Posology : מינונים

4.2    Posology and method of administration

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.
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.
Please refer to the prescribing information of peginterferon alfa-2a or interferon alfa-2a for prescribing information particular to either of these products.

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.

1
Copegus_UK SPC Version 3.7_dated February 2015                          Copegus 200 mg_PI_Ver 1.0 COPEGUS                                                        MoH Approved Prescribing Information Tablets 200 mg                                                                        October 2015 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 prescribing information 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) (800,000 IU/ml) at baseline or -      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 section 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 (800,000 IU/ml) at baseline who become HCV negative by week 4 of treatment and remain HCV negative by week 16. Overall 16 weeks of treatment may be associated with a lower chance of response and is associated with a higher risk of relapse than a 24 week treatment duration (see section 5.1). In these patients, tolerability to combination therapy and the presence of additional clinical or prognostic factors such as degree of fibrosis should be taken into account when considering deviations from standard 24 weeks treatment duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL (>800,000 IU/ml) at baseline who become HCV negative by week 4 should be considered with more caution as this may significantly negatively impact the sustained virological response (see Table 1).

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.


COPEGUS                                                                    MoH Approved Prescribing Information Tablets 200 mg                                                                                    October 2015 Table 1   Copegus Dosing Recommendations in Combination with Peginterferon alfa-2a for HCV patients
Genotype                  Daily Copegus      Duration of      Number of 200 mg tablets Dose          treatment
Genotype 1 LVL with      <75 kg = 1000 mg    24 weeks or       5 (2 morning, 3 evening) RVR*                     75 kg = 1200 mg      48 weeks        6 (3 morning, 3 evening) Genotype 1 HVL with      <75 kg = 1000 mg      48 weeks        5 (2 morning, 3 evening) RVR*                     75 kg = 1200 mg                      6 (3 morning, 3 evening) Genotype 4 with RVR*     <75 kg = 1000 mg    24 weeks or       5 (2 morning, 3 evening) 75 kg = 1200 mg      48 weeks        6 (3 morning, 3 evening)
Genotype 1 or 4          <75 kg = 1000 mg      48 weeks        5 (2 morning, 3 evening) without RVR*             75 kg = 1200 mg                      6 (3 morning, 3 evening) Genotype 2 or 3               800 mg(a)    16 weeks(a) or 24   4 (2 morning, 2 evening) LVL with RVR**                                  weeks
Genotype 2 or 3                800 mg          24 weeks        4 (2 morning, 2 evening) HVL with RVR**
Genotype 2 or 3                800 mg          24 weeks        4 (2 morning, 2 evening) without RVR**
*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 – Prior Treatment Non-responder and Relapser Patients: The recommended dosage of Pegasys and COPEGUS combination therapy is PEGASYS 180 g once a week by subcutaneous administration in the abdomen or thighFor patients < 75 kg and  75 kg, 1000 mg and 1200 mg of COPEGUS respectively, should be administered daily.
COPEGUS should be administered in divided doses (morning and evening) with food.
Patients who have detectable virus at week 12 should stop therapy.
The recommended duration of therapy is up to 72 weeks in genotype 1 or 4 patients and 48 weeks in genotype 2 or 3 patients.

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).


COPEGUS                                                             MoH Approved Prescribing Information Tablets 200 mg                                                                             October 2015 Table 2         Predictive Value of Week 12 Virological Response at the Recommended Dosing Regimen while receiving Copegus and peginterferon Combination
Therapy
Genotype                            Negative                          Positive No          No        Predictive     Response    Sustained     Predictive response    sustained      Value       by week 12   response        Value by week 12   response
Genotype 1                  102         97       95% (97/102)      467         271       58% (271/467) (N= 569)
Genotype 2 and 3           3           3         100% (3/3)       93           81        87% (81/93) (N=96)

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).

Table 3     Copegus Dosing Recommendations in Combination with
Interferon alfa-2a
Patient weight (kg) Daily Copegus    Duration of           Number of 200 mg tablets dose           treatment
<75                        1,000 mg      24 or 48 weeks      5 (2 morning, 3 evening) ≥75                        1,200 mg      24 or 48 weeks      6 (3 morning, 3 evening) 
Dosage modification for adverse reactions
Please refer to the prescribing information 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 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.


COPEGUS                                                                 MoH Approved Prescribing Information Tablets 200 mg                                                                                 October 2015 Dose modification of Copegus 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 4 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status.

Table 4      Dosage Modification Guidelines for Management of Treatment-Emergent Anaemia Laboratory Values       Reduce only Copegus dose to 600 mg/day* if:   Discontinue Copegus if:**
Haemoglobin in                              <10 g/dl                          <8.5 g/dl Patients with No
Cardiac Disease
Haemoglobin: Patients ≥2 g/dl decrease in haemoglobin during any 4    <12 g/dl despite 4 weeks with History of Stable  week period during treatment (permanent dose  at reduced dose Cardiac Disease         reduction)
*Patients whose dose of Copegus is reduced to 600 mg daily receive one 200 mg tablet in the morning and two 200 mg tablets 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 cut-off of 75 kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment. The total daily dose of Copegus should be reduced for patients with creatinine clearance less than or equal to 50 ml/min as shown in Table 5 (see also section 5.2).

Table 5          Dosage Modification for Renal Impairment
Creatinine Clearance                                            Copegus 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 (see section 4.4).

If severe adverse reactions or laboratory abnormalities develop, Copegus should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Copegus, Copegus 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 (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).


COPEGUS                                                        MoH Approved Prescribing Information Tablets 200 mg                                                                        October 2015 A case by case benefit/risk assessment with respect to the use of Copegus in children is needed (see section 4.4).