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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 05.04.2022
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Ribavirin BioPartners is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults.
Ribavirin BioPartners 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.
Ribavirin BioPartners 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.
Ribavirin BioPartners (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 Ribavirin BioPartners (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 Ribavirin BioPartners (ribavirin) aerosol (3 to 7 days) and should not be treated with the drug. Thus the decision to treat with Ribavirin BioPartners (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 Ribavirin BioPartners (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.
Ribavirin BioPartners is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC).
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 Ribavirin BioPartners for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Ribavirin BioPartners.
Ribavirin BioPartners capsules are to be administered orally each day in two divided doses (morning and evening) with food.
Adults
The recommended dose and duration of Ribavirin BioPartners 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 Ribavirin BioPartners
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 Ribavirin BioPartners 40 mg/mL oral solution.
Dosing of Ribavirin BioPartners 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 Ribavirin BioPartners as some combination regimens do not adhere to the Ribavirin BioPartners dosing guidance provided in Table 1.
| Table 1. Ribavirin BioPartners dose based on body weight when used in combination with interferon alfa-2b in paediatric patients | ||
| Patient weight (kg) | Daily Ribavirin BioPartners 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 Ribavirin BioPartners depends on the initial Ribavirin BioPartners posology which depends on the medicinal product that is used in combination with Ribavirin BioPartners.
If a patient has a serious adverse reaction potentially related to Ribavirin BioPartners, the Ribavirin BioPartners 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 Ribavirin BioPartners dose* if: | Discontinue Ribavirin BioPartners 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, Ribavirin BioPartners 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, Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners is by an additional 200 mg/day. Patients whose dose of Ribavirin BioPartners 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 Ribavirin BioPartners, refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners. However, as in younger patients, renal function must be determined prior to administration of Ribavirin BioPartners.
Paediatric patients (children 3 years of age and older and adolescents)
Ribavirin BioPartners may be used in combination with interferon alfa-2b. The selection of Ribavirin BioPartners formulation is based on individual characteristics of the patient.
The safety and efficacy of Ribavirin BioPartners 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 Ribavirin BioPartners for further dosage recommendations on co-administration.
Renal impairment
The pharmacokinetics of Ribavirin BioPartners 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 Ribavirin BioPartners. 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 Ribavirin BioPartners 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 | Ribavirin BioPartners 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 Ribavirin BioPartners and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of the medicinal products used in combination with Ribavirin BioPartners.
Method of administration
Ribavirin BioPartners 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 Ribavirin BioPartners for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Ribavirin BioPartners.
Ribavirin BioPartners oral solution is supplied in a concentration of 40 mg/mL.
Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners as some combination regimens do not adhere to the Ribavirin BioPartners dosing guidance provided in Table 1.
In clinical studies performed in this population, Ribavirin BioPartners was used in doses of 15 mg/kg/day (Table 1).
| Table 1 Ribavirin BioPartners 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 Ribavirin BioPartners capsules).
Dose modification for adverse reactions
Dose reduction of Ribavirin BioPartners depends on the initial Ribavirin BioPartners posology which depends on the medicinal product that is used in combination with Ribavirin BioPartners.
If a patient has a serious adverse reaction potentially related to Ribavirin BioPartners, the Ribavirin BioPartners 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 indirect bilirubin concentration.
There are no data for paediatric patients with cardiac disease.
| Table 2 Management of Adverse Reactions | ||
| Laboratory values | Reduce Ribavirin BioPartners dose* if: | Discontinue Ribavirin BioPartners 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 Ribavirin BioPartners plus peginterferon alfa-2b, 1st dose reduction of Ribavirin BioPartners is to 12 mg/kg/day, 2nd dose reduction of Ribavirin BioPartners is to 8 mg/kg/day.
In children and adolescent patients treated with Ribavirin BioPartners plus interferon alfa-2b, reduce Ribavirin BioPartners dose to 7.5 mg/kg/day.
In case of serious adverse reaction potentially related to medicinal products used in combination with Ribavirin BioPartners, please refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the Ribavirin BioPartners dose modification and/or discontinuation guidelines as described in Table 2.
Special populations
Paediatric patients (children 3 years of age and older and adolescents)
Ribavirin BioPartners may be used in combination with peginterferon alfa-2b or interferon alfa-2b. The selection of Ribavirin BioPartners 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 Ribavirin BioPartners for further dosage recommendations on co-administration.
Renal impairment
The pharmacokinetics of Ribavirin BioPartners 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 Ribavirin BioPartners. 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 Ribavirin BioPartners 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 | Ribavirin BioPartners 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 Ribavirin BioPartners and hepatic function. For use in patients with decompensated cirrhosis, see the corresponding SmPC of medicinal products used in combination with Ribavirin BioPartners.
Method of administration
Ribavirin BioPartners 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 Ribavirin BioPartners (ribavirin) SHOULD NOT BE ADMINISTERED WITH ANY OTHER AEROSOL GENERATING DEVICE.
The recommended treatment regimen is 20 mg/mL Ribavirin BioPartners (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 Ribavirin BioPartners (ribavirin) should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.
Non-mechanically ventilated infants
Ribavirin BioPartners (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 Ribavirin BioPartners (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
Ribavirin BioPartners 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 Ribavirin BioPartners for the treatment of hepatitis C.
Method of Administration
Ribavirin BioPartners 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 Ribavirin BioPartners is based on patient body weight, viral genotype and the medicinal product that is used in combination (see Table1). Ribavirin BioPartners tablets are to be administered orally each day in two divided doses (morning and evening) with food.
| Table 1. Ribavirin BioPartners dosing recommendation according to the medicinal product used in combination | ||
| Medicinal product used in combination | Daily Ribavirin BioPartners 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-naïve 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) |
| 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 Ribavirin BioPartners.
Dosage modification for adverse reactions
Dose modification of Ribavirin BioPartners 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 Ribavirin BioPartners dose to [1] [2] if: | Discontinue Ribavirin BioPartners 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, Ribavirin BioPartners 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, Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners is by an additional 200 mg/day. Patients whose dose of Ribavirin BioPartners 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 | Ribavirin BioPartners 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, Ribavirin BioPartners should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Ribavirin BioPartners, Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners.
Use in patients under the age of 18 years: Treatment with Ribavirin BioPartners 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 Ribavirin BioPartners in children is needed .
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- Pregnacy. In females of childbearing potential, Ribavirin BioPartners 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, Ribavirin BioPartners 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 Ribavirin BioPartners for contraindications specific to these products.
Ribavirin BioPartners (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 Ribavirin BioPartners (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. Ribavirin BioPartners 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 Ribavirin BioPartners for contraindications related to those products.
Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Ribavirin BioPartners has no direct cardiovascular effects, anaemia associated with Ribavirin BioPartners may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Ribavirin BioPartners 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 Ribavirin BioPartners the physician must comprehensively inform both male and female patients of the teratogenic risk of Ribavirin BioPartners, 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 Ribavirin BioPartners. For laboratory monitoring of pregnancy, please refer to Laboratory tests.
Acute hypersensitivity:
If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirin BioPartners 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 Ribavirin BioPartners for discontinuation or dose modification recommendations.
Renal impairment
The pharmacokinetics of Ribavirin BioPartners 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 Ribavirin BioPartners. Due to substantial increases in Ribavirin BioPartners plasma concentrations in patients with moderate and severe renal impairment, Ribavirin BioPartners 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 Ribavirin BioPartners 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/Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Ribavirin BioPartners 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/µl. 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 Ribavirin BioPartners 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 Ribavirin BioPartners due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.
Information on excipients
Each Ribavirin BioPartners 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.
Ribavirin BioPartners 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 Ribavirin BioPartners 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 in 7 % of children and adolescents treated with Ribavirin BioPartners in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Ribavirin BioPartners has no direct cardiovascular effects, anaemia associated with Ribavirin BioPartners may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease or both. Thus, Ribavirin BioPartners 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 Ribavirin BioPartners the physician must comprehensively inform both male and female patients of the teratogenic risk of Ribavirin BioPartners, 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 Ribavirin BioPartners. For laboratory monitoring of pregnancy, please refer to Laboratory tests.
Acute hypersensitivity
If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirin BioPartners 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 Ribavirin BioPartners for discontinuation or dose modification recommendations.
Renal impairment
The pharmacokinetics of Ribavirin BioPartners 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 Ribavirin BioPartners. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, Ribavirin BioPartners 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 Ribavirin BioPartners 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/ribavirin 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 Ribavirin BioPartners 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 Ribavirin BioPartners and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Ribavirin BioPartners 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/µL. 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 Ribavirin BioPartners.
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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners (ribavirin) USE IN INFANTS. Respiratory function should be carefully monitored during treatment. If initiation of aerosolized Ribavirin BioPartners (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 Ribavirin BioPartners (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 Ribavirin BioPartners (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, Ribavirin BioPartners (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 Ribavirin BioPartners (ribavirin) before pregnancy may be safely initiated is unknown (see CONTRAINDICATIONS, WARNINGS, and Information for Health Care Personnel).
Nursing Mothers
Ribavirin BioPartners (ribavirin) has been shown to be toxic to lactating animals and their offspring. It is not known if Ribavirin BioPartners (ribavirin) is excreted in human milk.
Information for Health Care Personnel
Health care workers directly providing care to patients receiving aerosolized Ribavirin BioPartners 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 Ribavirin BioPartners (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 Ribavirin BioPartners (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 Ribavirin BioPartners (ribavirin). Health care workers who are pregnant should consider avoiding direct care of patients receiving aerosolized Ribavirin BioPartners (ribavirin). If close patient contact cannot be avoided, precautions to limit exposure should be taken. These include administration of Ribavirin BioPartners (ribavirin) in negative pressure rooms; adequate room ventilation (at least six air exchanges per hour); the use of Ribavirin BioPartners (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 Ribavirin BioPartners (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.
Ribavirin BioPartners 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 Ribavirin BioPartners 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Ribavirin BioPartners 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 Ribavirin BioPartners may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Ribavirin BioPartners 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 Ribavirin BioPartners 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, Ribavirin BioPartners 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, Ribavirin BioPartners 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 Ribavirin BioPartners, 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners.
HIV/HCV Co-infection: Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin and the other medicinal products. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).
Chronic hepatitis C patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of serious adverse effects (e.g. lactic acidosis; peripheral neuropathy; pancreatitis).
Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with Ribavirin BioPartners 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 Ribavirin BioPartners to HAART.
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia.
During treatment co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Ribavirin BioPartners in combination with other medicinal products should be discontinued immediately in patients with hepatic decompensation.
Co-administration of Ribavirin BioPartners and didanosine is not recommended due to the risk of mitochondrial toxicity. Moreover, co-administration of Ribavirin BioPartners 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 Ribavirin BioPartners:
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/μL. Caution is therefore warranted in the treatment of patients with low CD4 counts.
Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate.
For women of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for 4 months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for 7 months thereafter.
Uric acid may increase with Ribavirin BioPartners due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.
Ribavirin BioPartners 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.
Ribavirin BioPartners 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.
Ribavirin BioPartners 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 Ribavirin BioPartners may have an effect. Refer to the SmPC of the medicinal products that are used in combination with Ribavirin BioPartners for further information.
Summary of the safety profile
The salient safety issue of Ribavirin BioPartners is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners for additional undesirable effects reported with these products.
Adults
Bitherapy with peginterferon alfa-2b or interferon alfa-2b
The safety of Ribavirin BioPartners capsules is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied Ribavirin BioPartners in combination with interferon alfa-2b, two trials studied Ribavirin BioPartners in combination with peginterferon alfa-2b.
Patients who are treated with interferon alfa-2b and Ribavirin BioPartners 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 naïve 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 Ribavirin BioPartners) 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners and peginterferon alfa-2b and 37 % of patients treated with Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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-Ribavirin BioPartners 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 Ribavirin BioPartners in combination with peginterferon alfa-2b when compared to patients receiving Ribavirin BioPartners 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 Ribavirin BioPartners capsules in combination with peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Ribavirin BioPartners in combination with peginterferon alfa-2b.
CD4 lymphocytes decrease
Treatment with Ribavirin BioPartners 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 Ribavirin BioPartners 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/µl.
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 Ribavirin BioPartners in combination withother medicinal products.
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 Ribavirin BioPartners, 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 Ribavirin BioPartners, 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 (< 3rd percentile 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 < 3rd 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 Ribavirin BioPartners, 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 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th 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 Ribavirin BioPartners, 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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 The salient safety issue of Ribavirin BioPartners is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Ribavirin BioPartners 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 Ribavirin BioPartners 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 Ribavirin BioPartners for additional undesirable effects reported with these products. 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 Ribavirin BioPartners, 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 Ribavirin BioPartners, 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 (< 3rd percentile 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 < 3rd 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 Ribavirin BioPartners, 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 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th 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 Ribavirin BioPartners, 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. 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 4 are based on experience from the two multicentre children and adolescents clinical trials using Ribavirin BioPartners 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.
Most of the changes in laboratory values in the Ribavirin BioPartners/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 Ribavirin BioPartners 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 Ribavirin BioPartners 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 naïve 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 Ribavirin BioPartners) 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.
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10.6 mg/kg Ribavirin BioPartners (Table7), while response rates in patients that received > 13.2 mg/kg Ribavirin BioPartners were even higher. 
