1. Name Of The Medicinal Product
Copegus 200 mg film-coated tablet
Copegus 400 mg film-coated tablet
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 200 milligrams of ribavirin.
Each film-coated tablet contains 400 milligrams of ribavirin.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet
Copegus 200mg: Light pink, flat oval-shaped film-coated tablet (marked with RIB 200 on one side and ROCHE on the opposite side).
Copegus 400mg: Reddish brown, flat oval-shaped film-coated tablet (marked with RIB 400 on one side and ROCHE on the opposite side).
4. Clinical Particulars
4.1 Therapeutic Indications
Copegus is indicated for the treatment of chronic hepatitis C and must only be used as part of a combination regimen with peginterferon alfa-2a or with interferon alfa-2a. Copegus monotherapy must not be used.
The combination of Copegus with peginterferon alfa-2a or interferon alfa-2a is indicated in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis. (See section 4.4) The combination with peginterferon alfa-2a is also indicated in patients co- infected with clinically stable HIV, including patients with compensated cirrhosis (See section 4.3). Copegus, in combination with peginterferon alfa-2a, is indicated in naive patients and patients who have failed previous treatment with interferon alpha (pegylated or non-pegylated) alone or in combination therapy with ribavirin.
Please refer to the Summary of Product Characteristics (SPC) of peginterferon alfa-2a or interferon alfa-2a for prescribing information particular to either of these products.
4.2 Posology And Method Of Administration
Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.
Method of Administration
Copegus 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. As Copegus is available in a 200 mg tablet, there is no need for dividing or cutting the 400 mg tablet in half.
Posology
Copegus is used in combination with peginterferon alfa-2a or interferon alfa-2a. The exact dose and duration of treatment depend on the interferon product used.
Please refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information on dosage and duration of treatment when Copegus is to be used in combination with either of these products.
Posology in combination with peginterferon alfa-2a:
Dose to be administered
The recommended dose of Copegus in combination with peginterferon alfa-2a solution for injection depends on viral genotype and the patient's body weight (see Table 1).
Duration of treatment
The duration of combination therapy with peginterferon alfa-2a depends on viral genotype. Patients infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment viral load should receive 48 weeks of therapy.
Treatment for 24 weeks may be considered in patients infected with
- genotype 1 with low viral load (LVL) (
- genotype 4
who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see 5.1). In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.
Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL (
Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 1000/1200 mg of ribavirin for 48 weeks is recommended.
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*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24;
**RVR = rapid viral response (HCV RNA negative) by week 4
LVL= 800,000 IU/mL; HVL= > 800,000 IU/mL
(a) It is presently not clear whether a higher dose of Copegus (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.
The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is unknown, taking into account the need for retreating non-responding and relapsing patients.
Chronic hepatitis C – treatment-experienced patients
The recommended dose of Copegus, in combination with 180 micrograms once weekly of peginterferon alfa-2a, is 1000 milligrams daily or 1200 milligrams daily for patients <75 kg and
Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks (see section 5.1).
HIV-HCV Co-infection
The recommended dosage for Copegus in combination with 180 micrograms once weekly of peginterferon alfa-2a is 800 milligrams, daily for 48 weeks, regardless of genotype. The safety and efficacy of combination therapy with ribavirin doses greater than 800 milligrams daily is currently being studied. A duration of therapy less than 48 weeks has not been adequately studied.
Predictability of response and non-response – treatment-naive patients
Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV RNA has been shown to be predictive for sustained response (see Table 2).
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A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with peginterferon alfa-2a monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.
Predictability of response and non-response – treatment-experienced patients
In non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100), respectively.
Posology in combination with interferon alfa-2a:
Dose to be administered
The recommended dose of Copegus in combination with interferon alfa-2a solution for injection depends on the patient's body weight (see Table 3).
Duration of treatment:
Patients should be treated with combination therapy with interferon alfa-2a for at least six months. Patients with HCV genotype 1 infections should receive 48 weeks of combination therapy. In patients infected with HCV of other genotypes, the decision to extend therapy to 48 weeks should be based on other prognostic factors (such as high viral load at baseline, male gender, age > 40 years and evidence of bridging fibrosis).
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Dosage modification for adverse reactions
Please refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information on dose adjustment and discontinuation of treatment for either of these products.
If severe adverse reactions or laboratory abnormalities develop during therapy with Copegus and peginterferon alfa-2a or interferon alfa-2a, modify the dosages of each product, until the adverse reactions abate. Guidelines were developed in clinical trials for dose modification (see Dosage Modification Guidelines for Management of Treatment-Emergent Anaemia, Table 4).
If intolerance persists after dose adjustment, discontinuation of Copegus or both Copegus and peginterferon alfa-2a or interferon alfa-2a may be needed.
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*Patients whose dose of Copegus is reduced to 600 mg daily receive 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, Copegus 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.
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. There are insufficient data on the safety and efficacy of ribavirin in patients with serum creatinine < 2 mg/dl or creatinine clearance > 50 ml/min, whether or not on haemodialysis, to support recommendations for dose adjustments (see section 5.2). Therefore, ribavirin should be used in such patients only when this is considered to be essential. 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 (see section 4.4).
Use in hepatic impairment: Hepatic function does not affect the pharmacokinetics of ribavirin (see section 5.2). Therefore, no dose adjustment of Copegus is required in patients with hepatic impairment. The use of peginterferon alfa-2a and interferon alfa-2a is contraindicated in patients with decompensated cirrhosis and other forms of severe 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 Copegus.
Use in patients under the age of 18 years: Treatment with Copegus is not recommended for use in children and adolescents (<18 years) due to insufficient data on safety and efficacy in combination with peginterferon alfa-2a and interferon alfa-2a. Only limited safety and efficacy data are available in children and adolescents (6-18 years) in combination with peginterferon alfa-2a (see section 5.1).
4.3 Contraindications
See peginterferon alfa-2a or interferon alfa-2a prescribing information for contraindications related to either of these products.
- hypersensitivity to ribavirin or to any of the excipients.
- pregnant women (see section 4.4). Copegus 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 (see section 4.6).
- a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.
- severe hepatic dysfunction or decompensated cirrhosis of the liver.
- haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia).
- Initiation of peginterferon alfa-2a is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score
4.4 Special Warnings And Precautions For Use
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Please refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information on special warnings and precautions for use related to either of these products.
All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (ie, patients with genotype 2 or 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment.
In patients with normal ALT, progression of fibrosis occurs on average at a slower rate than in patients with elevated ALT. This should be considered in conjunction with other factors, such as HCV genotype, age, extrahepatic manifestations, risk of transmission, etc. which influence the decision to treat or not.
Teratogenic risk: See 4.6 Pregnancy and lactation.
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 (see section 5.3).
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 Copegus 1000/1200 milligrams in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Copegus 800 milligram 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 Copegus may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Copegus 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, stop therapy (see section 4.2). 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 (see section 4.5).
The use of Copegus 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, Copegus 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, Copegus in combination with peginterferon alfa-2a or interferon alfa-2a 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 Copegus, preferably by estimating the patient's creatinine clearance. Substantial increases in ribavirin plasma concentrations are seen at the recommended dosing regimen in patients with serum creatinine >2 mg/dl or with creatinine clearance <50 ml/minute. There are insufficient data on the safety and efficacy of Copegus in such patients to support recommendations for dose adjustments (see section 5.2). Copegus therapy should not be initiated (or continued if renal impairment occurs while on treatment) in such patients, whether or not on haemodialysis, unless it is considered to be essential. Extreme caution is required. Haemoglobin concentrations should be monitored intensively during treatment and corrective action taken as necessary (see section 4.2).
Ocular changes: Copegus is used in combination therapy with alpha interferons. Retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction which may result in loss of vision have been reported in rare instances with combination therapy with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Patients with preexisting ophthalmologic disorders (eg, diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferons. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.
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 peginterferon alfa-2a with or without ribavirin. 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 Copegus 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 Copegus to HAART (see section 4.5).
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).
Co-infected patients should be closely monitored, assessing their Child-Pugh score during treatment, and should be immediately discontinued if they progress to a Child-Pugh score of 7 or greater.
Co-administration of Copegus and didanosine is not recommended due to the risk of mitochondrial toxicity (see Section 4.5). Moreover, co-adminstration of Copegus 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, 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 Copegus in combination with peginterferon alfa-2a or interferon alfa-2a:
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In patients co-infected with HIV-HCV, limited efficacy and safety data (N = 51) 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 Copegus due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.
Dental and periodontal disorders: Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Copegus and peginterferon alfa-2a combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Copegus and peginterferon alfa-2a. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction studies have been conducted with ribavirin in combination with peginterferon alfa-2a, interferon alfa-2b and antacids. Ribavirin concentrations are similar when given alone or concomitantly with interferon alfa-2b or peginterferon alfa-2a.
Any potential for interactions may persist for up to 2 months (5 half lives for ribavirin) after cessation of Copegus therapy due to the long half-life.
Results of in vitro studies using both human and rat liver microsome preparations indicated no cytochrome P450 enzyme mediated metabolism of ribavirin. Ribavirin does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes. Therefore, there is a minimal potential for P450 enzyme-based interactions.
Antacid: The bioavailability of ribavirin 600 milligrams was decreased by co-administration with an antacid containing magnesium, aluminium and methicone; AUCtf decreased 14%. It is possible that the decreased bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is not considered to be clinically relevant.
Nucleoside analogues: Ribavirin was shown in vitro to inhibit phosphorylation of zidovudine and stavudine. The clinical significance of these findings is unknown. However, these in vitro findings raise the possibility that concurrent use of Copegus with either zidovudine or stavudine might lead to increased HIV plasma viraemia. Therefore, it is recommended that plasma HIV RNA levels be closely monitored in patients treated with Copegus concurrently with either of these two agents. If HIV RNA levels increase, the use of Copegus concomitantly with reverse transcriptase inhibitors must be reviewed.
Didanosine (ddI): Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased in vitro when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactataemia/lactic acidosis have been reported with use of ribavirin.
Azathioprine: Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of Copegus and peginterferon alfa-2a concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering Copegus concomitantly with azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these drugs should be stopped (see section 4.4).
HIV-HCV co-infected patients
No apparent evidence of drug interaction was observed in 47 HIV-HCV co-infected patients who completed a 12 week pharmacokinetic substudy to examine the effect of ribavirin on the intracellular phosphorylation of some nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine or stavudine). However, due to high variability, the confidence intervals were quite wide. Plasma exposure of ribavirin did not appear to be affected by concomitant administration of nucleoside reverse transcriptase inhibitors (NRTIs).
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.
4.6 Pregnancy And Lactation
Preclinical data: Significant teratogenic and/or embryocidal potential have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted, occurring at doses well below the recommended human dose. 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 ribavirin dose. Survival of foetuses and offspring was reduced.
Female patients: Copegus must not be used by women who are pregnant (see section 4.3 and section 4.4). Extreme care must be taken to avoid pregnancy in female patients. Copegus therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Any birth control method can fail. . Therefore, it is critically important that women of childbearing potential must use a form of effective contraception, during treatment and for 4 months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time. If pregnancy does occur during treatment or within 4 months from stopping treatment the patient must be advised of the significant teratogenic risk of ribavirin to the foetus.
Male patients and their female partners: Extreme care must be taken to avoid pregnancy in partners of male patients taking Copegus. Ribavirin accumulates intracellularly and is cleared from the body very slowly. In animal studies, ribavirin produced changes in sperm at doses below the clinical dose. It is unknown whether the ribavirin that is contained in sperm will exert its known teratogenic effects upon fertilisation of the ova. Either male patients or their female partners of childbearing age must, therefore, be counselled to use a form of effective contraception during treatment with Copegus and for 7 months after treatment has been concluded. A pregnancy test must be performed before therapy is started. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the partner.
Lactation: It is not known whether ribavirin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment.
4.7 Effects On Ability To Drive And Use Machines
Copegus has no or negligible influence on the ability to drive and use machines. However, peginterferon alfa-2a or interferon alfa-2a used in combination with Copegus may have an effect. Please refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information.
4.8 Undesirable Effects
See peginterferon alfa-2a or interferon alfa-2a prescribing information for additional undesirable effects for either of these products.
Adverse events reported in patients receiving Copegus in combination with interferon alfa-2a are essentially the same as for those reported for Copegus in combination with peginterferon alfa-2a.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Chronic hepatitis C
The most frequently reported adverse events with Copegus in combination with peginterferon alfa-2a 180 micrograms were mostly mild to moderate in severity. Most of them were manageable without the need for discontinuation of therapy.
Chronic hepatitis C in prior non-responder patients
Overall, the safety profile for Copegus in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alfa-2a treatment and Copegus treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms. Similarly, for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alfa-2a treatment and Copegus treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.
In another clinical trial, non-responder patients with advanced fibrosisis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm3 were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750/mm3), and thrombocytopenia (13% experienced a platelet count <50,000/mm3) (see section 4.4).
Chronic hepatitis C and Human Immunodeficiency Virus Co-infection
In HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving Copegus and peginterferon alfa-2a combination therapy other undesirable effects have been reported in
Table 5 shows the undesirable effects reported in patients who have received Copegus and peginterferon alfa-2a or interferon alfa-2a therapy.
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