Last Updated on eMC 05-02-2015 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.3 - Contraindications
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:16-01-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text = new text

 

Strike through text = deleted text

 

4.1     Therapeutic indications

 

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

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.

 

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

 

[ … ]

 

Posology

 

Dose to be administered

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

 

 

 

Table 1. Copegus dosing recommendation according to the medicinal product used in combination

 

Medicinal product used in combination

Daily Copegus 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

4x 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 Copegus.

 

 

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) (£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.

 

Table 1    Copegus Dosing Recommendations in Combination with Peginterferon alfa-2a for       HCV patients

Genotype

Daily Copegus Dose

Duration of treatment

Number of 200/400 mg tablets

Genotype 1 LVL with RVR*

<75 kg = 1000 mg

³75 kg = 1200 mg

24 weeks or

48 weeks

5 x 200 mg

(2 morning, 3 evening)

6 x 200 mg

(3 morning, 3 evening)

Genotype 1 HVL with RVR*

<75 kg = 1000 mg

³75 kg = 1200 mg

48 weeks

5 x 200 mg

(2 morning, 3 evening)

6 x 200 mg

(3 morning, 3 evening)

Genotype 4 with RVR*

<75 kg = 1000 mg

³75 kg = 1200 mg

24 weeks or

48 weeks

5 x 200 mg

(2 morning, 3 evening)

6 x 200 mg

(3 morning, 3 evening)

Genotype 1 or 4

without RVR*

<75 kg = 1000 mg

³75 kg = 1200 mg

48 weeks

5 x 200 mg

(2 morning, 3 evening)

6 x 200 mg

(3 morning, 3 evening)

Genotype 2 or 3

LVL with RVR**

800 mg(a)

16 weeks(a) or 24 weeks

4 x 200 mg

(2 morning, 2 evening) or

2 x 400 mg

(1 morning, 1 evening)

Genotype 2 or 3

HVL with RVR**

800 mg

24 weeks

4 x 200 mg

(2 morning, 2 evening) or

2 x 400 mg

(1 morning, 1 evening)

Genotype 2 or 3

without RVR**

800 mg

24 weeks

4 x 200 mg

(2 morning, 2 evening) or

2 x 400 mg

(1 morning, 1 evening)

*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 mg daily or 1200 mg daily for patients <75 kg and ≥75 kg, respectively, regardless of genotype.

 

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, for 48 weeks, of peginterferon alfa-2a is as follows:

-            patients infected with HCV genotype 1 <75 kg: 1000 mg daily

-            patients infected with HCV genotype 1 ≥75 kg: 1200 mg daily

-            patients infected with HCV genotype other than 1 should receive 800 mg daily

 

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).

 

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 response by week 12

No sustained response

Predictive Value

Response by week 12

Sustained response

Predictive Value

Genotype 1

(N= 569)

102

97

95% (97/102)

467

271

58% (271/467)

 Genotype 2 and 3 (N=96)

3

3

100% (3/3)

93

81

87% (81/93)

 

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 dose

Duration of treatment

Number of 200 mg tablets

<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 rRefer to the SmPC 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.

 

 

Dosage modification for adverse reactions

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 2 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status.

 

Table 42          Dosage Modification Guidelines for Management of Treatment-Emergent Anaemia

 

Laboratory Values

Reduce only Copegus dose to 600 mg/day* ifto [1] [2] if:

 

Discontinue Copegus 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

*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.

 

[1] For patients receiving a 1000mg (<75kg) or 1200mg (>75kg) dose, Copegus 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, 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.

[2]For patients receiving an 800mg (<65kg)-1000mg (65-80kg)-1200mg (81-105kg) or 1400mg (>105kg) dose, 1st dose reduction of Copegus 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 Copegus is by an additional 200 mg/day. Patients whose dose of Copegus 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.”

 

 

 

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. 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 53 (see also section 5.2).

 

Table 53          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).

The dose of Copegus should not be further modified in patients with renal impairment. 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 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, efficacy and pharmacokinetics of ribavirin in patients with serum creatinine >2 mg/dl or creatinine clearance <50 ml/min, whether or not on haemodialysis, to support specific 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-2aother 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 Copegus in children is needed (see section 4.4).a should only be considered if indicated for use in the SmPC of the medicinal product used in combination with Copegus.  Refer to the SmPC of the medicinal products that are used in combination with Copegus (see section 5.1).

 

4.3     Contraindications

 

Copegus is contraindicated in the following:

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 listed in section 6.1.

-        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 ≥6, except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir and indinavir.

 

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

 

When Copegus is used in combination with peginterferon alfa-2a or interferon alfa-2a it is contraindicated in patients with severe hepatic dysfunction or decompensated cirrhosis of the liver. Initiation of peginterferon alfa-2a is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir and indinavir. (Refer to SmPC of peginterferon alfa-2a for Child-Pugh assessment).

 

4.4     Special warnings and precautions for use

 

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Copegus combination therapy with peginterferon alfa-2a or interferon alfa-2a, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alphaalfa interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with Copegus and peginterferon alfa-2a or interferon alfa-2a be discontinued, and the patient followed, with psychiatric intervention as appropriate.

 

Patients with existence of, or history of severe psychiatric conditions: If treatment with Copegus in combination with peginterferon alfa-2a or interferon alfa-2a is judged necessary in patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition.

 

Patients with substance use/abuse:

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alphaalfa interferon. If treatment with alphaalfa interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.

 

Growth and development (children and adolescents): During the course of therapy lasting up to 48 weeks in patients aged 5 to 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1).

 

At 2 years post-treatment with Pegasys, 16% of paediatric patients remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

 

Case by case benefit/risk assessment in children

 

The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1).

-        It is important to consider that the combination therapy induced a growth inhibition.

-        This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral load).

 

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.

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.

 

Copegus monotherapy must not be used

 

Combination therapy of ribavirin with (peg)interferon alfa.

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

 

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

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

- Severe ocular disorders

- Dental and periodontal disorders

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

 

Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding these adverse reactions before initiating therapy.

 

[ … ]

 

Liver function: In patients who develop evidence of hepatic decompensation during treatment, Copegus in combination with peginterferon alfa-2a or interferon alfa-2a 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 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, in whomtherefore Copegus dose adjustments are recommended in these patients (see sections 4.2 and 5.2).

. There are insufficient data on the safety, efficacy and pharmacokinetics of Copegus in such patients to support specific 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 alphaalfa 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 alphaalfa 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 alphaalfa interferons. Combination therapy with alphaalfa interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

 

Transplantation: The safety and efficacy of peginterferon-alfa-2a and Copegus 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 Copegus.

 

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 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).

 

[ … ]

 

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 Copegus in combination with other medicinal products peginterferon alfa-2a or interferon alfa-2a should be discontinued immediately in patients with hepatic decompensation.

 

Co-administration of Copegus and didanosine is not recommended due to the risk of mitochondrial toxicity (see section 4.5). Moreover, co-administration 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, 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 Copegus in combination with peginterferon alfa-2a or interferon alfa-2a:

 

Haemoglobin               ³12 g/dl (females); ³13 g/dl (males)

Platelets                                   ³90,000/mm3

Neutrophil Count                     ³1,500/mm3

 

[ … ]

 

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.

 

 

4.7     Effects on ability to drive and use machines

 

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

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

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

 

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

 

The salient safety issue of ribavirin is hemolytic anemia occurring within the first weeks of therapy. The hemolytic anemia associated with ribavirin therapy may result in deterioration of cardiac function and/or worsening of preexisting cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients (see below and section 4.4).

 

See peginterferon alfa-2a or interferon alfa-2a prescribing information for additional undesirable effects for either of these products.

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

 

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.

 

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

 

[ … ]

 

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 ≥1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alfa-2a treatment was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts <200/µl (see peginterferon alfa-2a SmPC).

 

Table 64 shows the undesirable effects reported in patients who have received Copegus primarily in combination with peginterferon alfa-2a or interferon alfa-2a. Table 5 shows the undesirable effects reported in patients who have received Copegus and peginterferon alfa-2a or interferon alfa-2a therapy.

 

Table 564   Undesirable Effects Reported with Copegus primarily in combination with Peginterferon alfa-2a or Interferon alfa-2a for HCV Patients

Body system

Very common ≥1/10

Common

≥1/100 to
<1/10

Uncommon

≥1/1000 to
<1/100

Rare

≥1/10,000 to
<1/1000

Very rare

<1/10,000

Frequency not known*

[ … ]

 

 

 

 

 

 

 

Neoplasms benign and malignant

 

 

Malignant hepatic neoplasm

 

 

 

Blood and lymphatic system disorders

Anaemia, neutropenia

Thrombo-cytopenia, lymphadeno-pathy

 

Pancytopenia

Aplastic anaemia

Pure red cell aplasia

[ … ]

 

 

 

 

 

 

 

Nervous system disorders

Headache, dizziness, concentration impaired

Memory impairment, syncope, weakness, migraine, hypoaesthe-sia, hyperaesthe-sia, paraesthesia, tremor, taste disturbance, nightmares, somnolence

Peripheral neuropathy

Coma, convulsions, facial palsy

Cerebral ischaemia

 

[ … ]

 

 

 

 

 

 

 

Ear and labyrinth disorders

 

Vertigo, earache, tinnitus

Hearing loss

 

 

 

Vascular disorders

 

Flushing, hypotension

Hypertension

Cerebral haemorrhage, vasculitis

Cerebral ischaemia

 

Gastrointestinal disorders

Diarrhoea, nausea, abdominal pain

Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouth

Gastrointes-tinal bleeding, cheilitis, gingivitis

Peptic ulcer, pancreatitis

 

Colitis ischaemic, colitis ulcerative, tongue pigmentation

General disorders and administration site conditions

Pyrexia, rigors, pain, asthenia, fatigue, njection site reaction, irritability

Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst

 

 

 

 

 

[ … ]

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the

Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.national reporting system listed in Appendix V*.

 

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

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

 

Mechanism of Action: Ribavirin is a synthetic nucleoside analog that shows in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin in combination with peginterferon alfa-2a or interferon alfa-2a exerts its effects against HCV is unknown.

 

[ … ]

 

Clinical efficacy and safety

 

Copegus in combination with DAA

 

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

 

Copegus in combination with peginterferon alfa-2a

 

Predictability of response

Please refer to section 4.2, Table 2.the peginterferon alfa-2a SmPC.

 

Study results in treatment-naive patients

Efficacy and safety of the combination of Copegus and peginterferon alfa-2a were established in two pivotal studies (NV15801 + NV15942), including a total of 2405 patients. The study population comprised interferon-naive patients with CHC confirmed by detectable levels of serum HCV RNA, elevated levels of ALT, and a liver biopsy consistent with chronic hepatitis C infection. Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 141513). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.

 

[ … ]

 

For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see tables 675, 786, 8 97 and 141513, respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICORÔ HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after the end of therapy.

 

Table 675        Virological Response in the overall population (including non-cirrhotic and
                        cirrhotic patients)

[ … ]

 

 

 

 

The virological responses of HCV monoinfected patients treated with Copegus and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, pre-treatment viral load and rapid virological response at week 4 are summarised in Table 7 86 and Table 8 97 respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype, baseline viral load and virological response at week 4 (see Tables 1, 7 86 and 897).

 

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

 

Table 768        Sustained Virological Response based on Genotype and Pre-treatment Viral Load after

Copegus Combination Therapy with peginterferon alfa-2a

[ … ]

 

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 897).

 

Table 897   Sustained Virological Response Based on Rapid Viral Response at week 4 for Genotype 1 and 4 after Copegus Combination Therapy with Peginterferon alfa-2a in HCV Patients

[ … ]

 

 

 

Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 9108).

 

Table 9108 Relapse of Virological Response at the End of Treatment for Rapid Virological Response Population

[ … ]

 

 

 

 

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on the sustained rapid virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 1109).

 

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

 

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 10119).

 

Table 10119    Sustained Virological Response Overall and Based on Rapid Viral Response by Week 4 for Genotype 2 or 3 after Copegus Combination Therapy with Peginterferon alfa-2a in HCV Patients

 

[ … ]

 

 

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 data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 111210)

 

Table 111210  Relapse of Virological Response after the End of Treatment in Genotype 2 or 3 Patients with a Rapid Viral Response

 

[ … ]

 

 

Chronic hepatitis C prior treatment non-responder patients

 

[ … ]

 

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 121311.

 

Table 12113    Week 12 Virological Response (VR) and Sustained Virological Response (SVR) in Patients with Virological Response at Week 12 after Treatment with Copegus and Peginterferon alfa-2a Combination Therapy in Non-Responders to Peginterferon alfa-2b plus Ribavirin

[ … ]

 

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa, monotherapy or in combination therapy with ribavirin, were treated with peginterferon alfa-2a 180 µg/week and Copegus 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Copegus combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 131412).

 

Table 131412  Sustained Virological Response in HALT-C by Previous Treatment Regimen in Non-Responder Population

 

[ … ]

 

 

 

[ … ]

 

HIV-HCV co-infected patients

The virological responses of patients treated with Copegus and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 14153.

 

Table 14153 Sustained Virological Response based on Genotype and Pre-treatment Viral

Load after Copegus Combination Therapy with peginterferon alfa-2a in HIV-HCV co-infected patients

[ … ]

 

5.2     Pharmacokinetic properties

 

[ … ]

 

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

 

Based on pharmacokinetic modelling and simulation, dose adjustments are recommended in patients with significant renal impairment (see section 4.2). These adjusted doses are expected to provide ribavirin plasma exposures comparable similar to those achieved in patients with normal renal function receiving the standard Copegus dose. Most of the recommended doses were derived from PK modelling and simulation and have not been studied in clinical trialsThese doses have not been studied in patients.

Though the dose of ribavirin would need to be reduced if used in patients with significant renal impairment, there are insufficient data on the safety and efficacy of ribavirin in such patients to support specific recommendations for dose adjustments (see section 4.2 and 4.4).

 

[ … ]

 

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

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

The pharmacokinetic properties of ribavirin have not been fully evaluated in patients under the age of 18 years. Copegus in combination with peginterferon alfa-2 or interferon alfa-2a is indicated for the treatment of chronic hepatitis C only in patients 18 years of age or older.

 

[ … ]

 

 

10.     DATE OF REVISION OF THE TEXT

 

16 January 2015[To be completed nationally]

 

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
  • Change from joint to individual SPC

Date of revision of text on the SPC:26-03-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underline Text = new text
Struck Through Text = deleted text

 

[ … ]

 

4.4     Special warnings and precautions for use

 

 

[ … ]

 

Patients with substance use/abuse:

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.

 

Growth and development (children and adolescents): During the course of therapy lasting up to 48 weeks in patients aged 5 to 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1).

 

At 2 years post-treatment with Pegasys, 16% of paediatric patients remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

 

Case by case benefit/risk assessment in children

 

The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1).

-        It is important to consider that the combination therapy induced a growth inhibition.

-        This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral load).

 

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.

 

[ … ]

 

4.8     Undesirable effects

 

[ … ]

 

Table 5 shows the undesirable effects reported in patients who have received Copegus and peginterferon alfa-2a or interferon alfa-2a therapy.

 

Table 5       Undesirable Effects Reported with Copegus in combination with Peginterferon alfa-2a for HCV Patients

Body system

Very common ≥1/10

Common

≥1/100 to
<1/10

Uncommon

≥1/1000 to
<1/100

Rare

≥1/10,000 to
<1/1000

Very rare

<1/10,000

Frequency not known*

Infections and infestations

 

 

Upper respiratory infection, bronchitis, oral candidiasis, herpes simplex

Lower respiratory tract infection, pneumonia, urinary tract infection, skin infection

Endocarditis,

Otitis externa

 

 

 

[ … ]

 

 

 

 

 

 

 

* Identified in postmarketing experience

 

[ … ]

 

10.     DATE OF REVISION OF THE TEXT

 

26 March 2014

 

 

Reasons for adding or updating:

  • Change to section 1 -Name of the Medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 9 - Date of first Authorisation/renewal of the Authorisation
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:31-08-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underline text = new text

Struck through text = deleted text

 

Update in line with current template for SPC + the following:

 

 

1.       NAME OF THE MEDICINAL PRODUCT

 

Copegus 200 mg film-coated tablets

Copegus 400 mg film-coated tablets

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

For athe full list of excipients, see section 6.1.

 

 

4.2     Posology and method of administration

 

[…]

 

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.

 

[...]

 

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).

 

[…]

 

 

4.3     Contraindications

 

[…]

 

-        hypersensitivity to ribavirin or to any of the excipients listed in section 6.1.

 

[…]

 

-         Initiation of peginterferon alfa-2a is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir and indinavir. (Please refer to  section 4.4 for Child-Pugh assessment).

 

 

4.4     Special warnings and precautions for use

 

[…]

 

Teratogenic risk: See 4.6 Pregnancy and lactation.Teratogenic risk: See section 4.6.

 

[…]

 

 

4.8     Undesirable effects

 

[…]

 

Table 5       Undesirable Effects Reported with Copegus in combination with Peginterferon alfa-2a for HCV Patients

Body system

Very common ≥1/10

Common

≥1/100 to
<1/10

Uncommon

≥1/1000 to
<1/100

Rare

≥1/10,000 to
<1/1000

Very rare

<1/10,000

Frequency not known*

Infections and infestations

 

 

Upper respiratory infection, bronchitis, oral candidiasis, herpes simplex

Lower respiratory tract infection, urinary tract infection, skin infection

Endocarditis, Otitis externa

 

 

Neoplasms benign and malignant

 

 

Malignant hepatic neoplasm

 

 

 

Blood and lymphatic system disorders

Anaemia

Thrombo-cytopenia, lymphadeno-pathy

 

Pancytopenia

Aplastic anaemia

Pure red cell aplasia

Immune system disorders

 

 

Sarcoidosis, thyroiditis

Anaphylaxis, systemic lupus erythemato-sus, rheumatoid arthritis

idiopathic or thrombotic thrombocyto-penic purpura

Liver and renal graft rejection, Vogt-Koyanagi-Harada disease

Endocrine disorders

 

Hypo-thyroidism, hyper-thyroidism

Diabetes

 

 

 

Metabolism and Nutrition Disorders

Anorexia

 

Dehydration

 

 

 

Psychiatric disorders

Depression, insomnia

Mood alteration, emotional disorders, anxiety,

aggression, nervousness, libido decreased

Suicidal ideation, hallucina-tions, anger

Suicide, psychotic disorder

 

Mania, bipolar disorders, homicidal ideation

Nervous system disorders

Headache, dizziness, concentration impaired

Memory impairment, syncope, weakness, migraine, hypoaesthe-sia, hyperaesthe-sia, paraesthesia, tremor, taste disturbance, nightmares, somnolence

Peripheral neuropathy

Coma, convulsions, facial palsy

 

 

Eye disorders

 

Vision blurred, eye pain, eye inflammation, xerophthalmia

Retinal haemorrhage

Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer

Vision loss

Serous retinal detachment

Ear and labyrinth disorders

 

Vertigo, earache

Hearing loss

 

 

 

Cardiac disorders

 

Tachycardia, palpitations, oedema peripheral

 

Myocardial infarction, congestive heart failure, angina, supraventri-cular tachycardia arrhythmia, atrial fibrillation, pericarditis

 

 

Vascular disorders

 

Flushing

Hypertension

Cerebral haemorrhage

 

 

Respiratory, thoracic and mediastinal disorders

Dyspnoea, cough

Dyspnoea exertional, epistaxis, nasopharyn-gitis, sinus congestion, nasal congestion, rhinitis, sore throat

Wheezing

Interstitial pneumonitis with fatal outcome, pulmonary embolism

 

 

Gastrointestinal disorders

Diarrhoea, nausea, abdominal pain

Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouth

Gastrointes-tinal bleeding, cheilitis, gingivitis

Peptic ulcer, pancreatitis

 

 

Hepato-biliary disorders

 

 

Hepatic dysfunction

Hepatic failure, cholangitis, fatty liver

 

 

Skin and subcutaneous tissue disorders

Alopecia, dermatitis, pruritus, dry skin

Rash, sweating increased, psoriasis, urticaria, eczema, skin disorder, photosensiti-vity reaction, night sweats

 

 

Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme

 

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia

Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps

 

Myositis

 

Rhabdomyo-lysis

Renal and Urinary Disorders

 

 

 

 

 

Renal failure, nephrotic syndrome

Reproductive system and breast disorders

 

Impotence

 

 

 

 

General disorders and administration site conditions

Pyrexia, rigors, pain, asthenia, fatigue, injection site reaction, irritability

Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst

 

 

 

 

Investigations

 

Weight decreased

 

 

 

 

Injury and poisoning

 

 

 

Substance overdose

 

 

* Identified in postmarketing experience

 

Postmarketing adverse events

 

Blood and lymphatic system disorders:

Pure red cell aplasia: frequency unknown.

Pure red cell aplasia has been reported with ribavirin in combination with interferons, including Pegasys.

 

Immune system disorders:

Liver and renal graft rejection: frequency unknown

Liver and renal graft rejections have been reported with Peginterferon-alfa2a, alone or in combination with Copegus.

 

Vogt-Koyanagi-Harada Syndrome: frequency unknown. Vogt-Koyanagi-Harada Syndrome has been reported with ribavirin in combinations with interferons, including Pegasys.

 

Psychiatric disorders:

Homicidal ideation: frequency unknown.

Mania, bipolar disorders: frequency unknown.  Mania and bipolar disorders have been reported with ribavirin in combination with interferons, including Pegasys.

 

Musculoskelatal connective tissue and bone disorders:

Rhabdomyolysis: frequency unknown.  Rhabdomyolysis has been reported with ribavirin in combination with interferons, including Pegasys.

 

Eye Disorders:

Serous retinal detachment: frequency unknown

Serous retinal detachment has been reported with ribavirin in combination with interferons, including Pegasys.

 

[…]

 

 

5.1     Pharmacodynamic properties

 

[…]

 

Clinical Trial ResultsClinical efficacy and safety

 

[…]

 

* peginterferon alfa-2a 180 mcµg + Copegus 800mg vs. Interferon alfa-2a 3MIU + Copegusribavirin 800mg: Odds Ratio (95% CI) =  5.40 (3.42 to 8.54),  ….P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001;

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Copegus 200mg:

Date of first authorisation: 13 November 2002

Date of last renewal: / 9 April 2007

 

[…]

 

10.     DATE OF REVISION OF THE TEXT

 

31 August 2012

 

 

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC:13-10-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike through deleted

4.2      Posology and method of administration

[…]

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.as follows:

-              patients infected with HCV genotype 1 ≤ 75 kg: 1000 mg daily

-              patients infected with HCV genotype 1 ≥ 75 kg: 1200 mg daily

-              patients infected with HCV genotype other than 1 should receive 800 mg daily

 

A duration of therapy less than 48 weeks has not been adequately studied.

[…]

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 ≥ 6, except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir and indinavir. (Please refer to the SPC of peginterferon alfa-2a section 4.4 for Child-Pugh assessment).

4.4      Special warnings and precautions for use

[…]

Transplantation: The safety and efficacy of peginterferon-alfa-2a and Copegus 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 Copegus.

[…]

During treatment Cco-infected patients should be closely monitored, for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic functions 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 Copegus in combination with peginterferon alfa-2a or interferon alfa-2a assessing their Child-Pugh score during treatment, and should be immediately discontinued immediately in patients with hepatic decompensation. if they progress to a Child-Pugh score of 7 or greater.

[…]

4.8      Undesirable effects

[…]

Immune system disorders:

Liver and renal graft rejection: frequency unknown

Liver and renal graft rejections have been reported with Peginterferon-alfa2a, alone or in combination with Copegus.

[…]

5.1      Pharmacodynamic properties

[…]

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

[…]

 

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  • Change to section 5.2 - Pharmacokinetic Properties
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4.6      Fertility, pPregnancy 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 and their partners must use 2a forms of effective contraception simultaneously, 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 Mmale patients andor their female partners of childbearing age must, therefore, be counselled to use 2a forms of effective contraception simultaneously 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.

 

5.2      Pharmacokinetic properties

[…]

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

 

 

Reasons for adding or updating:

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  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.9 - Overdose
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4.2     Posology and method of administration

 

[…]

 

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 and pharmacokinetics of ribavirin in patients with serum creatinine > 2 mg/dl or creatinine clearance < 50 ml/min, whether or not on haemodialysis, to support specific 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 and section 5.2).

 

4.4     Special warnings and precautions for use

[…]

Renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent clearance in these patients (see section 5.2). 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 and pharmacokinetics of Copegus in such patients to support specific 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. and section 5.2).

 

4.9     Overdose

 

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

 

5.2     Pharmacokinetic properties

 

[…]

Renal function: Single-dose ribavirin pharmacokinetics were altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects whose creatinine clearance was greater than 90 ml/minute. The clearance of ribavirin is substantially reduced in patients with serum creatinine > 2 mg/dl or creatinine clearance < 50 ml/min. There are insufficient data on the safety and efficacy of ribavirin in such patients to support recommendations for dose adjustments. Plasma concentrations of ribavirin are essentially unchanged by haemodialysis.

 

Renal function: The apparent clearance of ribavirin is reduced in patients with creatinine clearance ≤50 ml/min, including patients with ESRD on chronic haemodialysis, exhibiting approximately 30% of the value found in patients with normal renal function. Based on a small study in patients with moderate or severe renal impairment (creatinine clearance ≤50 ml/min) receiving reduced daily doses of 600 mg and 400 mg of Copegus, respectively ribavirin plasma exposure (AUC) was found to be higher compared to patients with normal renal function (creatinine clearance >80 ml/min) receiving the standard Copegus dose. Patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Copegus, exhibited mean ribavirin exposure (AUC) approximately 80% of the value found in patients with normal renal function receiving the standard 1000/1200 mg Copegus daily dose. Plasma ribavirin is removed by haemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed from the body by haemodialysis. Increased rates of adverse drug reactions were observed in patients with moderate and severe renal impairment receiving the doses evaluated in this study. Though the dose of ribavirin would need to be reduced if used in patients with significant renal impairment, there are insufficient data on the safety and efficacy of ribavirin in such patients to support specific recommendations for dose adjustments (see section 4.2 and 4.4).

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable Effects
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4.4     Special warnings and precautions for use

 

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Copegus combination therapy with peginterferon alfa-2a or interferon alfa-2a, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with Copegus and peginterferon alfa-2a or interferon alfa-2a be discontinued, and the patient followed, with psychiatric intervention as appropriate.

 

 

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).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

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).

 

4.8     Undesirable effects

 

Table 5 shows the undesirable effects reported in patients who have received Copegus and peginterferon alfa-2a or interferon alfa-2a therapy.

 

Table 5       Undesirable Effects Reported with Copegus in combination with Peginterferon alfa-2a for HCV Patients

Body system

Very Common ≥1/10

Common

≥1/100 to < 1/10

Uncommon

≥1/1000 to       < 1/100

Rare

≥1/10,000 to         < 1/1000

Very rare

 <1/10,000

Infections and infestations

 

 

Upper respiratory infection, bronchitis, oral candidiasis, herpes simplex

 

Lower respiratory tract infection, urinary tract infection, skin infection

Endocarditis,

Otitis externa

 

Neoplasms benign and malignant

 

 

 

Malignant hepatic neoplasm

 

 

Blood and lymphatic system disorders

 

Anaemia

Thrombocytopenia, lymphadenopathy

 

Pancytopenia

Aplastic anaemia

 

Immune system disorders

 

 

 

Sarcoidosis,

thyroiditis

Anaphylaxis, systemic lupus erythematosus,

rheumatoid arthritis

idiopathic or thrombotic thrombocytopenic purpura

Endocrine disorders

 

 

Hypothyroidism, hyperthyroidism

 

Diabetes

 

 

Metabolism and Nutrition Disorders

Anorexia

 

Dehydration

 

 

Psychiatric disorders

 

Depression, insomnia

Mood alteration, emotional disorders, anxiety,

aggression, nervousness, libido decreased

Suicidal ideation,

hallucinations, anger

Suicide, psychotic disorder

 

Nervous system disorders

 

Headache, dizziness, concentration impaired

Memory impairment, syncope, weakness, migraine, hypoaesthesia, hyperaesthesia, paraesthesia, tremor, taste disturbance, nightmares, somnolence

 

Hearing loss, pPeripheral neuropathy

Coma, convulsions, facial palsy

 

Eye disorders

 

 

Vision blurred, eye pain, eye inflammation, xerophthalmia

 

Retinal haemorrhage,

Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy,

corneal ulcer

Vision loss

Ear and labyrinth disorders

 

 

Vertigo, earache

Hearing loss

 

 

Cardiac disorders

 

 

Tachycardia, palpitations, oedema peripheral

 

Myocardial infarction, congestive heart failure, angina, Supraventricular tachycardia arrhythmia, atrial fibrillation,  pericarditis

 

 

Vascular disorders

 

Flushing

 

Hypertension

Cerebral haemorrhage

 

 

Respiratory, thoracic and mediastinal disorders

 

Dyspnoea, cough

Dyspnoea exertional, epistaxis, nasopharyngitis, sinus congestion, nasal congestion, rhinitis, sore throat

 

Wheezing

Interstitial pneumonitis with fatal outcome, pulmonary embolism

 

Gastrointestinal disorders

 

Diarrhoea, nausea, abdominal pain

Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouth

 

Gastrointestinal bleeding, cheilitis, gingivitis

Peptic ulcer, pancreatitis

 

Hepato-biliary disorders

 

 

 

Hepatic dysfunction

Hepatic failure, cholangitis,

fatty liver

 

Skin and subcutaneous tissue disorders

 

Alopecia, dermatitis, pruritus, dry skin

Rash, sweating increased, psoriasis, urticaria, eczema, skin disorder, photosensitivity reaction, night sweats

 

 

Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme

Musculoskeletal connective tissue and bone disorders

 

Myalgia, arthralgia

Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps

 

Myositis

 

Reproductive system and breast disorders

 

 

Impotence

 

 

 

General disorders and administration site conditions

 

Pyrexia, rigors, pain, asthenia, fatigue, injection site reaction, irritability

Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst

 

 

 

Investigations

 

Weight decreased

 

 

 

Injury and poisoning

 

 

 

 

Substance overdose

 

 

Blood and lymphatic system disorders:

Pure red cell aplasia: frequency unknown.

Pure red cell aplasia has been reported with ribavirin in combination with interferons, including Pegasys.

 

Immune system disorders:

Vogt-Koyanagi-Harada Syndrome: frequency unknown. Vogt-Koyanagi-Harada Syndrome has been reported with ribavirin in combinations with interferons, including Pegasys.

 

Psychiatric disorders:

Homicidal ideation: frequency unknown.

Mania, bipolar disorders: frequency unknown.  Mania and bipolar disorders have been reported with ribavirin in combination with interferons, including Pegasys.

 

Musculoskelatal connective tissue and bone disorders:

Rhabdomyolysis: frequency unknown.  Rhabdomyolysis has been reported with ribavirin in combination with interferons, including Pegasys.

 

 

10.     DATE OF REVISION OF THE TEXT

 

29 December 2010<[See Annex I - To be completed nationally]>

 

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic Properties

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4.2     Posology and method of administration

(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.

 

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).

 

5.1     Pharmacodynamic properties

Children and adolescents

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

 

 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties

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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). The combination regimens are Copegus, in combination with peginterferon alfa-2a, is indicated in previously untreated naive patients as well as in and patients who have previously responded to failed previous treatment with interferon alpha therapy and subsequently relapsed after treatment was stopped (pegylated or non-pegylated) alone or in combination therapy with ribavirin.

 

4.2     Posology and method of administration

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 ≥75 kg, respectively, regardless of genotype.

 

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).

 

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.

 

4.4     Special warnings and precautions for use

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.

 

The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

 

Patients treated with Copegus and alpha interferon (standard and pegylated) combination therapy and zidovudine could be at increased risk of developing anaemia.

 

4.5     Interaction with other medicinal products and other forms of interaction

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.

 

4.8     Undesirable effects

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).

 

Postmarketing adverse events

 

Eye Disorders:

Serous retinal detachment: frequency unknown

Serous retinal detachment has been reported with ribavirin in combination with interferons, including Pegasys.

 

5.1     Pharmacodynamic properties

Chronic hepatitis C prior treatment non-responder patients

 

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

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

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

·  peginterferon alfa-2a 180 mcg/week for 72 weeks

·  peginterferon alfa-2a 180 mcg/week for 48 weeks

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

 

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 12.

 

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

 

Copegus
1000/1200 mg

&

Peginterferon
alfa-2a
360/180 or 180 mcg

72 or 48 Weeks
(N = 942)

Pts with

VR at Wk 12 a
(N = 876)

Copegus 1000/1200 mg

&

Peginterferon alfa-2a 360/180 or 180 mcg

72 Weeks
(N = 473)

SVR in Pts with VR at Wk 12 b
(N = 100)

Copegus
1000/1200 mg

&

Peginterferon
alfa-2a
360/180 or 180 mcg

48 Weeks
(N = 469)

SVR in Pts with VR at Wk 12 b
(N = 57)

Overall

    Low viral load

    High viral load

   18% (157/876)

   35% (56/159)

   14% (97/686)

    57% (57/100)

    63% (22/35)

    54% (34/63)

     35% (20/57)

     38% (8/21)

     32% (11/34)

Genotype 1/4

   Low  viral load

   High viral load

   17% (140/846)

   35% (54/154)

   13% (84/663)

55% (52/94)

63% (22/35)

52% (30/58)

     35% (16/46)

     37% (7/19)

     35% (9/26)

Genotype 2/3

   Low  viral load

   High viral load

   58% (15/26)

           (2/5)

           (11/19)

             (4/5)

         (3/4)

             (3/10)

             (1/2)

             (1/7)

Cirrhosis Status

Cirrhosis

Noncirrhosis

 

     8% (19/239)

   22% (137/633)

 

             (6/13)

    59% (51/87)

 

              (3/6)

     34% (17/50)

Best Response during Previous Treatment

   ³2log10 decline in HCV RNA

   <2log10 decline in HCV RNA

Missing best previous response

 

 

   28% (34/121)

   12% (39/323)

   19% (84/432)

 

 

 

    68% (15/22)

    64% (16/25)

    49% (26/53)

 

 

              (6/12)

              (5/14)

     29% (9/31)

High viral load = >800,000 IU/mL, low viral load =  £ 800,000 IU/mL.

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

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

 

 

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa, monotherapy or in combination therapy with ribavirin, were treated with peginterferon alfa-2a 180 mcg/week and Copegus 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Copegus combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 13).

 

Table 13     Sustained Virological Response in HALT-C by Previous Treatment Regimen in Non-Responder Population

 

 

 

 

Previous Treatment

Copegus 1000/1200 mg

&

Peginterferon alfa-2A 180 mcg

48 weeks

Interferon

27% (70/255)

Pegylated interferon

34% (13/38)

Interferon plus ribavirin

13% (90/692)

Pegylated interferon plus ribavirin

11% (7/61)

 

 

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4.2     Posology and method of administration

 

Patients infected with HCV genotype 2/3 regardless of pre-treatment viral load should receive 24 weeks of therapy (see Table 1).

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).

 

5.1     Pharmacodynamic properties

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on the sustained rapid virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 10).

 

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

 

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 10).

 

Table 10     Sustained Virological Response Overall and Based on Rapid Viral Response by Week 4 for Genotype 2 or 3 after Copegus Combination Therapy with Peginterferon alfa-2a in HCV Patients

 

Study NV17317

 

Copegus 800 mg

&

Peginterferon alfa-2a

180 mcg

 

16 weeks

 

Copegus 800 mg

&

Peginterferon alfa-2a

180 mcg

 

24 weeks

 

Treatment difference

95%CI

p value

Genotype 2 or 3

65% (443/679)

76% (478/630)

-10.6% [-15.5% ; -0.06%]

P<0.0001

Genotype 2 or 3 RVR

Low viral load

High viral load

 

82%  (378/461)

89%  (147/166)

78%  (231/295)

90%  (370/410)

94%  (141/150)

88%  (229/260)

-8.2% [-12.8% ; -3.7%]

-5.4% [-12% ; 0.9%]

-9.7% [-15.9% ; -3.6%]

P=0.0006

P=0.11

P=0.002

Low viral load= ≤ 800,000 IU/mL at baseline; High viral load= > 800,000 IU/mL at baseline

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

 

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 11)

 

Table 11     Relapse of Virological Response after the End of Treatment in Genotype 2 or 3 Patients with a Rapid Viral Response

 

Study NV17317

 

Copegus 800 mg

&

Peginterferon alfa-2a

180 mcg

 

16 weeks

 

Copegus 800 mg

&

Peginterferon alfa-2a

180 mcg

 

24 weeks

 

Treatment difference

95%CI

p value

Genotype 2 or 3 RVR

Low viral load

High viral load

 

15%  (67/439)

6%  (10/155)

20%  (57/284)

6%  (23/386)

1%  (2/141)

9%  (21/245)

9.3% [5.2% ; 13.6%]

5% [0.6% ; 10.3%]

11.5% [5.6% ; 17.4%]

P<0.0001

P=0.04

P=0.0002

 

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:01-10-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8, Table 5
 
Addition of Dehydration as an undesirable effect

Reasons for adding or updating:

  • Correction of spelling/typing errors

Reasons for adding or updating:

  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.3 - Contra-indications
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 10 (date of (partial) revision of the text
  • Addition of Legal Category

Reasons for adding or updating:

  • Removal of Black Triangle

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data

Reasons for adding or updating:

  • New SPC for new product