Components:

Method of action:

Treatment option:

Immunosuppression, Infection, Fever, Respiratory Syncytial Virus, Chronic Hepatitis, Chronic Hepatitis C, Ventilator, Hemorrhagic Fever, Hepatitis, Hepatitis C

Medically reviewed by Fedorchenko Olga Valeryevna, PharmD. Last updated on 26.06.2023

Attention! Information on this page is intended only for medical professionals! Information is collected in open sources and may contain significant errors! Be careful and double-check all the information on this page!

Qualitative and quantitative composition

Ribavirin

Therapeutic indications

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

Da Chang is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults.

Da Chang is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) for paediatric patients (children 3 years of age and older and adolescents) not previously treated and without liver decompensation.

Da Chang (ribavirin) is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy.

Only severe RSV lower respiratory tract infection should be treated with Da Chang (ribavirin). The vast majority of infants and children with RSV infection have disease that is mild, self-limited, and does not require hospitalization or antiviral treatment. Many children with mild lower respiratory tract involvement will require shorter hospitalization than would be required for a full course of Da Chang (ribavirin) aerosol (3 to 7 days) and should not be treated with the drug. Thus the decision to treat with Da Chang (ribavirin) should be based on the severity of the RSV infection. The presence of an underlying condition such as prematurity, immunosuppression or cardiopulmonary disease may increase the severity of clinical manifestations and complications of RSV infection.

Use of aerosolized Da Chang (ribavirin) in patients requiring mechanical ventilator assistance should be undertaken only by physicians and support staff familiar with this mode of administration and the specific ventilator being used (see WARNINGS, and DOSAGE AND ADMINISTRATION).

Diagnosis

RSV infection should be documented by a rapid diagnostic method such as demonstration of viral antigen in respiratory tract secretions by immunofluorescence³ or ELISA⁵ before or during the first 24 hours of treatment. Treatment may be initiated while awaiting rapid diagnostic test results. However, treatment should not be continued without documentation of RSV infection. Non-culture antigen detection techniques may have false positive or false negative results. Assessment of the clinical situation, the time of year and other parameters may warrant reevaluation of the laboratory diagnosis.

Da Chang is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC).

Dosage (Posology) and method of administration

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.

Posology

Please refer also to the corresponding Summary of Product Characteristics (SmPC) of medicinal products used in combination with Da Chang for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Da Chang.

Da Chang capsules are to be administered orally each day in two divided doses (morning and evening) with food.

Adults

The recommended dose and duration of Da Chang depends on patient's weight and on the medicinal product that is used in combination. Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang

In the cases in which no specific dose recommendation is made, the following dose should be used: Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg.

Paediatric population

No data are available in children below 3 years of age.

Note: For patients who weigh < 47 kg, or are unable to swallow capsules, please refer to the SmPC for Da Chang 40 mg/mL oral solution.

Dosing of Da Chang for children and adolescent patients is determined by the patient body weight. For example, the body weight dosing used in conjunction with interferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang as some combination regimens do not adhere to the Da Chang dosing guidance provided in Table 1.

Table 1. Da Chang dose based on body weight when used in combination with interferon alfa-2b in paediatric patients
Patient weight (kg)	Daily Da Chang dose	Number of 200 mg capsules
47-49	600 mg	3 capsules ^a
50 - 65	800 mg	4 capsules ^b
> 65	Refer to adult dose recommendations

a: 1 morning, 2 evening

b: 2 morning, 2 evening

Dose modification for adverse reactions

Dose modification for adults

Dose reduction of Da Chang depends on the initial Da Chang posology which depends on the medicinal product that is used in combination with Da Chang.

If a patient has a serious adverse reaction potentially related to Da Chang, the Da Chang dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration, cardiac status and indirect bilirubin concentration.

Table 2 Management of Adverse Reactions
Laboratory values	Reduce Da Chang dose* if:	Discontinue Da Chang if:
Haemoglobin in patients with No Cardiac Disease	< 10 g/dL	< 8.5 g/dL
Haemoglobin: Patients with History of Stable Cardiac Disease	> 2 g/dL decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction)	< 12 g/dL despite 4 weeks at reduced dose
Bilirubin - Indirect	> 5 mg/dL	> 4 mg/dL (adults)

* For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, Da Chang dose should be reduced to 600 mg/day (administered as one 200 mg capsule in the morning and two 200 mg capsules in the evening). If the abnormality is reversed, Da Chang may be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.

For patients receiving a 800 mg (< 65 kg)-1,000 mg (65-80 kg)-1,200 mg (81-105 kg) or 1,400 mg (> 105 kg) dose, 1st dose reduction of Da Chang is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Da Chang is by an additional 200 mg/day. Patients whose dose of Da Chang is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

In case of serious adverse reaction potentially related to medicinal products used in combination with Da Chang, refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the Da Chang dose modification and/or discontinuation guidelines as described in Table 2.

Dose modification for paediatric patients

Dose reduction in paediatric patients without cardiac disease follows the same guidelines as adult patients without cardiac disease regarding haemoglobin levels (Table 2).

There are no data for paediatric patients with cardiac disease.

Table 3 provides guidelines for discontinuation based on the patient's indirect bilirubin concentration.

Table 3 Management of Adverse Reactions

Laboratory values

Discontinue Da Chang if:

Bilirubin - Indirect

> 5 mg/dL (for > 4 weeks)

(children and adolescents treated with interferon alfa-2b)

Special populations

Elderly (> 65 years of age)

There does not appear to be a significant age-related effect on the pharmacokinetics of Da Chang. However, as in younger patients, renal function must be determined prior to administration of Da Chang.

Paediatric patients (children 3 years of age and older and adolescents)

Da Chang may be used in combination with interferon alfa-2b. The selection of Da Chang formulation is based on individual characteristics of the patient.

The safety and efficacy of Da Chang used together with direct-acting-anti-virals in these patients has not been established. No data are available.

Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang for further dosage recommendations on co-administration.

Renal impairment

The pharmacokinetics of Da Chang are altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Da Chang. Adult patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance of < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered Da Chang 200 mg/day. Table 4 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment.

Table 4 Dosage Modification for Renal Impairment in Adult Patients
Creatinine Clearance	Da Chang Dose (daily)
30 to 50 mL/min	Alternating doses, 200 mg and 400 mg every other day
Less than 30 mL/min	200 mg daily
Haemodialysis (ESRD)	200 mg daily

Hepatic impairment: No pharmacokinetic interaction appears between Da Chang and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of the medicinal products used in combination with Da Chang.

Method of administration

Da Chang should be administered orally with food.

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.

Posology

Please refer to the corresponding Summary of Product Characteristics (SmPC) of medicinal products used in combination with Da Chang for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Da Chang.

Da Chang oral solution is supplied in a concentration of 40 mg/mL.

Da Chang oral solution is administered orally in two divided doses (morning and evening) with food.

Paediatric population

No data are available in children below 3 years of age.

Dosing of Da Chang for children and adolescent patients is determined by the patient body weight. For example, the body weight dosing used in conjunction with interferon alfa-2b or peginterferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang as some combination regimens do not adhere to the Da Chang dosing guidance provided in Table 1.

In clinical studies performed in this population, Da Chang was used in doses of 15 mg/kg/day (Table 1).

Table 1 Da Chang oral solution - Children and adolescents dosage to be administered with interferon alfa-2b or peginterferon alfa-2b
Body Weight (kg)	Measured Dose (Morning / Evening)
10-12	2 mL / 2 mL
13-14	3 mL / 2 mL
15-17	3 mL / 3 mL
18-20	4 mL / 3 mL
21-22	4 mL / 4 mL
23-25	5 mL / 4 mL
26-28	5 mL / 5 mL
29-31	6 mL / 5 mL
32-33	6 mL / 6 mL
34-36	7 mL / 6 mL
37-39	7 mL / 7 mL
40-41	8 mL / 7 mL
42-44	8 mL / 8 mL
45-47	9 mL / 8 mL

Patients who weigh > 47 kg and are able to swallow capsules may take the equivalent dose of ribavirin 200 mg capsules in two divided doses (Please see SmPC for Da Chang capsules).

Dose modification for adverse reactions

Dose reduction of Da Chang depends on the initial Da Chang posology which depends on the medicinal product that is used in combination with Da Chang.

Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and indirect bilirubin concentration.

There are no data for paediatric patients with cardiac disease.

Table 2 Management of Adverse Reactions
Laboratory values	Reduce Da Chang dose* if:	Discontinue Da Chang if:
Haemoglobin in patients with No Cardiac Disease	< 10 g/dL	< 8.5 g/dL
Bilirubin - Indirect	-	> 5 mg/dL (for > 4 weeks) (children and adolescents treated with interferon alfa-2b), or > 4 mg/dL (for > 4 weeks) (children and adolescents treated with peginterferon alfa-2b)

* In children and adolescent patients treated with Da Chang plus peginterferon alfa-2b, 1^st dose reduction of Da Chang is to 12 mg/kg/day, 2^nd dose reduction of Da Chang is to 8 mg/kg/day.

In children and adolescent patients treated with Da Chang plus interferon alfa-2b, reduce Da Chang dose to 7.5 mg/kg/day.

In case of serious adverse reaction potentially related to medicinal products used in combination with Da Chang, please refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the Da Chang dose modification and/or discontinuation guidelines as described in Table 2.

Special populations

Paediatric patients (children 3 years of age and older and adolescents)

Da Chang may be used in combination with peginterferon alfa-2b or interferon alfa-2b. The selection of Da Chang formulation is based on individual characteristics of the patient.

The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has not been established. No data are available.

Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang for further dosage recommendations on co-administration.

Renal impairment

The pharmacokinetics of Da Chang is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Da Chang. Adult patients with moderate renal impairment (creatinine clearance 30- 50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered Da Chang 200 mg/day. Table 3 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment.

Table 3 Dosage Modification for Renal Impairment in Adult Patients
Creatinine Clearance	Da Chang Dose (daily)
30 to 50 mL/min	Alternating doses, 200 mg and 400 mg every other day
Less than 30 mL/min	200 mg daily
Haemodialysis (ESRD)	200 mg daily

Hepatic impairment

No pharmacokinetic interaction appears between Da Chang and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of medicinal products used in combination with Da Chang.

Method of administration

Da Chang should be administered orally with food.

BEFORE USE, READ THOROUGHLY THE VALEANT SMALL PARTICLE AEROSOL GENERATOR SPAG-2 OPERATOR'S MANUAL FOR SMALL PARTICLE AEROSOL GENERATOR OPERATING INSTRUCTIONS. AEROSOLIZED Da Chang (ribavirin) SHOULD NOT BE ADMINISTERED WITH ANY OTHER AEROSOL GENERATING DEVICE.

The recommended treatment regimen is 20 mg/mL Da Chang (ribavirin) as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL the average aerosol concentration for a 12 hour delivery period would be 190 micrograms/liter of air. Aerosolized Da Chang (ribavirin) should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.

Non-mechanically ventilated infants

Da Chang (ribavirin) should be delivered to an infant oxygen hood from the

SPAG-2 aerosol generator. Administration by face mask or oxygen tent may be necessary If a hood cannot be employed (see SPAG-2 manual). However, the volume and condensation area are larger in a tent and this may alter delivery dynamics of the drug.

Mechanically Ventilated Infants

The recommended dose and administration schedule for infants who require mechanical ventilation is the same as for those who do not. Either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2. In either case, patients should have their endotracheal tubes suctioned every 1-2 hours, and their pulmonary pressures monitored frequently (every 2-4 hours). For both pressure and volume ventilators, heated wire connective tubing and bacteria filters in series in the expiratory limb of the system (which must be changed frequently, i.e., every 4 hours) must be used to minimize the risk of Da Chang (ribavirin) precipitation in the system and the subsequent risk of ventilator dysfunction. Water column pressure release valves should be used in the ventilator circuit for pressure cycled ventilators, and may be utilized with volume cycled ventilators (SEE SPAG-2 MANUAL FOR DETAILED INSTRUCTIONS).

Method of Preparation

Da Chang brand of ribavirin is supplied as 6 grams of lyophilized powder per 100 mL vial for aerosol administration only. By sterile technique, reconstitute drug with a minimum of 75 mL of sterile USP water for Infection or Inhalation in the original 100 mL glass vial. Shake well. Transfer to the clean, sterilized 500 mL SPAG-2 reservoir and further dilute to a final volume of 300 mL with Sterile Water for Injection, USP, or Inhalation. The final concentration should be 20 mg/mL. Important: This water should NOT have had any anti microbial agent or other substance added. The solution should be inspected visually for particulate matter and discoloration prior to administration. Solutions that have been placed in the SPAG-2 unit should be discarded at least every 24 hours and when the liquid level is low before adding newly reconstituted solution.

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.

Refer also to the SmPC of the medicinal products that are used in combination with Da Chang for the treatment of hepatitis C.

Method of Administration

Da Chang film-coated tablets are administered orally in two divided doses with food (morning and evening). Due to the teratogenic potential of ribavirin, the tablets should not be broken or crushed.

Posology

Dose to be administered

The dose of Da Chang is based on patient body weight, viral genotype and the medicinal product that is used in combination (see Table1). Da Chang tablets are to be administered orally each day in two divided doses (morning and evening) with food.

Table 1. Da Chang dosing recommendation according to the medicinal product used in combination
Medicinal product used in combination	Daily Da Chang Dose	Number of 200/400mg tablets
Direct acting antivirals (DAA)	<75kg=1000mg =>75 kg = 1200 mg	5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)
PegIFN alfa-2a with DAA	<75kg=1000mg =>75 kg = 1200 mg	5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)
PegIFN alfa-2a *without DAA*	Genotype 2/3 treatment-naÃ¯ve Genotype 2/3/4 with HIV-coinfection 800mg	4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening)
PegIFN alfa-2a *without DAA*	Genotype 1/4 Genotype 2/3 treatment-experienced Genotype 1 HIV-coinfection <75kg=1000mg =>75 kg = 1200 mg	5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)
IFN alfa-2a without DAA	<75kg=1000mg =>75 kg = 1200 mg	5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)
PegIFN alfa-2b *with or without DAA*	<65kg= 800 mg	4 x 200mg (2 morning, 2 evening) or 2 x 400(1 morning, 1 evening)
	65-80kg= 1,000 mg	5 (2 morning, 3 evening)
	81-105kg= 1,200 mg	6 (3 morning, 3 evening)
	>105kg= 1,400 mg	7 (3 morning, 4 evening)

Duration of treatment

Duration of treatment depends on medicinal products that it is being combined with and may depend on several patients or virus characteristics including genotype, co-infection status, previous history of treatment, on-treatment response.

Refer to the SPC of the medicinal product that is used in combination with Da Chang.

Dosage modification for adverse reactions

Dose modification of Da Chang depends on medicinal products that it is being combined with.

If a patient has a severe 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. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.

Table 2 Dosage Modification Guidelines for Management of Treatment-Emergent Anaemia
Laboratory Values	Reduce Da Chang dose to [1] [2] if:	Discontinue Da Chang if
Haemoglobin in Patients with No Cardiac Disease	<10 g/dl	<8.5 g/dl
Haemoglobin: Patients with History of Stable Cardiac Disease	>2 g/dl decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction)	<12 g/dl despite 4 weeks at reduced dose

[1] For patients receiving a 1000mg (<75kg) or 1200mg (>75kg) dose, Da Chang dose should be reduced to 600mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets or one 400 mg tablet in the evening). If the abnormality is reversed, Da Chang may be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.

[2]For patients receiving an 800mg (<65kg)-1000mg (65-80kg)-1200mg (81-105kg) or 1400mg (>105kg) dose, 1st dose reduction of Da Chang is by 200 mg/day (except in patients receiving the 1400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Da Chang is by an additional 200 mg/day. Patients whose dose of Da Chang is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

Refer to the SmPCs of peginterferon alfa or interferon alfa for dose modification and/or discontinuation in case of serious adverse reaction potentially related to these drugs.â€

Special populations

Use in renal impairment: The recommended dose regimens (adjusted by the body weight cutoff of 75 kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment.).

Table 3 Dosage Modification for Renal Impairment
Creatinine Clearance	Da Chang Dose (daily)
30 to 50 ml/min	Alternating doses, 200 mg and 400 mg every other day
Less than 30 ml/min	200 mg daily
Hemodialysis	200 mg daily

Therapy should be initiated (or continued if renal impairment develops while on therapy) with extreme caution and intensive monitoring of haemoglobin concentrations, with corrective action as may be necessary, should be employed throughout the treatment period.

If severe adverse reactions or laboratory abnormalities develop, Da Chang should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Da Chang, Da Chang therapy 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 Da Chang is required in patients with hepatic impairment. Use in elderly patients over the age of 65: There does not appear to be a significant age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined prior to administration of Da Chang.

Use in patients under the age of 18 years: Treatment with Da Chang is not recommended for use in children and adolescents (<18 years) due to insufficient data on safety and efficacy in combination with other medicinal products for the treatment of hepatitis C. Only limited safety and efficacy data are available in children and adolescents (6-18 years) in combination with peginterferon alfa-2a. A case by case benefit/risk assessment with respect to the use of Da Chang in children is needed .

Contraindications

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

- Pregnacy. In females of childbearing potential, Da Chang must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

- Breast-feeding.

- History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.

- Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).

- Pregnancy. In females of childbearing potential, Da Chang must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

- Breast-feeding.

- History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.

- Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).

Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang for contraindications specific to these products.

Da Chang (ribavirin) is contraindicated in individuals who have shown Hypersensitivity to the drug or its components, and in women who are or may become pregnant during exposure to the drug. Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted (rodents and rabbits). Therefore, although clinical studies have not been performed, it should be assumed that Da Chang (ribavirin) may cause fetal harm in humans. Studies in which the drug has been administered systemically demonstrate that ribavirin is concentrated in the red blood cells and persists for the life of the erythrocyte.

- pregnant women. Da Chang must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

- women who are breast-feeding.

- a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.

- haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia).

Refer also to the SmPC of the medicinal products that are used in combination with Da Chang for contraindications related to those products.

Special warnings and precautions for use

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

Da Chang must be used in combination with other medicinal products.

Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding the adverse reactions listed below before initiating therapy and other precautions associated with (peg)interferon alfa.

There are several serious adverse reactions associated with the combination therapy of Da Chang with (peg)interferon alfa.

These include:

- Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.)

- Growth inhibition in children and adolescents that may be irreversible in some patients

- Increased thyroid stimulating hormone (TSH) in children and adolescents

- Severe ocular disorders

- Dental and periodontal disorders.

Paediatric population

When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case

Haemolysis:

A decrease in haemoglobin levels to < 10 g/dl was observed in up to 14 % of adult patients and 7 % of children and adolescents treated with Da Chang in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Da Chang has no direct cardiovascular effects, anaemia associated with Da Chang may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Da Chang must be administered with caution to patients with pre-existing cardiac disease. Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped.

Cardiovascular:

Adult 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. There are no data in children or adolescents with a history of cardiac disease.

Teratogenic risk

Prior to initiation of treatment with Da Chang the physician must comprehensively inform both male and female patients of the teratogenic risk of Da Chang, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with Da Chang. For laboratory monitoring of pregnancy, please refer to Laboratory tests.

Acute hypersensitivity:

If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Da Chang must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.

Liver function:

Any patient developing significant liver function abnormalities during treatment must be monitored closely. Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang for discontinuation or dose modification recommendations.

Renal impairment

The pharmacokinetics of Da Chang is 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 Da Chang. Due to substantial increases in Da Chang plasma concentrations in patients with moderate and severe renal impairment, Da Chang dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment.

Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary.

Potential to exacerbate immunosuppression:

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and Da Chang 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.

HCV/HIV Co-infection:

Mitochondrial toxicity and lactic acidosis:

Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa-2b/Da Chang treatment.

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis:

Co-infected patients with advanced cirrhosis receiving combined anti-retroviral therapy (cART) may be at increased risk of hepatic decompensation and death. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentrations.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang for discontinuation or dose modification recommendations.Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

Patients treated with Da Chang and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Da Chang with zidovudine is not recommended.

Patients with low CD4 counts:

In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/Âµl. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the respective SmPC 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.

Laboratory tests: Standard haematologic tests and blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Da Chang therapy:

Haemoglobin

Adult: > 12 g/dl (females); > 13 g/dl (males)

Children and adolescents: > 11 g/dl (females); > 12 g/dl (males)

Platelets

> 100,000/mm³

Neutrophil Count

> 1,500/mm³

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment.

Uric acid may increase with Da Chang due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.

Information on excipients

Each Da Chang capsule contains 40 mg of lactose.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Da Chang must be used in combination with other medicinal products.

There are several serious adverse reactions associated with the combination therapy of Da Chang with (peg)interferon alfa. These include:

- Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.)

- Growth inhibition in children and adolescents that may be irreversible in some patients

- Increased thyroid stimulating hormone (TSH) in children and adolescents

- Severe ocular disorders

- Dental and periodontal disorders.

Paediatric population

Haemolysis

A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and in 7 % of children and adolescents treated with Da Chang in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Da Chang has no direct cardiovascular effects, anaemia associated with Da Chang may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease or both. Thus, Da Chang must be administered with caution to patients with pre-existing cardiac disease. Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped.

Cardiovascular

Teratogenic risk

Acute hypersensitivity

Liver function

Renal impairment

The pharmacokinetics of Da Chang is 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 Da Chang. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, Da Chang dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment.

Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary.

Potential to exacerbate immunosuppression

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis:

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPC of medicinal products used in combination with Da Chang for discontinuation or dose modification recommendations. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

Patients treated with Da Chang and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Da Chang with zidovudine is not recommended.

Patients with low CD4 counts

In patients co-infected with HCV/HIV, limited efficacy and safety data (N=25) are available in subjects with CD4 counts less than 200 cells/ÂµL. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the corresponding SmPC 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 Da Chang.

Laboratory tests

Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Da Chang therapy in children and adolescents:

- Haemoglobin > 11 g/dL (females); > 12 g/dL (males)

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment.

Uric acid may increase with Da Chang due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.

Information on excipients

This product contains sucrose and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucrose-isomaltase insufficiency should not take this medicine.

WARNINGS

SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH INITIATION OF AEROSOLIZED Da Chang (ribavirin) USE IN INFANTS. Respiratory function should be carefully monitored during treatment. If initiation of aerosolized Da Chang (ribavirin) treatment appears to produce sudden deterioration of respiratory function, treatment should be stopped and reinstituted only with extreme caution, continuous monitoring, and consideration of concomitant administration of bronchodilators.

Use with Mechanical Ventilators

USE OF AEROSOLIZED Da Chang (ribavirin) IN PATIENTS REQUIRING MECHANICAL VENTILATOR ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR WITH THIS MODE OF ADMINISTRATION AND THE SPECIFIC VENTILATOR BEING USED. Strict attention must be paid to procedures that have been shown to minimize the accumulation of drug precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary pressures. These procedures include the use of bacteria filters in series in the expiratory limb of the ventilator circuit with frequent changes (every 4 hours), water column pressure release valves to indicate elevated ventilator pressures, frequent monitoring of these devices and verification that ribavirin crystals have not accumulated within the ventilator circuitry, and frequent suctioning and monitoring of the patient (see Clinical Studies).

Those administering aerosolized Da Chang (ribavirin) in conjunction with mechanical ventilator use should be thoroughly familiar with detailed descriptions of these procedures as outlined in the SPAG-2 manual.

PRECAUTIONS

General

Patients with severe lower respiratory tract infection due to respiratory syncytial virus require optimum monitoring and attention to respiratory and fluid status (see SPAG-2 manual).

Carcinogenesis and Mutagenesis

Ribavirin increased the incidence of cell transformations and mutations in mouse Balb/c 3T3 (fibroblasts) and L5178Y (lymphoma) cells at concentrations of 0.015 and 0.03-5.0 mg/mL, respectively (without metabolic activation). Modest increases in mutation rates (3-4x) were observed at concentrations between 3.75-10.0 mg/mL in L5178Y cells in vitro with the addition of a metabolic activation fraction. In the mouse micronucleus assay, ribavirin was clastogenic at intravenous doses of 20-200 mg/kg, (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult). Ribavirin was not mutagenic in a dominant lethal assay in rats at intraperitoneal doses between 50-200 mg/kg when administered for 5 days (estimated human equivalent of 7.14-28.6 mg/kg, based on body surface area adjustment; see Pharmacokinetics).

In vivo carcinogenicity studies with ribavirin are incomplete. However, results of a chronic feeding study with ribavirin in rats, at doses of 16-100 mg/kg/day (estimated human equivalent of 2.3-14.3 mg/kg/day, based on body surface area adjustment for the adult), suggest that ribavirin may induce benign mammary, pancreatic, pituitary and adrenal tumors. Preliminary results of 2 oral gavage oncogenicity studies in the mouse and rat (18-24 months; doses of 20-75 and 10-40 mg/kg/day, respectively [estimated human equivalent of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for the adult]) are inconclusive as to the carcinogenic potential of ribavirin (see Pharmacokinetics). However, these studies have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages in mice) and retinal degeneration (in rats).

Impairment of Fertility

The fertility of ribavirin-treated animals (male or female) has not been fully investigated. However, in the mouse, administration of ribavirin at doses between 35-150 mg/kg/day (estimated human equivalent of 2.92-12.5 mg/kg/day, based on body surface area adjustment for the adult) resulted in significant seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology. Partial recovery of sperm production was apparent 3-6 months following dose cessation. In several additional toxicology studies, ribavirin has been shown to cause testicular lesions (tubular atrophy) in adult rats at oral dose levels as low as 16 mg/kg/day (estimated human equivalent of 2.29 mg/kg/day, based on body surface area adjustment; see Pharmacokinetics). Lower doses were not tested. The reproductive capacity of treated male animals has not been studied

Pregnancy: Category X

Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted. Teratogenic effects were evident after single oral doses of 2.5 mg/kg or greater in the hamster, and after daily oral doses of 0.3 and 1.0 mg/kg in the rabbit and rat, respectively (estimated human equivalent doses of 0.12 and 0.14 mg/kg, based on body surface area adjustment for the adult). Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. Ribavirin caused embryo lethality in the rabbit at daily oral dose levels as low as 1 mg/kg. No teratogenic effects were evident in the rabbit and rat administered daily oral doses of 0.1 and 0.3 mg/kg, respectively with estimated human equivalent doses of 0.01 and 0.04 mg/kg, based on body surface area adjustment (see Pharmacokinetics). These doses are considered to define the "No Observable Teratogenic Effects Level" (NOTEL) for ribavirin in the rabbit and rat.

Following oral administration of ribavirin in the pregnant rat (1.0 mg/kg) and rabbit (0.3 mg/kg), mean plasma levels of drug ranged from 0.104.20 µM[0.024-0.049 u/mL] at 1 hour after dosing, to undetectable levels at 24 hours. At 1 hour following the administration of 0.3 or 0.1 mg/kg in the rat and rabbit (NOTEL), respectively, mean plasma levels of drug in both species were near or below the limit of detection (0.05 µM; see Pharmacokinetics).

Although clinical studies have not been performed, Da Chang (ribavirin) may cause fetal harm in humans. As noted previously, ribavirin is concentrated in red blood cells and persists for the life of the cell. Thus the terminal half-life for the systemic elimination of ribavirin is essentially that of the half-life of circulating erythrocytes. The minimum interval following exposure to Da Chang (ribavirin) before pregnancy may be safely initiated is unknown (see CONTRAINDICATIONS, WARNINGS, and Information for Health Care Personnel).

Nursing Mothers

Da Chang (ribavirin) has been shown to be toxic to lactating animals and their offspring. It is not known if Da Chang (ribavirin) is excreted in human milk.

Information for Health Care Personnel

Health care workers directly providing care to patients receiving aerosolized Da Chang should be aware that ribavirin has been shown to be teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits). Although no reports of teratogenesis in offspring of mothers who were exposed to aerosolized Da Chang (ribavirin) during pregnancy have been confirmed, no controlled studies have been conducted in pregnant women. Studies of environmental exposure in treatment settings have shown that the drug can disperse into the immediate bedside area during routine patient care activities with highest ambient levels closest to the patient and extremely low levels outside of the immediate bedside area. Adverse reactions resulting from actual occupational exposure in adults are described below (see Adverse Events in Health Care Workers). Some studies have documented ambient drug concentrations at the bedside that could potentially lead to systemic exposures above those considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the most sensitive animal species).^7,8,9

A1992 study conducted by the National Institute of Occupational Safety and Health (NIOSH) demonstrated measurable urine levels of ribavirin in health care workers exposed to aerosol in the course of direct patient care.7 Levels were lowest in workers caring for infants receiving aerosolized Da Chang (ribavirin) with mechanical ventilation and highest in those caring for patients being administered the drug via an oxygen tent or hood. This study employed a more sensitive assay to evaluate ribavirin levels in urine than was available for several previous studies of environmental exposure that failed to detect measurable ribavirin levels in exposed workers. Creatinine adjusted urine levels in the NIOSH study ranged from less than 0.001 to 0.140 µM of ribavirin per gram of creatinine in exposed workers. However, the relationship between urinary ribavirin levels in exposed workers, plasma levels in animal studies, and the specific risk of teratogenesis in exposed pregnant women is unknown.

It is good practice to avoid unnecessary occupational exposure to chemicals wherever possible. Hospitals are encouraged to conduct training programs to minimize potential occupational exposure to Da Chang (ribavirin). Health care workers who are pregnant should consider avoiding direct care of patients receiving aerosolized Da Chang (ribavirin). If close patient contact cannot be avoided, precautions to limit exposure should be taken. These include administration of Da Chang (ribavirin) in negative pressure rooms; adequate room ventilation (at least six air exchanges per hour); the use of Da Chang (ribavirin) aerosol scavenging devices; turning off the SPAG-2 device for 5 to 10 minutes prior to prolonged patient contact; and wearing appropriately fitted respirator masks. Surgical masks do not provide adequate filtration of Da Chang (ribavirin) particles. Further information is available from NIOSH's Hazard Evaluation and Technical Assistance Branch and additional recommendations have been published in an Aerosol Consensus Statement by the American Respiratory Care Foundation and the American Association for Respiratory Care¹⁰

REFERENCES

7. Decker, John, Shultz, Ruth A., Health Hazaid Evaluation Report: Florida Hospital, Orlando, Florida. Cincinnati OH: U.S. Department of Health and Human Services, Public Health Service, Centers for NIOSH Report No. HETA 91 -104-2229.*

8. Barnes, D.J. and Doursew, M. Reference dose: Description and use in health risk assessments. Regul Tox. and Pharm. Vol. 8; p. 471-486, 1988.

9. Federal Register Vol. 53 No. 126 Thurs. June 30,1988 p. 2483424847.

10. American Association for Respiratory Care [1991]. Aerosol Consensus Statement-1991. Respiratory Care 36(9): 916-921.

Da Chang monotherapy must not be used

Combination therapy of ribavirin with (peg)interferon alfa.

There are several severe adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa.

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. For laboratory monitoring of pregnancy please refer to Laboratory tests.

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: A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Da Chang 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Da Chang 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. The risk of developing anaemia is higher in the female population. Although ribavirin has no direct cardiovascular effects, anaemia associated with Da Chang may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Da Chang 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.

Pancytopenia 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 Da Chang and peginterferon alfa-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, Da Chang 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, Da Chang 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 Da Chang, preferably by estimating the patient's creatinine clearance. Substantial increases in ribavirin plasma concentrations are seen in patients with serum creatinine >2 mg/dl or with creatinine clearance <50 ml/minute, therefore Da Chang dose adjustments are recommended in these patients.

Haemoglobin concentrations should be monitored intensively during treatment and corrective action taken as necessary.

Transplantation: The safety and efficacy of peginterferon-alfa-2a and Da Chang treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with peginterferon-alfa-2a, alone or in combination with Da Chang.

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 Da Chang in combination with interferons. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI). Caution should therefore be exercised when adding peginterferon alfa-2a and Da Chang 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 Da Chang in combination with other medicinal products should be discontinued immediately in patients with hepatic decompensation.

Co-administration of Da Chang and didanosine is not recommended due to the risk of mitochondrial toxicity. Moreover, co-administration of Da Chang 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] and differential, 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 Da Chang:

Haemoglobin >12 g/dl (females); >13 g/dl (males)

In patients co-infected with HIV-HCV, limited efficacy and safety data are available in subjects with CD4 counts less than 200 cells/Î¼L. 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 Da Chang due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.

Effects on ability to drive and use machines

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Film-coated tablet

Da Chang has no or negligible influence on the ability to drive and use machines; however, other medicinal products used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery.

Da Chang has no or negligible influence on the ability to drive and use machines. However peginterferon alfa or interferon alfa or other medicinal products used in combination with Da Chang may have an effect. Refer to the SmPC of the medicinal products that are used in combination with Da Chang for further information.

Undesirable effects

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

Summary of the safety profile

The salient safety issue of Da Chang is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Da Chang therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients.

The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when Da Chang was used in combination with interferon alfa-2b or peginterferon alfa-2b.

Please refer to the corresponding SmPC of medicinal products that are used in combination with Da Chang for additional undesirable effects reported with these products.

Adults

Bitherapy with peginterferon alfa-2b or interferon alfa-2b

The safety of Da Chang capsules is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naÃ¯ve patients): two trials studied Da Chang in combination with interferon alfa-2b, two trials studied Da Chang in combination with peginterferon alfa-2b.

Patients who are treated with interferon alfa-2b and Da Chang after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below.

Tabulated list of adverse reactions for adults

The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naÃ¯ve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with Da Chang) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferon monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Da Chang with pegylated interferon alfa-2b or interferon alfa-2b
System Organ Class	Adverse Reactions
Infections and infestations
Very common:	Viral infection, pharyngitis
Common:	Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection
Uncommon	Lower respiratory tract infection
Rare:	Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:	Neoplasm unspecified
Blood and lymphatic system disorders
Very common:	Anaemia, neutropenia
Common:	Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia
Very rare:	Aplastic anaemia*
Not known:	Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon:	Drug hypersensitivity
Rare:	Sarcoidosis*, rheumatoid arthritis (new or aggravated)
Not known:	Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis
Endocrine disorders
Common:	Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:	Anorexia
Common:	Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite
Uncommon:	Diabetes mellitus, hypertriglyceridemia*
Psychiatric disorders
Very common:	Depression, insomnia, anxiety, emotional lability
Common:	Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, decreased libido apathy, abnormal dreams, crying
Uncommon:	Suicide attempts, panic attack, hallucination
Rare:	Bipolar disorder*
Very rare:	Suicide*
Not known:	Homicidal ideation, mania, mental status change
Nervous system disorders
Very common:	Headache, dizziness, dry mouth, concentration impaired
Common:	Amnesia, memory impairment, syncope, migraine, ataxia, paraesthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia
Uncommon:	Neuropathy, peripheral neuropathy
Rare:	Seizure (convulsion)*
Very rare:	Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy, polyneuropathy
Not known:	Facial palsy, mononeuropathies
Eye disorders
Common:	Visual disturbance, blurred vision, conjunctivitis, eye irritation, eye pain, abnormal vision, lacrimal gland disorder, dry eye
Rare:	Retinal haemorrhages, retinopathies (including macular oedema), retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema, loss of visual acuity or visual field*, retinal exudates
Ear and labyrinth disorders
Common:	Vertigo, hearing impairment/loss, tinnitus, ear pain
Cardiac disorders
Common:	Palpitation, tachycardia
Uncommon:	Myocardial infarction
Rare:	Cardiomyopathy, arrhythmia
Very rare:	Cardiac ischaemia*
Not known:	Pericardial effusion, pericarditis
Vascular disorders
Common:	Hypotension, hypertension, flushing
Rare:	Vasculitis
Very rare:	Peripheral ischaemia*
Respiratory, thoracic and mediastinal disorders
Very common:	Dyspnoea, coughing
Common:	Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough
Very rare:	Pulmonary infiltrates, pneumonitis, interstitial pneumonitis*
Gastro-intestinal disorders
Very common:	Diarrhoea, vomiting, nausea, abdominal pain
Common:	Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophogeal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence
Uncommon:	Pancreatitis, oral pain
Rare:	Ischaemic colitis
Very rare:	Ulcerative colitis *
Not Known:	Periodontal disorder, dental disorder, tongue pigmentation
Hepatobiliary disorders
Common:	Hepatomegaly, jaundice, hyperbilirubinemia*
Very rare:	Hepatotoxicity (including fatalities)*
Skin and subcutaneous tissue disorders
Very common:	Alopecia, pruritus, skin dry, rash Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder*
Rare:	Cutaneous sarcoidosis
Very rare:	Stevens Johnson syndrome, toxic epidermal necrolysis, erythema multiforme*
Musculoskeletal and connective tissue disorders
Very common:	Arthralgia, myalgia, musculoskeletal pain
Common:	Arthritis, back pain, muscle spasms, pain in extremity
Uncommon:	Bone pain, muscle weakness
Rare:	Rhabdomyolysis, myositis
Renal and urinary disorders
Common:	Micturition frequency, polyuria, urine abnormally
Rare:	Renal failure renal insufficiency*
Very rare:	Nephrotic syndrome*
Reproductive system and breast disorders
Common:	Female : amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction, Sexual dysfunction (not specified)*
General disorders and administration site conditions
Very common:	Fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability
Common:	Chest pain, chest discomfort, peripheral oedema, malaise, feeling abnormal, thirst
Uncommon	Face oedema
Investigations
Very common:	Weight decrease
Common:	Cardiac murmur

* Since Da Chang is always prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using Da Chang in combination with interferon alfa-2b (pegylated or non-pegylated).

Description of selected adverse reactions

A reduction in haemoglobin concentrations by > 4 g/dl was observed in 30 % of patients treated with Da Chang and peginterferon alfa-2b and 37 % of patients treated with Da Chang and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dl in up to 14 % of adult patients and 7 % of children and adolescents treated with Da Chang in combination with either peginterferon alfa-2b or interferon alfa-2b.

Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with Da Chang capsules in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO grade 3 leukopenia was also reported in 7 % of this treatment group.

An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Da Chang used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials.

HCV/HIV co-infected patients:

For HCV/HIV co-infected patients receiving Da Chang in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-Da Chang for co-HCV infection.

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment. Haematological abnormalities were more frequently reported in patients receiving Da Chang in combination with peginterferon alfa-2b when compared to patients receiving Da Chang in combination with interferon alfa-2b. In Study 1 , decrease in absolute neutrophil count levels below 500 cells/mm³ was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm³ was observed in 4 % (8/194) of patients receiving Da Chang capsules in combination with peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Da Chang in combination with peginterferon alfa-2b.

CD4 lymphocytes decrease

Treatment with Da Chang in combination with peginterferon alfa-2b was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of Da Chang in combination with peginterferon alfa-2b had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected patients with CD4+ cell counts < 200/Âµl.

Paediatric population

In combination with peginterferon alfa-2b

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of peginterferon alfa-2b and Da Chang, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with pegylated interferon alfa-2b and Da Chang, growth inhibition was observed that resulted in reduced height in some patients. Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3^rdpercentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3^rd percentile). Ninety-four of 107 children enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among children treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weightfor- age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively.

For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term followup was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy.

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.

In combination with interferon alfa-2b

In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and Da Chang, 6 % discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44^th percentile, which was below the median of the normative population and less than their mean baseline height (48^th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with interferon alfa-2b and Da Chang, growth inhibition is observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children.

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs. 1 %) during treatment and during the 6 month follow-up after treatment. As in adult patients, children and adolescents also experienced other psychiatric adverse reactions (e.g., depression, emotional lability, and somnolence). In addition, injection site disorders, pyrexia, anorexia, vomiting and emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropenia.

Tabulated list of adverse reactions in paediatric population

Reported adverse reactions listed in Table 6 are based on experience from the two multicentre children and adolescents clinical trials using Da Chang with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10), and uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Da Chang in combination with interferon alfa-2b or peginterferon alfa-2b

System Organ Class

Adverse Reactions

Infections and infestations

Very common:

Viral infection, pharyngitis

Common:

Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis

Uncommon

Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common:

Neoplasm unspecified

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Thrombocytopenia, lymphadenopathy

Endocrine disorders

Very common:

Hypothyroidism

Common:

Hyperthyroidism, virilism

Metabolism and nutrition disorders

Very common:

Anorexia, increased appetite, decreased appetite

Common:

Hypertriglyceridemia, hyperuricemia

Psychiatric disorders

Very common:

Depression, insomnia, emotional lability

Common:

Suicidal ideation, aggressiion, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy

Uncommon:

Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare

Nervous system disorders

Very common:

Headache, dizziness

Common:

Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep

Uncommon:

Neuralgia, lethargy, psychomotor hyperactivity

Eye disorders

Common:

Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder

Uncommon:

Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia

Ear and labyrinth disorders

Common:

Vertigo

Cardiac disorders

Common:

Tachycardia, palpitations

Vascular disorders

Common:

Pallor, flushing

Uncommon:

Hypotension

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain

Uncommon:

Wheezing, nasal discomfort

Gastro-intestinal disorders

Very common:

Abdominal pain, abdominal pain upper, vomiting, diarrhoea, nausea

Summary of safety profile

Please refer to the corresponding SmPC of medicinal products that are used in combination with Da Chang for additional undesirable effects reported with these products.

Paediatric population

In combination with peginterferon alfa-2b

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3^rd percentile). Ninety-four of 107 children enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among children treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy.

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.

In combination with interferon alfa-2b

In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and Da Chang, 6 % discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44^th percentile, which was below the median of the normative population and less than their mean baseline height (48^th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with interferon alfa-2b and Da Chang, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children.

Tabulated list of adverse reactions in paediatric population

Reported adverse reactions listed in Table 4 are based on experience from the two multicentre children and adolescents clinical trials using Da Chang with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10), and uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Da Chang in combination with interferon alfa-2b or peginterferon alfa-2b
System Organ Class	Adverse Reactions
Infections and infestations
Very common:	Viral infection, pharyngitis
Common:	Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis
Uncommon:	Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:	Neoplasm unspecified
Blood and lymphatic system disorders
Very common:	Anaemia, neutropenia
Common:	Thrombocytopenia, lymphadenopathy
Endocrine disorders
Very common:	Hypothyroidism
Common:	Hyperthyroidism, virilism
Metabolism and nutrition disorders
Very common:	Anorexia, increased appetite, decreased appetite
Common:	Hypertriglyceridemia, hyperuricemia
Psychiatric disorders
Very common:	Depression, insomnia, emotional lability
Common:	Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy
Uncommon:	Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare
Nervous system disorders
Very common:	Headache, dizziness
Common:	Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep
Uncommon:	Neuralgia, lethargy, psychomotor hyperactivity
Eye disorders
Common:	Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Uncommon:	Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
Ear and labyrinth disorders
Common:	Vertigo
Cardiac disorders
Common:	Tachycardia, palpitations
Vascular disorders
Common:	Pallor, flushing
Uncommon:	Hypotension
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain
Uncommon:	Wheezing, nasal discomfort
Gastro-intestinal disorders
Very common:	Abdominal pain, abdominal pain upper, vomiting , diarrhoea, nausea
Common:	Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophoageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, oral pain
Uncommon:	Gingivitis
Hepatobiliary disorders
Common:	Hepatic function abnormal
Uncommon:	Hepatomegaly
Skin and subcutaneous tissue disorders
Very common:	Alopecia, rash
Common:	Pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise
Uncommon:	Pigmentation disorder, dermatitis atopic, skin exfoliation
Musculoskeletal and connective tissue disorders
Very common:	Arthralgia, myalgia, musculoskeletal pain
Common:	Pain in extremity, back pain, muscle contracture
Renal and urinary disorders
Common:	Enuresis, micturition disorder, urinary incontinence, proteinuria
Reproductive system and breast disorders
Common:	Female: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: testicular pain
Uncommon:	Female: dysmenorrhoea
General disorders and administration site conditions
Very common:	Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability
Common:	Chest pain, oedema, pain, feeling cold
Uncommon:	Chest discomfort, facial pain
Investigations
Very common:	Growth rate decrease (height and/or weight decrease for age)
Common:	Blood thyroid stimulating hormone increased, thyroglobulin increased
Uncommon:	Anti-thyroid antibody positive
Injury, poisoning and procedural complications
Common:	Skin laceration
Uncommon:	Contusion

Most of the changes in laboratory values in the Da Chang/peginterferon alfa-2b clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy. While changes in laboratory values were observed in some patients treated with Da Chang used in combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

Adults

Adverse reactions reported with a > 10 % incidence in adult patients treated with Da Chang capsules in combination with interferon alfa-2b or pegylated interferon alfa-2b for one year have also been reported in children and adolescents. The side effect profile was also similar at the lower incidences.

Tabulated list of adverse reactions for adults

The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naÃ¯ve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with Da Chang) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferons monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Da Chang with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class

Adverse Reactions

Infections and infestations

Very common:

Viral infection, pharyngitis

Common:

Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection

Uncommon:

Lower respiratory tract infection

Rare:

Pneumonia*

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common:

Neoplasm unspecified

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia

Very rare:

Aplastic anaemia*

Not known:

Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Immune system disorders

Uncommon:

Drug hypersensitivity

Rare:

Sarcoidosis* rheumatoid arthritis (new or aggravated)

Not known:

Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis

Endocrine disorders

Common:

Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

Very common:

Anorexia

Common:

Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite

Uncommon:

Diabetes mellitus, hypertriglyceridemia*

Psychiatric disorders

Very common:

Depression, anxiety, emotional lability, insomnia

Common:

Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour,nervousness, sleep disorder, decreased libido, apathy, abnormal dreams, crying

Uncommon:

Suicide attempts, panic attack, hallucination

Rare:

Bipolar disporder*

Very rare:

Suicide*

Not known:

Homicidal ideation*, mania*, mental status change

Nervous system disorders

Very common:

Headache, dizziness, dry mouth, concentration impaired

Common:

Amnesia, memory impairment, syncope, migraine, ataxia, paresthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia

Uncommon:

Neuropathy, peripheral neuropathy

Rare:

Seizure (convulsion)

Very rare:

Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy*

Not known:

Facial palsy, mononeuropathies

Eye disorders

Common:

Visual disturbance, blurred vision, conjunctivitis, eye irritiation, eye pain, abnormal vision, lacrimal gland disorder, dry eye

Rare:

Retinal haemorrhages*, retinopathies (including macular oedema)*, retinal artery occlusion*, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates

Ear and labyrinth disorders

Common:

Vertigo, hearing impaired/loss, tinnitus, ear pain

Cardiac disorders

Common:

Palpitation, tachycardia

Uncommon:

Myocardial infarction

Rare:

Cardiomyopathy, arrhythmia*

Very rare:

Cardiac ischaemia*

Not known:

Pericardial effusion*, pericarditis*

Vascular disorders

Common:

Hypotension, hypertension, flushing

Rare:

Vasculitis

Very rare:

Peripheral ischaemia*

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea, coughing

Common:

Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough

Very rare:

Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*

Gastro-intestinal disorders

Very common:

Diarrhoea, vomiting, nausea, abdominal pain

Common:

Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophoageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence

Uncommon:

Pancreatitis, oral pain

Rare:

Ischaemic colitis

Very rare:

ulcerative colitis*

Not known:

Periodontal disorder, dental disorder, tongue pigmentation

Hepatobiliary disorders

Common:

Hepatomegaly, jaundice, hyperbilirubinemia*

Very rare:

Hepatotoxicity (including fatalities)*

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus, skin dry, rash

Common:

Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder*

Rare:

Cutaneous sarcoidosis

Very rare:

Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia, musculoskeletal pain

Common:

Arthritis, back pain, muscle spasms, pain in extremity

Uncommon:

Bone pain, muscle weakness

Rare:

Rhabdomyolysis*, myositis*

Renal and urinary disorders

Common:

Micturition frequency, polyuria, urine abnormality

Rare:

Renal failure*, renal insufficiency*

Very rare:

Nephrotic syndrome*

Reproductive system and breast disorders

Common:

The description of adverse reactions is based on events from clinical studies (approximately 200 patients) conducted prior to 1986, and the controlled trial of aerosolized Da Chang (ribavirin) conducted in 1989-1990. Additional data from spontaneous post-marketing reports of adverse events in individual patients have been available since 1986.

Deaths

Deaths during or shortly after treatment with aerosolized Da Chang (ribavirin) have been reported in 20 cases of patients treated with Da Chang (ribavirin) (12 of these patients were being treated for RSV infections). Several cases have been characterized as "possibly related" to Da Chang (ribavirin) by the treating physician; these were in infants who experienced worsening respiratory status related to bronchospasm while being treated with the drug. Several other cases have been attributed to mechanical ventilator malfunction in which Da Chang (ribavirin) precipitation within the ventilator apparatus led to excessively high pulmonary pressures and diminished oxygenation. In these cases the monitoring procedures described in the current package insert were not employed (see Description of Studies, WARNINGS, and DOSAGE AND ADMINISTRATION).

Pulmonary and Cardiovascular

Pulmonary function significantly deteriorated during aerosolized Da Chang (ribavirin) treatment in six of six adults with chronic obstructive lung disease and in four of six asthmatic adults. Dyspnea and chest soreness were also reported in the latter group. Minor abnormalities in pulmonary function were also seen in healthy adult volunteers.

In the original study population of approximately 200 infants who received aerosolized Da Chang (ribavirin) , several serious adverse events occurred in severely ill infants with life-threatening underlying diseases, many of whom required assisted ventilation. The role of Da Chang (ribavirin) in these events is indeterminate. Since the drug's approval in 1986, additional reports of similar serious, though non-fatal, events have been filed infrequently. Events associated with aerosolized Da Chang (ribavirin) use have included the following:

Pulmonary: Worsening of respiratory status, bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis and ventilator dependence.

Cardiovascular: Cardiac arrest, hypotension, bradycardia and digitalis toxicity. Bigeminy, bradycardia and tachycardia have been described in patients with underlying congenital heart disease.

Some subjects requiring assisted ventilation experienced serious difficulties, due to inadequate ventilation and gas exchange. Precipitation of drug within the ventilatory apparatus, including the endotracheal tube, has resulted in increased positive end expiratory pressure and increased positive inspiratory pressure. Accumulation of fluid in tubing ("rain out") has also been noted. Measures to avoid these complications should be followed carefully (see DOSAGE AND ADMINISTRATION).

Hematologic

Although anemia was not reported with use of aerosolized Da Chang (ribavirin) in controlled clinical trials, most infants treated with the aerosol have not been evaluated 1 to 2 weeks post-treatment when anemia is likely to occur. Anemia has been shown to occur frequently with experimental oral and intravenous Da Chang (ribavirin) in humans. Also, cases of anemia (type unspecified), reticulocytosis and hemolytic anemia associated with aerosolized Da Chang (ribavirin) use have been reported through post-marketing reporting systems. All have been reversible with discontinuation of the drug.

Other

Rash and conjunctivitis have been associated with the use of aerosolized Da Chang (ribavirin). These usually resolve within hours of discontinuing therapy. Seizures and asthenia associated with experimental intravenous Da Chang (ribavirin) therapy have also been reported. Adverse Events in Health Care Workers Studies of environmental exposure to aerosolized Da Chang (ribavirin) in health care workers administering care to patients receiving the drug have not detected adverse signs or symptoms related to exposure. However, 152 health care workers have reported experiencing adverse events through post-marketing surveillance. Nearly all were in individuals providing direct care to infants receiving aerosolized Da Chang (ribavirin). Of 358 events from these 152 individual health care worker reports, the most common signs and symptoms were headache (51% of reports), conjunctivitis (32%), and rhinitis, nausea, rash, dizziness, pharyngitis, or lacrimation (10-20% each). Several cases of bronchospasm and/or chest pain were also reported, usually in individuals with known underlying reactive airway disease. Several case reports of damage to contact lenses after prolonged close exposure to aerosolized Da Chang (ribavirin) have also been reported. Most signs and symptoms reported as having occurred in exposed health care workers resolved within minutes to hours of discontinuing close exposure to aerosolized Da Chang (ribavirin) (also see Information for Health Care Personnel).

The symptoms of RSV in adults can include headache, conjunctivitis, sore throat and/or cough, fever, hoarseness, nasal congestion and wheezing, although RSV infections in adults are typically mild and transient. Such infections represent a potential hazaid to uninfected hospital patients. It is unknown whether certain symptoms cited in reports from health care workers were due to exposure to the drug or infection with RSV. Hospitals should implement appropriate infection control procedures.

The salient safety issue of ribavirin is hemolytic anemia occurring within the first weeks of therapy.).

The adverse events listed in this section are reported in clinical trials and/or as adverse drug reactions from spontaneous reports primarily when Da Chang was used in combination with interferon alfa-2a or peginterferon alfa-2a.

Adverse events reported in patients receiving Da Chang in combination with interferon alfa-2a are essentially the same as for those reported for Da Chang in combination with peginterferon alfa-2a.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Refer also to the SmPC of the medicinal products that are used in combination with Da Chang for additional undesirable effects reported with these products.

Chronic hepatitis C

The most frequently reported adverse events with Da Chang in combination with peginterferon alfa-2a 180 Âµg were mostly mild to moderate in severity. Most of them were manageable without the need for discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients

Overall, the safety profile for Da Chang in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alfa-2a treatment and Da Chang treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms. Similarly, for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alfa-2a treatment and Da Chang treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.

In another clinical trial, non-responder patients with advanced fibrosisis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm³ were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750/mm³), and thrombocytopenia (13% experienced a platelet count <50,000/mm³).

Chronic hepatitis C and Human Immunodeficiency Virus Co-infection

In HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving Da Chang and peginterferon alfa-2a combination therapy other undesirable effects have been reported in >1% to â‰¤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alfa-2a treatment was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts <200/Âµl (see peginterferon alfa-2a SmPC).

Table 4 shows the undesirable effects reported in patients who have received Da Chang primarily in combination with peginterferon alfa-2a or interferon alfa-2a.

Table 4 Undesirable Effects Reported with Da Chang primarily in combination with Peginterferon alfa-2a or Interferon alfa-2a for HCV Patients
Body system	Very common >1/10	Common >1/100 to <1/10	Uncommon >1/1000 to <1/100	Rare >1/10,000 to <1/1000	Very rare <1/10,000	Frequency not known*
Infections and infestations		Upper respiratory infection, bronchitis, oral candidiasis, herpes simplex	Lower respiratory tract infection, pneumonia, urinary tract infection, skin infection	Endocarditis, Otitis externa
Blood and lymphatic system disorders	Anaemia, neutropenia	Thrombo-cytopenia, lymphadeno-pathy		Pancytopenia	Aplastic anaemia	Pure red cell aplasia
Immune system disorders			Sarcoidosis, thyroiditis	Anaphylaxis, systemic lupus erythematosus, rheumatoid arthritis	idiopathic or thrombotic thrombocyto-penic purpura	Liver and renal graft rejection, Vogt-Koyanagi-Harada disease
Endocrine disorders		Hypo-thyroidism, hyper-thyroidism	Diabetes
Metabolism and Nutrition Disorders	Anorexia		Dehydration
Psychiatric disorders	Depression, insomnia	Mood alteration, emotional disorders, anxiety, aggression, nervousness, libido decreased	Suicidal ideation, hallucinations, anger	Suicide, psychotic disorder		Mania, bipolar disorders, homicidal ideation
Nervous system disorders	Headache, dizziness, concentration impaired	Memory impairment, syncope, weakness, migraine, hypoaesthesia, hyperaesthe-sia, paraesthesia, tremor, taste disturbance, nightmares, somnolence	Peripheral neuropathy	Coma, convulsions, facial palsy	Cerebral ischaemia
Eye disorders		Vision blurred, eye pain, eye inflammation, xerophthalmia	Retinal haemorrhage	Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer	Vision loss	Serous retinal detachment
Ear and labyrinth disorders		Vertigo, earache, tinnitus	Hearing loss
Cardiac disorders		Tachycardia, palpitations, oedema peripheral		Myocardial infarction, congestive heart failure, angina, supraventri-cular tachycardia arrhythmia, atrial fibrillation, pericarditis
Vascular disorders		Flushing, hypotension	Hypertension	Cerebral haemorrhage, vasculitis
Respiratory, thoracic and mediastinal disorders	Dyspnoea, cough	Dyspnoea exertional, epistaxis, nasopharyn-gitis, sinus congestion, nasal congestion, rhinitis, sore throat	Wheezing	Interstitial pneumonitis with fatal outcome, pulmonary embolism
Gastrointestinal disorders	Diarrhoea, nausea, abdominal pain	Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouth	Gastrointestinal bleeding, cheilitis, gingivitis	Peptic ulcer, pancreatitis		Colitis ischaemic, colitis ulcerative, tongue pigmentation
Hepato-biliary disorders			Hepatic dysfunction	Hepatic failure, cholangitis, fatty liver
Skin and subcutaneous tissue disorders	Alopecia, dermatitis, pruritus, dry skin	Rash, sweating increased, psoriasis, urticaria, eczema, skin disorder, photosensitivity reaction, night sweats			Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme
Musculoskeletal and connective tissue disorders	Myalgia, arthralgia	Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps		Myositis		Rhabdomyo-lysis
Renal and Urinary Disorders						Renal failure, nephrotic syndrome
Reproductive system and breast disorders		Impotence
General disorders and administration site conditions	Pyrexia, rigors, pain, asthenia, fatigue, irritability	Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst
Investigations		Weight decreased
Injury and poisoning				Substance overdose

* Identified in postmarketing experience

Laboratory values: In clinical trials of Da Chang in combination with peginterferon alfa-2a or interferon alfa-2a, the majority of cases of abnormal laboratory values were managed with dose modifications. With peginterferon alfa-2a and Da Chang combination treatment, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of treatment.

Haemolysis is the dose limiting toxicity of ribavirin therapy. A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Da Chang 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Da Chang 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. In most cases the decrease in haemoglobin occurred early in the treatment period and stabilised concurrently with a compensatory increase in reticulocytes.

Most cases of anaemia, leucopenia and thrombocytopenia were mild (WHO grade 1). WHO grade 2 laboratory changes were reported for haemoglobin (4% of patients), leucocytes (24% of patients) and thrombocytes (2% of patients). Moderate (absolute neutrophil count (ANC): 0.749-0.5x10⁹/l) and severe (ANC: <0.5x10⁹/l) neutropenia was observed in 24% (216/887) and 5% (41/887) of patients receiving 48 weeks of Da Chang 1000/1200 mg in combination with peginterferon alfa-2a.

An increase in uric acid and indirect bilirubin values associated with haemolysis were observed in some patients treated with Da Chang used in combination with peginterferon alfa-2a or interferon alfa-2a and values returned to baseline levels within 4 weeks after the end of therapy. In rare cases (2/755) this was associated with clinical manifestation (acute gout).

Laboratory values for HIV-HCV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm³ was observed in 13% and 11% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm³was observed in 10% and 8% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Anaemia (haemoglobin <10 g/dl) was reported in 7% and 14% of patients treated with peginterferon alfa-2a monotherapy or in combination therapy, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

Overdose

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

In clinical trials with Da Chang used in combination with peginterferon alfa-2b or interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Da Chang (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted.

In clinical trials with Da Chang used in combination with interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Da Chang (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted.

No overdosage with Da Chang (ribavirin) by aerosol administration has been reported in humans. The LDM in mice is 2 g orally and is associated with hypoactivity and gastrointestinal symptoms (estimated human equivalent dose of 0.17 g/kg, based on body surface area conversion). The mean plasma half-life after administration of aerosolized Da Chang (ribavirin) for pediatric patients is 9.5 hours. Da Chang (ribavirin) is concentrated and persists in red blood cells for the life of the erythrocyte (see Pharmacokinetics).

No cases of overdose of Da Chang have been reported in clinical trials. Hypocalcaemia and hypomagnesaemia have been observed in persons administered dosages greater than four times the maximal recommended dosages. In many of these instances ribavirin was administered intravenously. Due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed by haemodialysis.

Pharmacodynamic properties

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Film-coated tablet

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04.

Mechanism of action

Da Chang is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Da Chang in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Da Chang monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Da Chang monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

Clinical efficacy and safety

Da Chang in combination with Direct Antiviral Agent (DAA):

Please refer to the SmPC of the corresponding DAA for a full description of the clinical data with such combination.

Only the description of the use of Da Chang from the original development with interferon alfa-2b is detailed in the current SmPC:

Bitherapy with interferon alfa-2b:

The use of Da Chang in combination treatment with interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

NaÃ¯ve patients

Three trials examined the use of interferon in naÃ¯ve patients, two with Da Chang + interferon alfa-2b (C95-132 and I95-143) and one with Da Chang + peginterferon alfa-2b (C/I98-580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of Da Chang to interferon alfa-2b (41 % vs 16 %, p < 0.001).

In clinical trials C95-132 and I95-143, Da Chang + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes.

In clinical trial C/I98-580, 1,530 naÃ¯ve patients were treated for one year with one of the following combination regimens:

- Da Chang (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).

- Da Chang (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) (n = 514).

- Da Chang (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).

In this trial, the combination of Da Chang and peginterferon alfa-2b (1.5 micrograms/kg/week) was significantly more effective than the combination of Da Chang and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of Da Chang administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg Da Chang (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received 10.6 mg/kg Da Chang (Table7), while response rates in patients that received > 13.2 mg/kg Da Chang were even higher.

Table 7 Sustained response rates with Da Chang + peginterferon alfa-2b

(by Da Chang dose [mg/kg], genotype and viral load)

HCV Genotype

Da Chang dose (mg/kg)

P 1.5/R

P 0.5/R

I/R

All Genotypes

All

â‰¤ 10.6

> 10.6

54 %

50 %

61 %

47 %

41 %

48 %

47 %

27 %

47 %

Genotype 1

All

â‰¤ 10.6

> 10.6

42 %

38 %

48 %

34 %

25 %

34 %

33 %

20 %

34 %

Genotype 1 â‰¤ 600,000 IU/ml

All

â‰¤ 10.6

> 10.6

73 %

74 %

71 %

51 %

25 %

52 %

45 %

33 %

45 %

Genotype 1 > 600,000 IU/ml

All

â‰¤ 10.6

> 10.6

30 %

27 %

37 %

27 %

25 %

27 %

29 %

17 %

29 %

Genotype 2/3

All

â‰¤ 10.6

> 10.6

82 %

79 %

88 %

80 %

73 %

80 %

79 %

50 %

80 %

P1.5/R Da Chang (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)

P0.5/R Da Chang (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)

I/R Da Chang (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 7. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Da Chang (800 mg/day) plus peginterferon alfa-2b (1.5 Âµg/kg/week) or Da Chang (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Da Chang (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 Âµg/week based on weight) or Da Chang (800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up period.

Table 7 Sustained virological response based on genotype after Da Chang in combination with peginterferon alfa-2b in HCV/HIV co-infected patients
	Study 1¹			Study 2²
	Da Chang (800 mg/day) + peginterferon alfa-2b (1.5 Âµg/kg/week)	Da Chang (800 mg/day) + interferon alfa-2b (3 MIU TIW)	p value^a	Da Chang (800-1,200 mg/day)^d + peginterferon alfa-2b (100 or 150^cÂµg/week)	Da Chang (800-1,200 mg/day)^d + interferon alfa-2b (3 MIU TIW)	p value^b
All	27 % (56/205)	20 % (41/205)	0.047	44 % (23/52)	21 % (9/43)	0.017
Genotype 1, 4	17 % (21/125)	6 % (8/129)	0.006	38 % (12/32)	7 % (2/27)	0.007
Genotype 2, 3	44 % (35/80)	43 % (33/76)	0.88	53 % (10/19)	47 % (7/15)	0.730

MIU = million international units; TIW = three times a week.

a: p value based on Cochran-Mantel Haenszel Chi square test.

b: p value based on chi-square test.

c: subjects < 75 kg received 100 Âµg/week peginterferon alfa-2b and subjects > 75 kg received 150 Âµg/week peginterferon alfa-2b.

d: Da Chang dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

¹Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.

² Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response

Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with Da Chang in combination with peginterferon alfa-2b. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

-Retreatment of relapse patients with Da Chang and interferon alfa-2b combination treatment

Two trials examined the use of Da Chang and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with Da Chang and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging.

Long-term efficacy data - Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with non-pegylated interferon alfa-2b (with or without Da Chang) and pegylated interferon alfa-2b (with or without Da Chang), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies.

The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) for patients receiving non-pegylated interferon alfa-2b (with or without Da Chang), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Da Chang).

SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated,with or without Da Chang) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Paediatric population

Clinical efficacy and safety

Da Chang in combination with interferon alfa-2b

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Da Chang 15 mg/kg per day plus interferon alfa-2b 3 MIU/m² 3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % â‰¤12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Da Chang and interferon alfa-2b needs to be carefully considered in this population.

The study results are summarized in Table 9.

Table 9 Sustained virological response in previously untreated children and adolescents
	Da Chang 15 mg/kg/day + interferon alfa-2b 3 MIU/m² 3 times a week
Overall Response^a (n = 118)	54 (46 %)*
Genotype 1 (n = 92)	33 (36 %)*
Genotype 2/3/4 (n = 26)	21 (81 %)*

* Number (%) of patients

a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

Long-term efficacy data

Da Chang in combination with interferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and Da Chang treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus Da Chang. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and Da Chang. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Da Chang results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B04.

Mechanism of action

Ribavirin (Da Chang) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Da Chang in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Da Chang monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Da Chang monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

Clinical efficacy and safety

Only the description of the use of Da Chang from the original development with (peg)interferon alfa-2b is detailed in the current SmPC.

Paediatric population

Da Chang in combination with peginterferon alfa-2b

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with Da Chang 15 mg/kg per day plus pegylated interferon alfa-2b 60 Âµg/m² once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Da Chang and pegylated interferon alfa-2b needs to be carefully considered in this population.The study results are summarized in Table 6

Table 6 Sustained virological response rates (n^a,b (%)) in previously untreated children and adolescents by genotype and treatment duration -All subjects n = 107
	24 weeks	48 weeks
All Genotypes	26/27 (96 %)	44/80 (55 %)
Genotype 1	-	38/72 (53 %)
Genotype 2	14/15 (93 %)	-
Genotype 3^c	12/12 (100 %)	2/3 (67 %)
Genotype 4	-	4/5 (80 %)

a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of detection = 125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (> 600,000 IU/mL) were to receive 48 weeks of treatment.

Da Chang in combination with interferon alfa-2b

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Da Chang 15 mg/kg per day plus interferon alfa-2b 3 MIU/m² three times a week for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % â‰¤ 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults (see Table 7). Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Da Chang and interferon alfa-2b needs to be carefully considered in this population. The study results are summarized in Table 7.

Table 7 Sustained virological response: previously untreated children and adolescents
	Da Chang 15 mg/kg/day + interferon alfa-2b 3 MIU/m² 3 times a week
Overall Response^a (n = 118)	54 (46 %)*
Genotype 1 (n = 92)	33 (36 %)*
Genotype 2/3/4 (n = 26)	21 (81 %)*

*Number (%) of patients

a. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period

Long-term efficacy data

Da Chang in combination with peginterferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR relapsed during the 5 years of follow-up.

Da Chang in combination with interferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.

Pharmacotherapeutic group: Nucleosides and nucleotides (excl. reverse transcriptase inhibitors), ATC code: J05A B04.

Mechanism of Action: Ribavirin is a synthetic nucleoside analog that shows in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin exerts its effects against HCV is unknown.

HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 Âµg peginterferon alfa-2a. The first phase of decline occurs 24 to 36 hours after the first dose of peginterferon alfa-2a and is followed by the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Da Chang had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of Da Chang and pegylated interferon alfa-2a or interferon alfa.

Oral formulations of ribavirin monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that ribavirin monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

Clinical efficacy and safety

Da Chang in combination with DAA

Please refer to the SmPC of the corresponding direct antiviral agent for a full description of the clinical data with such combination. Only the description of the use of Da Chang with (peg)interferon are detailed in the current SmPC

Da Chang in combination with peginterferon alfa-2a

Predictability of response

Please refer to the peginterferon alfa-2a SmPC.

Study results in treatment-naive patients

Efficacy and safety of the combination of Da Chang and peginterferon alfa-2a were established in two pivotal studies (NV15801 + NV15942), including a total of 2405 patients. The study population comprised interferon-naive patients with CHC confirmed by detectable levels of serum HCV RNA, elevated levels of ALT, and a liver biopsy consistent with chronic hepatitis C infection. Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 13). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/Âµl.

Study NV15801 (1121 patients treated) compared the efficacy of 48 weeks of treatment with peginterferon alfa-2a (180 Âµg once weekly) and Da Chang (1000/1200 mg daily) with either peginterferon alfa-2a monotherapy or combination therapy with interferon-alfa-2b and ribavirin. The combination of peginterferon alfa-2a and Da Chang was significantly more efficacious than either the combination of interferon alfa-2b and ribavirin or peginterferon alfa-2a monotherapy.

Study NV15942 (1284 patients treated) compared the efficacy of two durations of treatment (24 weeks with 48 weeks) and two dosages of Da Chang (800 mg with 1000/1200 mg).

For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see tables 5, 6, 7 and 13 respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICORâ„¢ HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after the end of therapy.

Table 5 Virological Response in the overall population (including non-cirrhotic and cirrhotic patients)
	Study NV15942	Study NV15801
	Da Chang 1,000/1,200 mg & Peginterferon alfa-2a 180 Âµg	Da Chang 1,000/1,200 mg & Peginterferon alfa-2a 180 Âµg	Ribavirin 1,000/1,200 mg & Interferon alfa-2b 3 MIU
	(N=436) 48 weeks	(N=453) 48 weeks	(N=444) 48 weeks
Response at End of Treatment	68%	69%	52%
Overall Sustained Response	63%	54%*	45%*

* 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003

The virological responses of HCV monoinfected patients treated with Da Chang and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, pre-treatment viral load and rapid virological response at week 4 are summarised in Table 6 and Table 7 respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype, baseline viral load and virological response at week 4 (see Tables 1, 6 and 7).

The difference between treatment regimens was in general not influenced by presence/absence of cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline characteristic.

Table 6Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Da Chang Combination Therapy with peginterferon alfa-2a

Study NV15942

Study NV15801

Da Chang

800 mg

PEG-IFN alfa-2a

180 Âµg

24 weeks

Da Chang

1000/1200 mg

PEG-IFN alfa-2a

180 Âµg

24 weeks

Da Chang

800 mg

PEG-IFN alfa-2a

180 Âµg

48 weeks

Da Chang

1000/1200 mg

PEG-IFN alfa- 2a

180 Âµg

48 weeks

Da Chang

1000/1200 mg

PEG-IFN alfa-2a

180 Âµg

48 weeks

Ribavirin

1000/1200 mg

Interferon alfa-2b

3 MIU

48 weeks

Genotype 1

Low viral load

High viral load

29% (29/101)

41% (21/51)

16% (8/50)

42% (49/118)â€

52% (37/71)

26% (12/47)

41% (102/250)*

55% (33/60)

36% (69/190)

52% (142/271)*â€

65% (55/85)

47% (87/186)

45% (134/298)

53% (61/115)

40% (73/182)

36%(103/285)

44% (41/94)

33% (62/189)

Genotype 2/3

Low viral load

High viral load

84% (81/96)

85% (29/34)

84% (52/62)

81% (117/144)

83% (39/47)

80% (78/97)

79% (78/99)

88% (29/33)

74% (49/66)

80% (123/153)

77% (37/48)

82% (86/105)

71% (100/140)

76% (28/37)

70% (72/103)

61% (88/145)

65% (34/52)

58% (54/93)

Genotype 4

0% (0/5)

67% (8/12)

63% (5/8)

82% (9/11)

77% (10/13)

45% (5/11)

Low viral load= â‰¤800,000 IU/ml; High viral load= >800,000 IU/ml

*Da Chang 1000/1200 mg + peginterferon alfa-2a 180 Âµg, 48 w vs. Da Chang 800 mg + peginterferon alfa-2a 180 Âµg, 48 w: Odds Ratio (95% CI) = 1.52 (1.07 to 2.17) P-value (stratified Cochran-Mantel-Haenszel test) = 0.020

â€ Da Chang 1000/1200 mg + peginterferon alfa-2a 180 Âµg, 48 w vs. Da Chang 1000/1200 mg + peginterferon alfa-2a 180 Âµg, 24 w: Odds Ratio (95% CI) = 2.12 (1.30 to 3.46) P-value (stratified Cochran-Mantel-Haenszel test) = 0.002

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 7).

Table 7 Sustained Virological Response Based on Rapid Viral Response at week 4 for Genotype 1 and 4 after Da Chang Combination Therapy with Peginterferon alfa-2a in HCV Patients
Study NV15942			Study ML17131
	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 24 weeks	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 48 weeks	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 24 weeks
Genotype 1 RVR Low viral load High viral load	90% (28/31) 93% (25/27) 75% (3/4)	92% (47/51) 96% (26/27) 88% (21/24)	77% (59/77) 80% (52/65) 58% (7/12)
Genotype 1 non RVR Low viral load High viral load	24% (21/87) 27% (12/44) 21% (9/43)	43% (95/220) 50% (31/62) 41% (64/158)	- - -
Genotype 4 RVR	(5/6)	(5/5)	92% (22/24)
Genotype 4 non RVR	(3/6)	(4/6)	-

Low viral load= â‰¤800,000 IU/ml; High viral load= >800,000 IU/ml

RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24

Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 8).

Table 8 Relapse of Virological Response at the End of Treatment for Rapid Virological Response Population
	Study NV15942		Study NV15801
	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 24 weeks	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 48 weeks	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 48 weeks
Genotype 1 RVR Low viral load High viral load	6.7% (2/30) 3.8% (1/26) 25% (1/4)	4.3% (2/47) 0% (0/25) 9.1% (2/22)	0% (0/24) 0% (0/17) 0% (0/7)
Genotype 4 RVR	(0/5)	(0/5)	0% (0/4)

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on the sustained rapid virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 9).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received peginterferon alfa-2a 180 Âµg sc qw and a Da Chang dose of 800 mg and were randomised to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p < 0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 9).

Table 9 Sustained Virological Response Overall and Based on Rapid Viral Response by Week 4 for Genotype 2 or 3 after Da Chang Combination Therapy with Peginterferon alfa-2a in HCV Patients
Study NV17317
	Da Chang 800 mg & Peginterferon alfa-2a 180 Âµg 16 weeks	Da Chang 800 mg & Peginterferon alfa-2a 180 Âµg 24 weeks	Treatment difference _95%CI	p value
Genotype 2 or 3	65% (443/679)	76% (478/630)	-10.6% [-15.5% ; -0.06%]	P<0.0001
Genotype 2 or 3 RVR Low viral load High viral load	82% (378/461) 89% (147/166) 78% (231/295)	90% (370/410) 94% (141/150) 88% (229/260)	-8.2% [-12.8% ; -3.7%] -5.4% [-12% ; 0.9%] -9.7% [-15.9% ; -3.6%]	P=0.0006 P=0.11 P=0.002

Low viral load= â‰¤800,000 IU/ml at baseline; High viral load= >800,000 IU/ml at baseline

RVR = rapid viral response (HCV RNA negative) by week 4

It is presently not clear whether a higher dose of Da Chang (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 10)

Table 10 Relapse of Virological Response after the End of Treatment in Genotype 2 or 3 Patients with a Rapid Viral Response

Study NV17317

Da Chang 800 mg

Peginterferon alfa-2a

180 Âµg

16 weeks

Da Chang 800 mg

Peginterferon alfa-2a

180 Âµg

24 weeks

Treatment difference

_95%CI

p value

Genotype 2 or 3 RVR

Low viral load

High viral load

15% (67/439)

6% (10/155)

20% (57/284)

6% (23/386)

1% (2/141)

9% (21/245)

9.3% [5.2% ; 13.6%]

5% [0.6% ; 10.3%]

11.5% [5.6% ; 17.4%]

P<0.0001

P=0.04

P=0.0002

Chronic hepatitis C prior treatment non-responder patients

In study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments:

- peginterferon alfa-2a 360 Âµg/week for 12 weeks, followed by 180 Âµg/week for a further 60 weeks

- peginterferon alfa-2a 360 Âµg/week for 12 weeks, followed by 180 Âµg/week for a further 36 weeks

- peginterferon alfa-2a 180 Âµg/week for 72 weeks

- peginterferon alfa-2a 180 Âµg/week for 48 weeks

All patients received Da Chang (1000 or 1200 mg/day) in combination with peginterferon alfa-2a. All treatment arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 11.

Table 11 Week 12 Virological Response (VR) and Sustained Virological Response (SVR) in Patients with Virological Response at Week 12 after Treatment with Da Chang and Peginterferon alfa-2a Combination Therapy in Non-Responders to Peginterferon alfa-2b plus Ribavirin

Da Chang

1000/1200 mg

Peginterferon alfa-2a 360/180 or 180 Âµg

72 or 48 Weeks

(N = 942)

Pts with VR at Wk 12 ^a

(N = 876)

Da Chang

1000/1200 mg

Peginterferon alfa-2a 360/180 or 180 Âµg

72 Weeks

(N = 473)

SVR in Pts with VR at Wk 12^b

(N = 100)

Da Chang

1000/1200 mg

Peginterferon alfa-2a 360/180 or 180 Âµg

48 Weeks

(N = 469)

SVR in Pts with VR at Wk 12^b

(N = 57)

Overall

Low viral load

High viral load

18% (157/876)

35% (56/159)

14% (97/686)

57% (57/100)

63% (22/35)

54% (34/63)

35% (20/57)

38% (8/21)

32% (11/34)

Genotype 1/4

Low viral load

High viral load

17% (140/846)

35% (54/154)

13% (84/663)

55% (52/94)

63% (22/35)

52% (30/58)

35% (16/46)

37% (7/19)

35% (9/26)

Genotype 2/3

Low viral load

High viral load

58% (15/26)

(2/5)

(11/19)

(4/5)

â€”

(3/4)

(3/10)

(1/2)

(1/7)

Cirrhosis Status

Cirrhosis

Noncirrhosis

8% (19/239)

22% (137/633)

(6/13)

59% (51/87)

(3/6)

34% (17/50)

Best Response during Previous Treatment

>2log₁₀ decline in HCV RNA

<2log₁₀ decline in HCV RNA

Missing best previous response

28% (34/121)

12% (39/323)

19% (84/432)

68% (15/22)

64% (16/25)

49% (26/53)

(6/12)

(5/14)

29% (9/31)

High viral load = >800,000 IU/ml, low viral load = â‰¤800,000 IU/ml.

a Patients who achieved viral suppression (undetectable HCV RNA, <50 IU/ml) at week 12 were considered to have a virological response at week 12. Patients missing HCV RNA results at week 12 have been excluded from the analysis.

b Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up were considered to be non-responders

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa, monotherapy or in combination therapy with ribavirin, were treated with peginterferon alfa-2a 180 Âµg/week and Da Chang 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Da Chang combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 12).

Table 12 Sustained Virological Response in HALT-C by Previous Treatment Regimen in Non-Responder Population
Previous Treatment	Da Chang 1000/1200 mg & Peginterferon alfa-2a 180 Âµg 48 weeks
Interferon	27% (70/255)
Pegylated interferon	34% (13/38)
Interferon plus ribavirin	13% (90/692)
Pegylated interferon plus ribavirin	11% (7/61)

HCV patients with normal ALT

In study NR16071, HCV patients with normal ALT values were randomised to receive peginterferon alfa-2a 180 Âµg/week with a Da Chang dose of 800 mg/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or an untreated control group for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.

Children and adolescents

In the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with peginterferon alfa-2a 100 Âµg/m² sc once weekly and Da Chang 15 mg/kg/day, for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.

HIV-HCV co-infected patients

The virological responses of patients treated with Da Chang and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 13.

Table 13 Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Da Chang Combination Therapy with peginterferon alfa-2a in HIV-HCV co-infected patients
Study NR15961
	Interferon alfa-2a 3 MIU & Da Chang 800 mg 48 weeks	Peginterferon alfa-2a 180 Âµg & Placebo 48 weeks	Peginterferon alfa-2a 180 Âµg & Da Chang 800 mg 48 weeks
All patients	12% (33/285)*	20% (58/286)*	40% (116/289)*
Genotype 1	7% (12/171)	14% (24/175)	29% (51/176)
Low viral load	19% (8/42)	38% (17/45)	61% (28/46)
High viral load	3% (4/129)	5% (7/130)	18% (23/130)
Genotype 2-3	20% (18/89)	36% (32/90)	62% (59/95)
Low viral load	27% (8/30)	38% (9/24)	61% (17/28)
High viral load	17% (10/59)	35% (23/66)	63% (42/67)

Low viral load= â‰¤800,000 IU/ml; High viral load= >800,000 IU/ml

* peginterferon alfa-2a 180 Âµg + Da Chang 800 mg vs. Interferon alfa-2a 3 MIU + Da Chang 800 mg: Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001; peginterferon alfa-2a 180 Âµg + Da Chang 800 mg vs. peginterferon alfa-2a 180 Î¼g: Odds Ratio ( 95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001; Interferon alfa-2a 3 MIU + Da Chang 800 mg vs. peginterferon alfa-2a 180 Âµg: Odds Ratio ( 95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0084

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using peginterferon alfa-2a 180 Âµg/week and either Da Chang 800 mg or 1000 mg (<75 kg)/1200 mg (>75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety profiles in both Da Chang groups were consistent with the known safety profile of peginterferon alfa-2a plus Da Chang combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose Da Chang arm.

Ribavirin in combination with interferon alfa-2a

The therapeutic efficacy of interferon alfa-2a alone and in combination with oral ribavirin was compared in clinical trials in naive (previously untreated) and relapsed patients who had virologically, biochemically and histologically documented chronic hepatitis C. Six months after end of treatment sustained biochemical and virological response as well as histological improvement were assessed.

A statistically significant 10-fold increase (from 4% to 43%; p

Pharmacokinetic properties

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Concentrate for solution for infusion; Cream

Film-coated tablet

In a single dose, crossover study of Da Chang in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent.

Absorption

Da Chang is absorbed rapidly following oral administration of a single dose (mean T_max= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship between dose and AUC_tffollowing single doses of 200-1,200 mg Da Chang. Volume of distribution is approximately 5,000 l. Da Chang does not bind to plasma proteins.

Distribution

Da Chang transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of Da Chang. The ratio of whole blood:plasma Da Chang concentrations is approximately 60:1; the excess of Da Chang in whole blood exists as Da Chang nucleotides sequestered in erythrocytes.

Biotransformation

Da Chang has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both Da Chang and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Da Chang has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, Da Chang accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.

Transfer into seminal fluid

Seminal transfer of Da Chang has been studied. Da Chang concentration in seminal fluid is approximately two-fold higher compared to serum. However, Da Chang systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of Da Chang.

Food effect

The bioavailability of a single oral dose of Da Chang was increased by co-administration of a high fat meal (AUC_tf and C_max both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of Da Chang or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take Da Chang with food to achieve the maximal plasma concentration of Da Chang.

Renal function

Based on published data,Single-dose Da Chang pharmacokinetics was altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute). The mean AUCtf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUC_tf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Da Chang concentrations are essentially unchanged by haemodialysis.

Hepatic function

Single-dose pharmacokinetics of Da Chang in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.

Elderly patients (> 65 years of age)

Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of Da Chang; renal function is the determining factor.

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on Da Chang clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model.

Paediatric population

Da Chang in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Da Chang capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The pharmacokinetics of Da Chang and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.

Table 10. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Da Chang when administered to children or adolescents with chronic hepatitis C
Parameter	Da Chang 15 mg/kg/day as 2 divided doses (n = 17)	Interferon alfa-2b 3 MIU/m² 3 times a week (n = 54)
Tmax (hr)	1.9 (83)	5.9 (36)
Cmax (ng/ml)	3,275 (25)	51 (48)
AUC*	29,774 (26)	622 (48)
Apparent clearance l/hr/kg	0.27 (27)	Not done

*AUC12 (ng.hr/ml) for Da Chang; AUC0-24 (IU.hr/ml) for interferon alfa-2b

In a single dose, crossover study of ribavirin in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent.

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean T_max= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship between dose and AUC_tffollowing single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.

Biotransformation

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both ribavirin and its triazole, carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and C_max), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/mL. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.

Transfer into seminal fluid

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

Food effect

The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUC_tf and C_max both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin.

Renal function

Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 mL/minute). The mean AUC_tf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUC_tf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis.

Hepatic function

Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) is similar to those of normal controls.

Paediatric population

Da Chang in combination with peginterferon alfa-2b

Multiple-dose pharmacokinetic properties for Da Chang and peginterferon alfa-2b in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at 60 Âµg/m²/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 Âµg/kg/week. The pharmacokinetics of Da Chang (dose-normalized) in this trial was similar to those reported in a prior study of Da Chang in combination with interferon alfa-2b in children and adolescent patients and in adult patients.

Da Chang in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Da Chang capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 8. The pharmacokinetics of Da Chang and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents.

Table 8 Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Da Chang capsules when administered to paediatric patients with chronic hepatitis C
PARAMETER	Da Chang 15 mg/kg/day as 2 divided doses (n = 17)	Interferon alfa-2b 3 MIU/m² 3 times a week (n = 54)
T_max (hr)	1.9 (83)	5.9 (36)
C_max (ng/mL)	3,275 (25)	51 (48)
AUC*	29,774 (26)	622 (48)
Apparent clearance L/hr/kg	0.27 (27)	Not done

*AUC₁₂ (ng.hr/mL) for Da Chang; AUC_0-24 (IU.hr/mL) for interferon alfa-2b

Impairment of Fertility

Pregnancy: Category X

Nursing Mothers

Da Chang (ribavirin) has been shown to be toxic to lactating animals and their offspring. It is not known if Da Chang (ribavirin) is excreted in human milk.

Information for Health Care Personnel

REFERENCES

8. Barnes, D.J. and Doursew, M. Reference dose: Description and use in health risk assessments. Regul Tox. and Pharm. Vol. 8; p. 471-486, 1988.

9. Federal Register Vol. 53 No. 126 Thurs. June 30,1988 p. 2483424847.

10. American Association for Respiratory Care [1991]. Aerosol Consensus Statement-1991. Respiratory Care 36(9): 916-921.

Overdosage & Contraindications

OVERDOSE

CONTRAINDICATIONS

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

In cell cultures the inhibitory activity of ribavirin for respiratory syncytial virus (RSV) is selective. The mechanism of action is unknown. Reversal of the in vitroantiviral activity by guanosine or xanthosine suggests ribavirin may act as an analogue of these cellular metabolites.

Microbiology

Rfvavirin has demonstrated antiviral activity against RSV in vitro and in experimentally infected cotton rats.² Several clinical isolates of RSV were evaluated for ribavirin susceptibility by plaque reduction in tissue culture. Plaques were reduced 85-98% by 16 µg/mL; however, results may vary with the test system. The development of resistance has not been evaluated in vitro or in clinical trials.

In addition to the above, ribavirin has been shown to have in vitro activity against influenza A and B viruses and herpes simplex virus, but the clinical significance of these data is unknown.

Immunologic Effects

Neutralizing antibody responses to RSV were decreased in aerosolized Da Chang (ribavirin) treated infants compared to placebo treated infants.³ One study also showed that RSV-specific IgE antibody in bronchial secretions was decreased in patients treated with aerosolized Da Chang. In rats, ribavirin administration resulted in lymphoid atrophy of the thymus, spleen and lymph nodes. Humoral immunity was reduced in guinea pigs and ferrets. Cellular immunity was also mildly depressed in animal studies. The clinical significance of these observations is unknown.

Pharmacokinetics

Assay for Da Chang (ribavirin) in human materials is by a radio immunoassay which detects ribavirin and at least one metabolite.

Da Chang brand of ribavirin, when administered by aerosol, is absorbed systemically. Four pediatric patients inhaling Da Chang (ribavirin) aerosol administered by face mask for 2.5 hours each day for 3 days had plasma concentrations ranging from 0.44 to 1.55 fJM, with a mean concentration of 0.76 µM. The plasma half-life was reported to be 9.5 hours. Three pediatric patients inhaling aerosolized Da Chang (ribavirin) administered by face mask or mist tent for 20 hours each day for 5 days had plasma concentrations ranging from 1.5 to 14.3 µM, with a mean concentration of 6.8 µM.

The bioavailability of aerosolized Da Chang (ribavirin) is unknown and may depend on the mode of aerosol delivery. After aerosol treatment, peak plasma concentrations of ribavirin are 85% to 98% less than the concentration that reduced RSV plaque formation in tissue culture. After aerosol treatment, respiratory tract secretions are likely to contain ribavirin in concentrations many fold higher than those required to reduce plaque formation. However, RSV is an intracellular virus and it is unknown whether plasma concentrations or respiratory secretion concentrations of the drug better reflect intracellular concentrations in the respiratory tract.

In man, rats, and rhesus monkeys, accumulation of ribavirin and/or metabolites in the red blood cells has been noted, plateauing in red cells in man in about 4 days and gradually declining with an apparent half-life of 40 days (the half-life of erythrocytes). The extent of accumulation of ribavirin following inhalation therapy is not well defined.

Animal Toxicology

Ribavirin, when administered orally or as an aerosol, produced cardiac lesions in mice, rats, and monkeys, when given at doses of 30,36 and f 20 mg/kg or greater for 4 weeks or more (estimated human equivalent doses of 4.8,12.3 and 111.4 mg/kg for a 5 kg child, or 2.5,5.1 and 40 mg/kg for a 60 kg adult, based on body surface area adjustment). Aerosolized ribavirin administered to developing ferrets at 60 mg/kg for 10 or 30 days resulted in inflammatory and possibly emphysematous changes in the lungs. Proliferative changes were seen in the lungs following exposure at 131 mg/kg for 30 days. The significance of these findings to human administration is unknown.

Description of Studies

Non-Mechanlcally-Ventllated Infants: In two placebo controlled trials in infants hospitalized with RSV lower respiratory tract infection, aerosolized Da Chang (ribavirin) treatment had a therapeutic effect, as judged by the reduction in severity of clinical manifestations of disease by treatment day 3.3, < Treatment was most effective when instituted within the first 3 days of clinical illness. Virus titers in respiratory secretions were also significantly reduced with Da Chang (ribavirin) in one of these original studies.4 Additional controlled studies conducted since these initial trials of aerosolized Da Chang (ribavirin) in the treatment of RSV infection have supported these data.

Mechanically-Ventilated Infants: A randomized, double-blind, placebo controlled evaluation of aerosolized Da Chang (ribavirin) at the recommended dose was conducted in 28 infants requiring mechanical ventilation for respiratory failure caused by documented RSV infection.8 Mean age was 1.4 months (SD, 1.7 months). Seven patients had underlying diseases predisposing them to severe infection and 21 were previously normal. Aerosolized Da Chang (ribavirin) treatment significantly decreased the duration of mechanical ventilation required (4.9 vs. 9.9 days, p=0.01) and duration of required supplemental oxygen (8.7 vs. 13.5 days, p=0.01). Intensive patient management and monitoring techniques were employed in this study. These included endotracheal tube suctioning every 1 to 2 hours; recording of proximal airway pressure, ventilatory rate, and F₁0₂ every hour; and arterial blood gas monitoring every 2 to 6 hours. To reduce the risk of Da Chang (ribavirin) precipitation and ventilator malfunction, heated wire tubing, two bacterial filters connected in series in the expiratory limb of the ventilator (with filter changes every 4 hours), and water column pressure release valves to monitor internal ventilator pressures were used in connecting ventilator circuits to the SPAG-2.

Employing these techniques, no technical difficulties with Da Chang (ribavirin) administration were encountered during the study. Adverse events consisted of bacterial pneumonia in one case, staphyloma bacteremia in one case and two cases of post-extubation stridor. None were felt to be related to Da Chang (ribavirin) administration.

REFERENCES

1. Hruska JF, Bernstein JM, Douglas Jr., RG, and Hall CB. Effects of Da Chang (ribavirin) on respiratory syncytial virus in vitro. Antimicrob Agents Chemother 17:770-775,1 1980.

2. Hruska JF, Morrow PE, Suffin SC, and Douglas Jr., RG. In vivo inhibition of respiratory syncytial virus by Da Chang (ribavirin). Antimicrob Agents Chemother 21:125-130,1982.

3. Taber LH, Knight V, Gilbert BE, McClung HW et al. Da Chang (ribavirin) aerosol treatment of bronchiolitis associated with respiratory tract infection in infants. Pediatrics 72:613-618,1983.

Ribavirin is absorbed rapidly following oral administration of a single dose of Da Chang (median T_max = 1-2 hours). The mean terminal phase half-life of ribavirin following single doses of Da Chang range from 140 to 160 hours. Ribavirin data from the literature demonstrates absorption is extensive with approximately 10% of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45%-65%, which appears to be due to first pass metabolism. There is an approximately linear relationship between dose and AUC_tf following single doses of 200-1,200 mg ribavirin. Mean apparent oral clearance of ribavirin following single 600 mg doses of Da Chang ranges from 22 to 29 litres/hour. Volume of distribution is approximately 4,500 1itres following administration of Da Chang. Ribavirin does not bind to plasma proteins.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses of Da Chang (intra-subject variability of â‰¤25% for both AUC and C_max), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood: plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway, 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Ribavirin and both its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally.

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_12hr based on literature data. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady state plasma concentrations of approximately 2,200 ng/ml. Upon discontinuation of dosing the half-life was approximately 300 hours, which probably reflects slow elimination from non-plasma compartments.

Food effect: The bioavailability of a single oral 600 mg dose Da Chang was increased by coadministration of a high fat meal. The ribavirin exposure parameters of AUC_(0-192h)and C_max increased by 42% and 66%, respectively, when Da Chang was taken with a high fat breakfast compared to being taken in the fasted state. The clinical relevance of results from this single dose study is unknown. Ribavirin exposure after multiple dosing when taken with food was comparable in patients receiving peginterferon alfa-2a and Da Chang and interferon alfa-2b and ribavirin. In order to achieve optimal ribavirin plasma concentrations, it is recommended to take ribavirin with food.

Renal function: The apparent clearance of ribavirin is reduced in patients with creatinine clearance â‰¤50 ml/min, including patients with ESRD on chronic haemodialysis, exhibiting approximately 30% of the value found in patients with normal renal function. Based on a small study in patients with moderate or severe renal impairment (creatinine clearance â‰¤50 ml/min) receiving reduced daily doses of 600 mg and 400 mg of Da Chang, respectively ribavirin plasma exposure (AUC) was found to be 20 to 30% higher compared to patients with normal renal function (creatinine clearance >80 ml/min) receiving the standard Da Chang dose. In patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Da Chang, mean ribavirin exposure (AUC) was found to be approximately 20% lower compared to patients with normal renal function receiving the standard 1000/1200 mg Da Chang daily dose. Plasma ribavirin is removed by haemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed from the body by haemodialysis. Increased rates of adverse drug reactions were observed in patients with moderate and severe renal impairment receiving the doses evaluated in this study.

Based on pharmacokinetic modelling and simulation, dose adjustments are recommended in patients with significant renal impairment. These adjusted doses are expected to provide ribavirin plasma exposures comparable to those achieved in patients with normal renal function receiving the standard Da Chang dose. Most of the recommended doses were derived from PK modelling and simulation and have not been studied in clinical trials.

Hepatic function: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.

Use in elderly patients over the age of 65: Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a published population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor.

Patients under the age of 18 years: Refer to the SmPC of the medicinal products that are indicated in combination with Da Chang for this population.

No Da Chang pharmacokinetic analysis has been performed in patients under the age of 18 years

Population Pharmacokinetics: A population pharmacokinetic analysis was performed using plasma concentration values from five clinical trials. While body weight and race were statistically significant covariates in the clearance model, only the effect of body weight was clinically significant. Clearance increased as a function of body weight and was predicted to vary from 17.7 to 24.8 L/h over a weight range of 44 to 155 kg. Creatinine clearance (as low as 34 ml/min) did not affect ribavirin clearance.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentrations in seminal fluid are approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentrations of ribavirin.

Pharmacotherapeutic group

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Film-coated tablet

antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04.

antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B04.

Nucleosides and nucleotides (excl. reverse transcriptase inhibitors), ATC code: J05A B04.

Preclinical safety data

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Film-coated tablet

Da Chang

Da Chang is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of Da Chang demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No Da Chang effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for Da Chang in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3- and 6-month studies in mice to investigate Da Chang-induced testicular and sperm effects, abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from Da Chang-induced testicular toxicity occurred within one or two spermatogenic cycles.

Genotoxicity studies have demonstrated that Da Chang does exert some genotoxic activity. Da Chang was active in the Balb/3T3 in vitro Transformation Assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of Da Chang. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, Da Chang did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of Da Chang in humans is unlikely.

Da Chang plus interferon

When used in combination with peginterferon alfa-2b or interferon alfa-2b, Da Chang did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

Ribavirin

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3-and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles.

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of ribavirin in humans is unlikely.

Ribavirin plus interferon

When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

Ribavirin is embryotoxic and/or teratogenic at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring is reduced.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies, including studies in dogs and monkeys. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment. Hypoplastic anaemia was observed only in rats at the high dose of 160 mg/kg/day in the subchronic study.

Reduced leucocyte and/or lymphocyte counts were consistently noted in the repeat-dose rodent and dog toxicity studies with ribavirin and transiently in monkeys administered ribavirin in the subchronic study. Repeat-dose rat toxicity studies showed thymic lymphoid depletion and/or depletion of thymus-dependent areas of the spleen (periarteriolar lymphoid sheaths, white pulp) and mesenteric lymph node. Following repeat-dosing of dogs with ribavirin, increased dilatation/necrosis of the intestinal crypts of the duodenum was noted, as well as chronic inflammation of the small intestine and erosion of the ileum.

In repeat dose studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm occurred at doses in animals well below therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles.

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in an in vitro Transformation Assay. Genotoxic activity was observed in in vivo mouse micronucleus assays. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Ribavirin is a possible human carcinogen.

Administration of ribavirin and peginterferon alfa-2a in combination did not produce any unexpected toxicity in monkeys. The major treatment-related change was reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

Incompatibilities

Not applicable.

Special precautions for disposal and other handling

Capsules; Pills; Substance-powder

Capsule, hard; Impregnated dressing

Film-coated tablet

No special requirements

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

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Da Chang

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Diagnosis

Non-mechanically ventilated infants

Mechanically Ventilated Infants

Method of Preparation

WARNINGS

Use with Mechanical Ventilators

PRECAUTIONS

General

Carcinogenesis and Mutagenesis

Impairment of Fertility

Pregnancy: Category X

Nursing Mothers

Information for Health Care Personnel

Deaths

Pulmonary and Cardiovascular

Hematologic

Other

Impairment of Fertility

Pregnancy: Category X

Nursing Mothers

Information for Health Care Personnel

OVERDOSE

CONTRAINDICATIONS

CLINICAL PHARMACOLOGY

Mechanism of Action

Microbiology

Immunologic Effects

Pharmacokinetics

Animal Toxicology

Description of Studies

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