RIBATAGIN®500

Composition: Each caplet contains:
Ribavirin . . . . . . . . . . . . . . . . . . . . . . . . 500 mg
Presentation:
2 blisters of 10 caplets in a carton box.
Indications:
Ribavirin is indicated for treatment of chronic hepatitis C in patients with compensated liver disease who have not been treated with interferon or who have relapsed after previous treatment with interferon alpha-2b.
Ribavirin should be used in combination with interferon alpha-2b or peginterferon alpha-2b, ribavirin monotherapy is ineffective. This combination therapy is also effective in hepatitis C virus patients with HIV coinfection.

Additional information

Dosage and administration

Dosage:
Oral ribavirin is combined with interferon injection (3 – 5 MIU once, 3 times per week) or peginterferon injection at dose of 1.5 micrograms/kg/once per week.
Patient with body weight < 75kg: 500mg (one caplet), twice daily.
The duration of treatment depends on the genotype of the hepatitis C virus and whether the patient has previously been treated with interferon.
HCV-monoinfected patients with genotype 1, 4: Treatment for 48-weeks; with genotype 2 or 3: treatment for 24-weeks. Relatively little is known about the treatment of genotype 5 or 6 infection. In case of HIV coinfection, treatment for 48 weeks is given, regardless of genotype. Patients who relapsed after interferon treatment: Co-administration with ribavirin is given for 24 weeks.
The safety and efficacy of this combination have not been established when the treatment is longer than 6 months.
After 24 weeks of therapy, the response to the treatment should be checked: Measure the serum levels of HCV RNA. If there is no response, ribavirin caplets should be stopped because of potential failure of the further treatment.
Change the dose:
For patients who need to change the dose due to side effects or renal failure, the doctor will prescribe the appropriate dosage forms of ribavirin and follow the instructions below: Dose modification for adverse reactions
Dose modification of ribavirin depends on the medicinal product that is used in combination with ribavirin.
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.
Ribavirin should be used with caution in patients with a history of heart disease. Patients should be evaluated before starting treatment and should be monitored appropriately during treatment. If there is any deterioration of cardiovascular status, therapy should be stopped (see Conditions where caution should be taken).
Guidelines for dose modifications based on the patient's hemoglobin concentration
– Reduce ribavirin dose [1] [2] if:
+ Hemoglobin in patients with no cardiac disease < 10g/dl
+ Hemoglobin: Patients with history of stable cardiac disease ≥ 2g/dl decrease in hemoglobin during any 4 week period during treatment (permanent dose reduction)
– Discontinue ribavirin if:
+ Hemoglobin in patients with no cardiac disease < 8.5g/dl
+ Hemoglobin: Patients with history of stable cardiac disease < 12g/dl despite 4 weeks at reduced dose
[1] For patients receiving a 1, 000mg dose (< 75kg), ribavirin dose should be reduced to 600mg/day (administered as one 200mg caplet in the morning and two 200mg caplets or one 400mg caplet in the evening). If the abnormality is reversed, ribavirin may be restarted at 600mg daily, and further increased to 800mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.
[2] For patients receiving a 1, 000mg (65-80kg) dose, 1st dose reduction of ribavirin is by 200mg/day. If needed, 2nd dose reduction of ribavirin is by an additional 200mg/day. Patients whose dose of ribavirin is reduced to 600mg daily receive one 200mg caplet in the morning and two 200mg caplets or one 400mg caplet in the evening.
Refer to the instructions for use of peginterferon alpha or interferon alpha for dose modification and/or discontinuation in case of serious adverse reaction potentially related to these drugs.
Use in renal impairment: The recommended dose regimens (adjusted by the body weight cutoff of 75kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment. The total daily dose of ribavirin should be reduced for patients with creatinine clearance less than or equal to 50ml/min as shown below
– Creatinine clearance ~ Ribavirin dose (daily)
+ 30 to 50ml/minute ~ Alternating doses, 200mg and 400mg every other day
+ Less than 30ml/minute ~ 200mg daily
+ Haemodialysis ~ 200mg daily
Therapy should be initiated (or continued if renal impairment develops while on therapy) with extreme caution and intensive monitoring of hemoglobin concentrations, with corrective action as may be necessary, should be employed throughout the treatment period.
If severe adverse reactions or laboratory abnormalities develop, Ribatagin 500 should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance develops after resuming ribavirin, the treatment with ribavirin should be discontinued. No data are available for pediatric subjects with renal impairment.
Use in hepatic impairment: Hepatic function does not affect the pharmacokinetics of ribavirin. Therefore, no dose adjustment of Ribatagin 500 is required in patients with hepatic impairment.
Discontinuation of dosing
Discontinuation of peginterferon alpha-2a /ribavirin therapy should be considered if the patient has not been able to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.
Peginterferon alpha-2a / ribavirin should not be used in patients with impaired hepatic function during the treatment.
Administration:
Ribatagin 500 film-coated caplets should be taken twice a day, regardless of the meal, but ribavirin is better absorbed if taken with a high fat meal.

Contraindications

Hypersensitivity to ribavirin or to any of the excipients of the medicine.
Pregnant women and a male partner of a pregnant woman.
Breastfeeding mothers.
Patients with a history of unstable heart disease, myocardial ischaemia, severe heart disease, unstable or uncontrolled cardiac disease in the previous six months.
Patients with severe renal failure, chronic renal failure or creatinine clearance < 50 mL/ min or on dialysis.
Autoimmune hepatitis, severe hepatic impairment, decompensated cirrhosis, liver cirrhosis with chronic HCV infection, decompensated cirrhosis co-infected with HIV before and during treatment.
Anemia, hemoglobinopathies (thalassemia, sickle-cell disease).
Patients with psychiatric disorders.

Warnings and precautions for use

Ribavirin should be used cautiously in patients below the age of 18 years, particularly when it is combined with interferon alpha-2b, because safety and effect have not been known.
Ribavirin is not used as monotherapy because the treatment of hepatitis C is not effective.
Ribavirin should be used with caution in patients with advanced cirrhosis or renal failure.
Ribavirin should not be used for patients who continue to inject illicit drugs (high risk of re-infection) and heavy drinkers (risk of increased liver damage).
(Peg)interferon-alpha 2a and ribavirin combination therapy:
There are several severe adverse reactions associated with (peg)interferon-alpha 2a and ribavirin combination therapy, including:
– Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behavior, etc.).
– Severe ocular disorders.
– Dental and periodontal disorders.
– Growth inhibition in children and adolescents that may be irreversible in some patients.
Refer to the instructions for use of (peg)interferon alpha for details on the recommendations of monitoring and management regarding these adverse reactions before initiating therapy.
Teratogenic risk:
Women of childbearing age: Extreme care must be taken to avoid pregnancy or plan to become pregnant during therapy and for many months after completion of the therapy because of the potential for teratogenicity of ribavirin.
Prior to initiation of treatment with ribavirin, the physician must comprehensively inform the patient of the teratogenic risk of ribavirin, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during treatment with ribavirin. Laboratory tests should be performed to make sure the patient is not pregnant before taking the medication.
Carcinogenicity: Ribavirin is mutagenic in some in vivo and in vitro genotoxicity assays. A potential carcinogenic effect of ribavirin cannot be excluded.
Haemolysis and cardiovascular system:
Ribavirin causes hemolytic anemia which can worsen any heart problems (myocardial infarction). Before starting the treatment with Ribatagin 500 caplets, blood tests must be exercised (including blood cell count, white blood cell count, platelets and clotting time), the appearance of anemia must be monitored. The tests are repeated at week 2 and 4 of treatment, thereafter periodically performed in according to clinical conditions.
A decrease in hemoglobin levels to <10g/dl was observed in up to 15% of patients treated for 48 weeks with ribavirin 1000/1200mg in combination with peginterferon alpha-2a and up to 19% of patients in combination with interferon alpha-2a. When ribavirin 800mg was combined with peginterferon alpha-2a for 24 weeks, 3% of patients had a decrease in hemoglobin levels to <10g/dl. The risk of developing anaemia is higher in the female population. Although ribavirin has no direct cardiovascular effects, anaemia associated with ribavirin may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, ribavirin must be administered with caution to patients with pre-existing cardiac disease.
Cardiac status must be assessed before the start of therapy and monitored clinically during therapy. If any deterioration occurs, stop therapy. Patients with a history of congestive heart failure, myocardial infarction, and/or previous or current arrhythmic disorders must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of therapy.
Aplastic anemia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of ribavirin and a peginterferon concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone.
The use of ribavirin and peginterferon alpha-2a combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse events. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.
Acute hypersensitivity: If an acute hypersensitivity reaction (e.g. urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribatagin 500 must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.
Liver function: In patients who develop evidence of hepatic decompensation during treatment, Ribatagin 500 in combination with other medicinal products should be discontinued. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued.
Renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Ribatagin 500, preferably by estimating the patient's creatinine clearance. Substantial increases in ribavirin plasma concentrations are seen in patients with serum creatinine >2mg/dl or with creatinine clearance <50ml/minute, therefore Ribatagin 500 dose adjustments are recommended in these patients.
Hemoglobin concentrations should be monitored intensively during treatment and corrective action taken as necessary.
Transplantation: The safety and efficacy of peginterferon-alpha-2a and ribavirin treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with peginterferon-alpha-2a, alone or in combination with ribavirin.
HIV/HCV co-infection: Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin and the other medicinal products. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).
Chronic hepatitis C patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of serious adverse effects (e.g. lactic acidosis; peripheral neuropathy; pancreatitis).
Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with ribavirin in combination with interferons. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: Increased serum bilirubin, decreased hemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI). Caution should therefore be exercised when adding peginterferon alpha-2a and ribavirin to HAART.
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia.
During treatment co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g. Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with ribavirin in combination with other medicinal products should be discontinued immediately in patients with hepatic decompensation.
Co-administration of ribavirin and didanosine is not recommended due to the risk of mitochondrial toxicity. Moreover, co-administration of ribavirin and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity.
Laboratory tests: Standard haematologic tests and blood chemistries (complete blood count [CBC], platelet count, electrolytes, glucose, serum creatinine, liver function tests, uric acid) must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of ribavirin:
Hemoglobin ≥12g/dl (females); ≥13g/dl (males).
In patients co-infected with HIV-HCV, limited efficacy and safety data are available in subjects with CD4 counts less than 200cells/μL. Caution is therefore warranted in the treatment of patients with low CD4 counts.
Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate.
For women of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for 4 months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for 7 months thereafter.
Uric acid may increase with ribavirin due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.
This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Recommendation for pregnancy and breastfeeding

Pregnancy:
Ribavirin may cause fetal harm and has been shown to be teratogenic. Ribavirin must not be used by pregnant women. Before starting ribavirin therapy, a pregnancy test must be performed to make sure patient is not pregnant.
Lactation:
It is not known whether ribavirin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, ribavirin should not be used by breastfeeding mothers. Nursing must be discontinued prior to initiation of treatment.

Effects on ability to drive and use machines

There is no evidence to prove ribavirin has influence on the ability to drive or use machines. However, caution should be considered since ribavirin can cause headache, fatigue, dizziness, decreased concentration.

Interactions, incompatibilities of medicine

Ribavirin is not inhibited and metabolized by the cytochrome P450 enzyme system. Thus, it is unlikely to interact with P450 enzyme-induced drugs or to be metabolized by this enzyme system.
Coadministration of ribavirin with an antacid containing magnesium, aluminum and simethicone reduces the area under the curve of ribavirin.
Interferon: When used in combination with interferon, ribavirin may increase the risk of interferon alpha-induced neutropenia. There is no evidence of pharmacokinetic interactions of these two drugs.
Nucleoside reverse transcriptase inhibitors (NRTIs) such as stavudine, zidovudine, lamivudine: Co-administration of ribavirin with these agents may increase the risk of adverse events associated with mitochondrial disorders such as fatal hepatic failure, peripheral neuropathy, pancreatitis, lactic acidosis. Thus, concomitant use of these drugs should be avoided and ribavirin is contraindicated in co-administration with didanosine because of the possible serious adverse reactions.
HIV-HCV co-infected patients:
No apparent evidence of drug interaction was observed in 47 HIV-HCV co-infected patients who completed a 12-week pharmacokinetic substudy to examine the effect of ribavirin on the intracellular phosphorylation of some nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine or stavudine). However, due to high variability, the confidence intervals were quite wide. Plasma exposure of ribavirin did not appear to be affected by concomitant administration of nucleoside reverse transcriptase inhibitors (NRTIs).
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia. Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.

Undesirable effects (ADRs)

Orally, undesirable effects of ribavirin occur primarily in combination with interferon alpha-2b for the treatment of chronic hepatitis C. Although this combination was well tolerated, 19% of interferon alpha-2b treatment-naive patients and 6% of treatment-experienced patients had relapse, then, the combination therapy was discontinued due to adverse effects. Toxicohemia (as hemolytic anemia) is one of the primary unwanted effects and about 10% of patients on combination therapy had heart and respiratory events due to anemia.
Common: ADR > 1/100
Body as a whole: Headache, fatigue, rigor, pyrexia, influenza-like symptoms, myasthenia, weight loss, chest pain, discomfort, coma, hot flushes, thirst.
Blood and lymphatic system disorders: Low hemoglobin count, anemia, neutropenia, thrombocytopenia, swollen lymph nodes.
Gastrointestinal disorders: Nausea, anorexia, diarrhea, abdominal pain, vomiting, dry mouth, constipation, abdominal distension, gingival bleeding, mouth ulceration, pancreatitis, dyspepsia, dysphagia, glossitis.
Cardiovascular disorders: Tachycardia, increased or decreased blood pressure.
Musculoskeletal and connective tissue disorders: Muscular pain, joint pain, musculoskeletal pain, back pain, bone pain, neck pain, muscle cramps.
Nervous system disorders: Paraesthesia, flushing, confusion, dizziness, memory impairment, absent-mindedness, fainting, asthenia, migraine, hypoaesthesia or hyperaesthesia, tremor, nightmares, somnolence.
Psychiatric disorders: Depression, irritability, insomnia, anxiety, concentration impaired, emotional lability, mood alteration.
Skin and subcutaneous tissue disorders: Alopecia, pruritus, dry skin, urticaria, rash, increased sweating, psoriasis, eczema, photo-sensitivity reaction, night sweats.
Respiratory, thoracic and mediastinal disorders: Pharyngitis, rhinitis, sinusitis, cough, dyspnea, chest pain, nosebleed, nasal congestion.
Sensory disorders: Taste disorders.
Endocrine and reproductive system disorders: Menstrual disorders, hypothyroidism or hyperthyroidism, decreased libido, impotence.
Infections and parasitic infection: Upper respiratory tract infections, bronchitis, oral candidiasis, herpes simplex.
Eye disorders: Blurred vision, eye pain, eye inflammation, dry eye.
Ear and labyrinth disorders: Dizziness, ear pain, tinnitus.
Cardiac disorders: Rapid heart rate, palpitations, peripheral edema.
Vascular disorders: Flushing, hypotension.
Uncommon, 1/1000 <ADR <1/100
Infections and infestations: Lower respiratory tract infection, pneumonia, urinary tract infection, skin infection.
Immune system disorders: Sarcoidosis, thyroiditis.
Endocrine disorders: Diabetes.
Metabolism and nutrition disorders: Dehydration.
Psychiatric disorders: Depression, suicidal ideation, hallucination, anger.
Nervous system disorders: Peripheral neuropathy.
Eye disorders: Retinal hemorrhage.
Ear and labyrinth disorders: Hearing loss.
Vascular disorders: Hypertension.
Respiratory, thoracic and mediastinal disorders: Wheezing.
Gastrointestinal disorders: Gastrointestinal bleeding, cheilitis, gingivitis.
Hepato-biliary disorders: Hepatic dysfunction.
Rarely, ADR <1/1000
Infections and infestations: Endocarditis, otitis media.
Blood and lymphatic system disorders: Hemolytic anemia.
Immune system disorders: Anaphylaxis, systemic lupus erythematosus, rheumatoid arthritis.
Psychiatric disorders: Suicide, psychotic disorder.
Nervous system disorders: Coma, convulsions, facial palsy.
Eye disorders: Papilloedema, optic neuropathy, retinal vascular disorder, retinopathy, corneal ulcer.
Cardiac disorders: Myocardial infarction, congestive heart failure, angina, supraventri-cular tachycardia arrhythmia, atrial fibrillation, pericarditis.
Vascular disorders: Cerebral hemorrhage, vasculitis.
Respiratory, thoracic and mediastinal disorders: Bronchospasm (patients with obstructive ventilation syndrome taking ribavirin aerosol), interstitial pneumonitis with fatal outcome, pulmonary embolism.
Gastrointestinal disorders: Peptic ulcer, pancreatitis.
Hepatobiliary disorders: Hepatic failure, cholangitis, fatty liver.
Musculoskeletal and connective tissue disorders: Myositis.
Very rare, ADR <1 / 10, 000
Blood and lymphatic system disorders: Aplastic anaemia.
Immune system disorders: Idiopathic or thrombotic thrombocytopenic purpura.
Nervous system disorders: Cerebral ischaemia.
Eye disorders: Vision loss.
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme.

Overdose and management

Overdose:
Data regarding overdose is limited. Acute ingestion of up to 20g of ribavirin capsules which was associated with an increased incidence and severity of the usual adverse effect was reported.
Management:
There is no specific antidote for ribavirin overdose. In case of overdose, symptomatic treatment is required.
Hemodialysis and peritoneal dialysis are not effective.

Pharmacodynamic properties

Ribavirin is a synthetic nucleoside analogue structurally related to guanosine. It acts by hindering viral RNA and DNA synthesis and then inhibits protein synthesis and virus replication.
The mechanism of ribavirin action has not been known adequately. When entering the body, ribavirin is transported into cells and quickly converted to deribosylated ribavirin and phosphorylated to ribavirin-5'-monophosphate, -diphosphate and-triphosphate by the action of adenosine kinase and other enzymes. Phosphorylation can occur in both infectious and non-infected cells, the rates of formed derivatives vary by individual case. Thus, the anti-viral effect of ribavirin may be altered among different individuals. Antiviral effects are mainly due to the -mono and -triphosphat derivatives. The structure of the phosphorylated derivatives is similar to the structure of the cellular metabolites such as guanosine nucleotide. The competition between ribavirin-5'-triphosphate with adenosine-5'-triphosphate and guanosine -5'-triphosphate, the substrate of the RNA polymerase inhibited the viral protein synthesis, reducing the ability to replicate and spread virus to other cells. Ribavirin does not stimulate the production of interferon, has negligible activity on immune response and antitumor (in the host).
Cytotoxic effects usually occur only at levels 100 to 200 times higher than those for inhibiting viral DNA synthesis.
+ Spectrum of activity:
Ribavirin is active in vitro against DNA viruses such as Herpes simplex virus type 1 and 2; human cytomegalovirus, adenovirus, poxvirus etc. However, in vivo, cytomegalovirus may be insensitive.
Ribavirin has effects on RNA viruses such as respiratory syncytial virus (RSV), many strains of influenza A and B, parainfluenza, Lassa fever, rotavirus, measles virus, mumps virus, enterovirus 72 (formerly known as hepatitis A virus), yellow fever virus. However, in vivo, some viruses including arbovirus, rhinovirus, and rotavirus may not be inhibited.
+ Drug resistance:
The development of in vitro and in vivo drug resistance has not been fully assessed. Unlike some antivirals such as acyclovir, amantadine etc, ribavirin resistance has not been seen when it is used many times to treat the most susceptible virus. This may be because ribavirin has multiple mechanisms of antiviral activity. Cross-resistance to other antiviral drugs has not been reported.

Pharmacokinetic properties

Absorption:
After oral administration, ribavirin is immediately absorbed, peak levels are reached within 1-2 hours after ingestion. However, oral bioavailability is approximately 45%-65%, which appears to be due to hepatic first pass metabolism. If taken with food, especially high-fat foods, the bioavailability is increased by 70%. Plasma steady state is achieved in about 4 weeks with a twice-daily dose regimen and significantly higher, approximately 4 times, than that with single-daily dose regimen.
Metabolism:
In cells, ribavirin is phosphorylated to mono-(MP), di-(DP), and tri-phosphate (TP). MP and TP forms have stronger activity. Besides, it is also degraded via deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite.
Distribution:
The drug is distributed to the plasma, the respiratory secretions and red blood cells. It accumulates highly in red blood cells.
Ribavirin is distributed slowly into the cerebrospinal fluid. When prolonged use (4-7 weeks) is indicated to patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), ribavirin level in the cerebrospinal fluid is approximately 70% of that in plasma level, the measure is taken simultaneously. It is unknown whether ribavirin can cross the placenta or enter breast milk. Ribavirin poorly binds to plasma proteins.
Elimination:
Ribavirin is very slowly excreted as unchanged and metabolite primarily via kidney. In adults with normal renal function, about 53% of the single dose is excreted in the urine within 72 to 80 hours; a small amount is excreted via the faeces.
Very little ribavirin is removed via dialysis.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.