetol: 3-17 years old: 15 mg/kg/d PO divided BID, plus peginterferon alfa-2b 60 mcg/sq.meter SC qWeek
Copegus (tablets)
•<5 years: Safety and efficacy not established
•5-17 years: ~15 mg/kg/day PO divided BID with weekly SC peginterferon alfa-2a
•23-33 kg: 200 mg PO BID
•34-46 kg: 200 mg PO qAM and 400 mg PO qPM
•47-59 kg: 400 mg PO BID
•60-74 kg: 400 mg PO qAM and 600 mg PO qPM
•75 kgor greater: 600 mg PO BID
Lassa Fever Prophylaxis
>9 years old: As adult; Load 30 mg/kg IV (up to 2 g), THEN 16 mg/kg IV (up to 1 g) q6hr x4 d, THEN 8 mg/kg IV (up to 500 mg) q8hr x6 d
6-9 years old: 400 mg PO q6hr
Adverse 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
Contraindications & Cautions
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
General: hypersensitivity
Virazole: pregnancy; adults; nonsevere RSV infections
CrCl <50 mL/min
Pancreatitis
Hemoglobinopathies (eg, thalassemia major, sickle cell anemia)
Coadministration with didanosine
Pregnancy/planning pregnancy, including men whose female partners are pregnant/planning to get pregnant
In combination with alpha interferons
•Autoimmune hepatitis
•Hepatic decompensation in patients with cirrhosis
Cautions
Virazole: mechanically ventilated pts
HCV
•Preexisting cardiac dz 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
•See also cautions for corresponding peginterferons
Ribavirin may cause birth defects &/or death of unborn child
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 & 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
Absorption: Inhalation: systemic; dependent upon respiratory factors & method of drug delivery; maximal absorption occurs with use of aerosol generator via endotracheal tube; highest concentrations in respiratory tract & erythrocytes
Distribution: distribution significantly prolonged in erythrocyte (16-40 d), which can be used as marker for intracellular metabolism
Vd: 2825 L
Protein Bound: oral: none
Metabolism: hepatically and intracellularly (forms active metabolites); may be necessary for drug action
Bioavailability: PO: 64%
Half-life, elimination: oral capsule, single dose: 24 hr in healthy adults, 44 hr with chronic hepatitis C infection (increases to ~298 hr at steady state)
